March 2021   |   Volume 19   |   Issue 2

Canine Heartworm

in this issue

in this issue

Canine Heartworm

Pancytopenia & Icterus in a Cat

Top 5 Situations for Judicious NSAID Use

Vehicular Trauma

Consistently Low Neutrophil Count in a Healthy Dog

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Ellevet CB March 2021

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Galliprant CB March 2021

Canine Heartworm

Andrew R. Moorhead, DVM, MS, PhD, DACVM (Parasitology), University of Georgia

Parasitology

|Peer Reviewed

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Canine Heartworm

Dirofilaria immitis (ie, canine heartworm), a potentially deadly disease, is arguably the most important parasite that affects dogs in North America, with ≈100,000 new cases reported annually.1 It is thus important that all clinicians (including those in historically nonendemic regions) be knowledgeable regarding the heartworm life cycle, as this will allow for better understanding of treatment and prevention strategies.

Life Cycle

Adult female heartworms can grow to a length of 10 to 12 inches; male heartworms typically reach 4 to 6 inches. Adult worms can live up to 5 to 7 years in dogs, where they mate and produce microfilariae (>300 µm in length) that circulate in the blood. Microfilariae are then ingested by an intermediate mosquito host—this is essential for heartworm development—in which they migrate for an average period of ≈14 days and develop to first-stage larvae (L1). The L1 then molt twice and become infectious third-stage larvae (L3) that are ≈1 mm in length and exist in the head of the mosquito. The ambient temperature must be >57.2°F (14°C) for larval development in the mosquito.2 When the mosquito lands and takes a blood meal, the L3 emerge from the proboscis (ie, mosquito mouthparts) and surround the stylet (ie, piercing part of the proboscis) in a pool of mosquito hemolymph (Figure). When the stylet is removed, the larvae enter the host through the hole created by the stylet. This process is in contrast to the commonly held belief that larvae are injected by the mosquito into the definitive host.3

Once inside the definitive host, the larvae follow a complicated migration pathway. The L3 remain at the site of entrance for ≈3 to 4 days; during which time they molt to fourth-stage larvae (L4). Molting is usually completed within 4 days but may not occur until day 12.3 L4 typically molt to the last stage (ie, juvenile adults) between day 50 to 58, then migrate through the subcutaneous tissue and musculature.4 Worms begin arriving in the pulmonary artery (ie, the final location) by days 67 to 704,5; most worms reach this location by day 120. By day 180, worms are sexually mature and begin to produce microfilariae; thus, completing the life cycle.4 This timeline can vary.

L3 in a hemolymph pool, with the mosquito stylet still inserted in the definitive host
L3 in a hemolymph pool, with the mosquito stylet still inserted in the definitive host

FIGURE L3 in a hemolymph pool, with the mosquito stylet still inserted in the definitive host

FIGURE L3 in a hemolymph pool, with the mosquito stylet still inserted in the definitive host

Pathophysiology

Heartworm disease can result in death, especially in cases with a large number of worms (ie, caval syndrome). Although this acute presentation can be remarkable, pathology is most often observed secondary to the prolonged presence of worms in the pulmonary arteries, which can occur as early as day 60 to 70 of infection.4,5 Severity of disease and extent of pathology are influenced by multiple factors (eg, number of adult worms, duration of infection, host immune response, presence of dead worms). The presence of dead worms is especially important, as they are carried by the blood flow further into the pulmonary vessels, resulting in pulmonary thromboembolism (PTE). 

Heartworms are constantly pushed back and forth by the pulsing blood flow; this can cause trauma to the vessels that results in thickening of the tunica intima and inflammation of the vessel wall characterized by a pathognomonic roughened, stippled appearance.6,7 This prolonged damage can eventually lead to vessel inelasticity, resulting in increasing pressure on the main pulmonary artery, right heart, and vena cava. In turn, this pressure can lead to chronic, passive congestion and pulmonary hypertension that results in right-sided heart enlargement and (eventually) failure.8 Right-sided heart failure can cause liver congestion and ascites. In addition, renal lesions (eg, glomerulonephritis) can develop secondary to immune complex deposition.9 Damage increases with the persistence of worms in the vessels.

Although worms can cause damage, data suggest that endosymbiotic Wolbachia spp can cause some of the inflammation associated with heartworm disease, specifically after worm death. These bacteria are endosymbionts of many filarial worms, are transmitted vertically, and live within the worm; they do not result in overt pathology.10 When the worms die (either of a natural cause or due to drug treatment), the surface proteins of Wolbachia spp are exposed to the host, and the host’s immune system responds.11 It is therefore important to eliminate Wolbachia spp from the worms before treatment is initiated.

Clinical Signs

Dogs infected with D immitis may be presented with no to mild, moderate, or severe clinical signs or with caval syndrome. Although the severity of clinical signs depends on many factors, the presence or absence of clinical signs is important for staging the disease (see Clinical Signs of Heartworm Disease).

CLINICAL SIGNS OF HEARTWORM DISEASE

  • No to mild signs: Patients are subclinical or have a mild cough but otherwise appear healthy.
  • Moderate signs: Patients have a moderate cough, can have difficulty breathing, and can be slightly exercise intolerant (eg, inability to run, tire more easily than normal on walks).
  • Severe signs: Patients are dyspneic and can be severely exercise intolerant (eg, difficulty walking or walking with labored breathing). Syncope and hemoptysis may be present. Signs of right-sided congestive heart failure (eg, ascites) are present.
  • Caval syndrome: Patients typically have associated acute presentation of signs (eg severe dyspnea, collapse) normally related to a large numbers of worms obstructing blood flow through the tricuspid valve. Hemoglobinemia and pigmenturia are characteristic. Onset is rapid and results in death after 12 to 72 hours if not treated.8

Diagnostics

A 3-dose melarsomine treatment protocol is safe,8 but complications are possible. Disease staging should thus be performed prior to treatment. Diagnostics should include physical examination, immunodiagnosis, microfilariae testing, radiography, and cardiac ultrasonography, as well as CBC, serum chemistry profile, and urinalysis. However, if diagnostic staging cannot be performed, the 3-dose protocol is recommended over other treatment protocols. 

Physical Examination

Physical examination should occur first and clinical signs indicative of disease severity (see Clinical Signs of Heartworm Disease) should be assessed.

Immunodiagnosis

Antigen testing is considered the gold standard for diagnosing heartworm disease. Antigen tests are highly sensitive and specific for infections of adult female worms >8 months of age because older worms tend to produce more antigens. However, single-sex infections of only males are undetectable using this method. Antigen tests do not routinely detect prepatent infections (worms <5 months of age) and are not quantitative. The color of any test is not correlated with worm burden. Antigen tests can also be used to determine the effectiveness of adulticidal treatment. If all worms are killed, adult antigens should be cleared from the blood by 9 months after treatment.8

In a subset of dogs with adult female heartworms, no detectable antigen is present. This may be due to immune complex formation between a heartworm-derived antigen and antibodies against the antigen. Therefore, it is crucial to test all dogs for microfilariae at the same time as antigen testing in case the antigen test is negative due to sequestration of the antigen by immune complex formation.12 Immune complexes can be dissociated with heat treatment of the sample. Current recommendations for heat treatment of serum/plasma are when no antigen is directed but the patient is microfilaremic and/or has clinical signs.

Microfilariae Testing

Several methods can be used to evaluate for the presence of microfilariae, regardless of antigen status. Examination of a drop of blood or direct smear detects fewer infections than a concentration technique (eg, Knott or filter test). For the aforementioned reasons regarding the formation of immune complexes, microfilarial testing should be performed simultaneously with antigen testing. Because as many as 20% of dogs may be amicrofilaremic, this is not recommended as a stand-alone diagnostic test.8

In addition, D immitis should be differentiated from Acanthocheilonema (Dipetalonema) reconditum, which is a nonpathogenic worm that is transmitted by fleas, lives in the subcutaneous tissue, and does not require treatment. The easiest way to differentiate these microfilariae in a clinical setting is to observe their movement under a microscope. A reconditum moves progressively, whereas D immitis are mobile but remain in a single location.

Radiography

Radiography enables assessment of damage that has already occurred.

Cardiac Ultrasonography

ECG is not a first-line diagnostic method for heartworm disease. However, visualization of heartworms via ultrasound can confirm infection; lack of visualization does not rule out infection.

CBC, Serum Chemistry Profile, & Urinalysis

Liver and kidney function should be assessed before administration of melarsomine. Existing disease should be considered prior to treatment.8

Treatment

Previously, intravenous thiacetarsamide sodium was used to treat D immitis, but this drug had serious adverse effects.13 Later, melarsomine dihydrochloride was introduced and considered to be a significant improvement for treatment, with early treatment protocols involving a straightforward 2-dose injection protocol and the 3-dose protocol being reserved for more complicated cases.14 Due to advancements in knowledge about D immitis, treatment protocol now involves additional components, including melarsomine dihydrochloride, macrocyclic lactones, corticosteroids, and doxycycline.

Protocol

The timing of each component of heartworm disease treatment is detailed by the AHS.8 Macrocyclic lactone and 4-week doxycycline treatment should be initiated at the time of diagnosis. After 1 month and then monthly, a macrocyclic lactone should be administered unless a sustained-release moxidectin product was chosen as the macrocyclic lactone in the beginning of the treatment protocol. Two months after diagnosis, the first dose of melarsomine should be administered, followed 1 month later by a second and third dose given 24 hours apart. It is thought that the month in between the end of doxycycline and the start of melarsomine therapy is necessary for worm-mediated degradation of Wolbachia spp killed by doxycycline,15 ensuring no immunogenic Wolbachia spp surface proteins are released into the bloodstream. Because Wolbachia spp is an endosymbiont, killing the bacteria should also weaken the worm, as Wolbachia spp is required for worm survival.

Macrocyclic Lactones

Macrocyclic lactone preventive treatment should be started at the time of diagnosis (ie, 2 months prior to the first melarsomine treatment). This can help prevent further infections and help eliminate developing larvae.

Doxycycline

The antibiotic doxycycline (recommended dosage, 10 mg/kg every 12 hours for 28 days) is critical in the treatment of heartworm disease because of the drug’s activity against Wolbachia spp.8

Melarsomine Dihydrochloride

The labeled dosage for melarsomine is 2.5 mg/kg IM twice in the epaxial muscles 24 hours apart.8 However, the AHS recommends an alternate or 3-dose regimen, in which 1 injection (2.5 mg/kg) is administered, then 2 doses are given 30 days later at a 24-hour interval. This regimen has increased safety and efficacy but includes an additional month of exercise restriction, increased total arsenical dose, and additional cost of a third injection.8

Corticosteroids

Prednisone (0.5 mg/kg every 12 hours the first week, 0.5 mg/kg every 24 hours the second week, 0.5 mg/kg every 48 hours the third and fourth weeks) can be administered.8 It is recommended to taper the anti-inflammatory dosage concurrent with the first and third injections of melarsomine. In addition, prednisone administered concurrently with doxycycline is recommended if there are clinical signs of heartworm disease.8

Slow-Kill Methods

Numerous studies have evaluated the efficacy of slow-kill modalities, which consist of a prophylactic dose of ivermectin, topical moxidectin, or injectable moxidectin and concurrent administration of doxycycline as an adulticidal protocol.15-18 These protocols have varying efficacy and require a longer time period than the 3-dose regimen of melarsomine. Although these protocols may be considered advantageous in certain settings, they are salvage procedures. The use of the slow-kill method versus the 3-dose regimen is analogous to femoral head osteotomy versus total hip replacement in a dog. The slow-kill method can be successful, but it is not ideal, as the worms remain in the vessels longer, and the time of worm death is variable as compared with melarsomine treatment.

Pulmonary Thromboembolism & Pulmonary Damage

PTE and pulmonary damage are inevitable consequences of successful adulticidal therapy. Although no current tests are predictive for PTE, the severity of clinical signs can be reduced via administration of doxycycline and corticosteroids during treatment.8 Clinical signs of embolism include fever, cough, hemoptysis, and exacerbation of right-sided heart failure. These signs are usually seen within 7 to 10 days but may occur for up to 4 weeks posttreatment. Therefore, exercise restriction for 6 to 8 weeks posttreatment (total of 10-12 weeks) is essential.8 This can be difficult, but cage rest (leash walk only) is as important as melarsomine injections.

Compromise may be necessary to ensure adherence to exercise restriction. If the dog is anxious in a crate, confinement in a small room may be preferred to ease anxiety. Assessing the ease at which the pet owner is able to restrict the dog can help with tailoring exercise restriction recommendations. For example, the owner may be asked to rate (on a scale of 1 to 10) the ease of crate resting the dog for 10 to 12 weeks (considering this duration includes 4 weeks after the first injection of melarsomine, then 6-8 weeks after the second and third injections of melarsomine). Recommendations can be given based on the answer.

Prognosis & Prevention

Prognosis is typically good with treatment and appropriate exercise restriction. To prevent reinfection, preventives labeled for use against heartworms should be adherently administered.

Clinical Follow-Up/Monitoring

Dogs should be tested for microfilariae 30 days posttreatment. If the test is positive, a microfilaricide should be given. A test for antigen should be given 9 months post-treatment. If the test is positive, the dog should be retreated with a 2-dose protocol.

Conclusion

Treatment recommendations for heartworm disease are constantly changing. It is thus important to keep current on developments. The 3-dose treatment protocol is the recommended approach to treatment in most cases.

References

For global readers, a calculator to convert laboratory values, dosages, and other measurements to SI units can be found here.

All Clinician's Brief content is reviewed for accuracy at the time of publication. Previously published content may not reflect recent developments in research and practice.

Material from Digital Edition may not be reproduced, distributed, or used in whole or in part without prior permission of Educational Concepts, LLC. For questions or inquiries please contact us.


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Hill's CB March 2021

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Clevor CB March 2021

Vehicular Trauma

Cassandra Gilday, DVM, University of Tennessee

Adesola Odunayo, DVM, MS, DACVECC, University of Tennessee

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Vehicular Trauma
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ANCILLARY MATERIALS

THORACOCENTESIS

Thoracocentesis is often a life-saving treatment that should be performed during initial stabilization, ideally prior to radiographic confirmation of pneumothorax or pleural effusion to prevent patient decompensation in radiology.1,2,4

ANALGESIA IN TRAUMA

Quick and effective analgesia is essential for patients with vehicular trauma. Opioids are the drug of choice because of their efficacy and limited adverse effects. NSAIDs should be avoided until the patient is hemodynamically stable. In addition, butorphanol has minimal analgesic effects and should not be used. IM or SC administration of pure μ-receptor agonists may cause vomiting; IV administration is strongly preferred.1,13

  • Morphine (0.1-0.5 mg/kg IV every 4 hours)
  • Hydromorphone (0.05-0.2 mg/kg IV every 4-6 hours)
  • Methadone (0.1-0.5 mg/kg IV every 4-6 hours)
  • Fentanyl (2-5 µg/kg bolus, then 2-6 µg/kg/hour IV CRI)
  • Buprenorphine (0.01-0.03 mg/kg IV or IM every 6-8 hours)

Table 1

GENERAL GUIDELINES FOR FLUID RESUSCITATION & BLOOD TRANSFUSION IN PATIENTS WITH TRAUMA

Perfusion Parameters Normal Endpoints
Whole blood5

Dogs: 20-30 mL/kg given over 30 minutes to 4 hours, depending on how critical the patient is

Cats: 50-60 mL/cat (NOT mL/kg) given over same time period as for dogs

Packed RBCs5

Dogs: 15 mL/kg given over same time frame as whole blood

Cats: 30-40 mL/cat (NOT mL/kg) given over same time frame as for dogs

Synthetic colloid (controversial)5 1-5 mL/kg given over 15 minutes
Fresh frozen plasma5 15-30 mL/kg for patients with coagulopathy and active hemorrhage
Isotonic fluid shock bolus (LRS, Norm-R, 0.9% sodium chloride, Plasma-Lyte)5,9

10-25 mL/kg given over 15 minutes. End goals should be reassessed; may be repeated until entire shock dose administered.

Dog shock dose: 90 mL/kg/hour; cat shock dose: 50-60 mL/kg/hour

Hypertonic saline5,9 4-6 mL/kg given over 15 minutes; may be repeated 2-3 times in 24 hours
Mannitol9 0.5-1.5 g/kg IV given over 15 minutes, may be repeated 2-3 times in 24 hours
Lidocaine3 2 mg/kg IV bolus, followed by 50-80 μg/kg/minute if rhythm converts

 

SYSTEMIC CONSEQUENCES OF TRAUMA

  • Common metabolic consequences6,12
    • Activation of the coagulation cascade
    • Hypothermia
    • GI disturbance (eg, vomiting, diarrhea)
    • Systemic inflammation (eg, SIRS, MODS)
  • Common clinical pathologic abnormalities2,6,12
    • Hyperglycemia
    • Hyperlactatemia
    • Metabolic acidosis
    • Hypoalbuminemia
    • Anemia
    • Thrombocytopenia
    • Increased ALT
    • Increased CK
    • Prolonged PT/PTT 

Table 2

RESUSCITATION ENDPOINTS

Perfusion Parameters Normal Endpoints
Heart rate

Dogs: 60-120 bpm

Cats: 140-200 bpm

MM color Pink
CRT 1-2 seconds
Temperature 99°F-102.5°F (37.2°C-39.2°C)
Mentation Alert
SAP (systolic BP) >90 mm Hg
MAP (mean BP) >70 mm Hg
Urine output 1-2 mL/kg/hour
Lactate <22.5 mg/dL

 

THREE COMPARTMENT MODEL

  1. Dorsal column: laminae, spinous processes and their ligaments
  2. Middle column: dorsal longitudinal ligament, dorsal annulus, dorsal cortex of the vertebral bodies
  3. Ventral column: ventral longitudinal ligament, ventral annulus, ventral cortex of the vertebral bodies

AFAST = abdominal focused assessment with sonography for trauma, BP = blood pressure, CK = creatine kinase, CPR = cardiopulmonary resuscitation, CRT = capillary refill time, Hct = hematocrit, LRS = lactated Ringer’s solution, MAP = mean arterial pressure, MgCl = magnesium chloride, MM = mucous membrane, MODS = multiple organ dysfunction, PCV = packed cell volume, PE = pericardial effusion, POCUS = point of care ultrasound, PT = prothrombin time, PTT = partial thromboplastin time, RR = respiratory rate, SAP = serum alkaline phosphatase, SIRS = systemic inflammatory response syndrome, SpO2 = oxygen saturation, TFAST = thoracic focused assessment with sonography for trauma, TP = total protein, TS = total solids, VPC = ventricular premature contraction

References

For global readers, a calculator to convert laboratory values, dosages, and other measurements to SI units can be found here.

All Clinician's Brief content is reviewed for accuracy at the time of publication. Previously published content may not reflect recent developments in research and practice.

Material from Digital Edition may not be reproduced, distributed, or used in whole or in part without prior permission of Educational Concepts, LLC. For questions or inquiries please contact us.


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Royal Canin CB March 2021

Brucella canis in Dogs from South Dakota Reservations

Radford G. Davis, DVM, MPH, DACVPM, Iowa State University

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<em>Brucella canis </em>in Dogs from South Dakota Reservations

In the literature

Daly R, Willis KC, Wood J, et al. Seroprevalence of Brucella canis in dogs rescued from South Dakota Indian reservations, 2015-2019. Prev Vet Med. 2020;184:105157.


FROM THE PAGE…

Brucella canis is a long-recognized cause of abortion, reproductive failure, and many other health disorders in dogs, including epididymitis, orchitis, prostatitis, diskospondylitis, osteomyelitis, and meningoencephalitis.1,2 Zoonotic transmission can occur through contact with the reproductive fluids, blood, urine, feces, saliva, and nasal secretions of infected dogs.1,2 Treatment failure and relapse are common in dogs, and euthanasia is frequently chosen. This disease carries significant emotional and economic hardships for dog owners and breeders, and management can be challenging for clinicians, shelters, and public health officials. The full impact of B canis on human health and the true prevalence in dogs remain unknown.1,2

This study examined the seroprevalence of B canis in stray and owner-surrendered dogs on 2 reservations and surrounding areas in South Dakota from 2015 to 2019.1 Rescue groups operate in and around these reservations, where stray dogs are common. Investigators aimed to characterize the seroprevalence of infection among dogs from these reservations and adjacent areas after an adopted dog was discovered to be seropositive for B canis, as this could have a negative impact on future rescue operations. 

In the first year of the study, dogs were tested via indirect immunofluorescence assay; positive results were confirmed with agarose gel immunodiffusion. In subsequent years, testing was done using the rapid slide agglutination test, followed by the 2-mercaptoethanol test in cases with initial positive results. There was no significant difference in seropositivity rates between the testing methods. The overall apparent seroprevalence was 6.8% of 3,898 dogs tested, with an estimated true prevalence in the population of 29.4%. Higher seropositivity rates were noted in intact and older dogs (especially those >2 years of age). No sex predisposition was noted. Dogs originating from one reservation were much more likely to be positive than those from the other reservation or surrounding areas; the reason for this is unknown.


…TO YOUR PATIENTS

Key pearls to put into practice:

1

The true prevalence of B canis among dogs is unknown and varies by geographic region, individual, age, and reproductive status.1,2

 

2

Infection is transmitted between dogs venereally or through oral contact with reproductive fluids and tissues.1

 

3

Infection is likely to be higher among stray dogs than owned dogs or those surrendered to a shelter.1

References

For global readers, a calculator to convert laboratory values, dosages, and other measurements to SI units can be found here.

All Clinician's Brief content is reviewed for accuracy at the time of publication. Previously published content may not reflect recent developments in research and practice.

Material from Digital Edition may not be reproduced, distributed, or used in whole or in part without prior permission of Educational Concepts, LLC. For questions or inquiries please contact us.


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Use of Hydrolyzed Diets in Cats with Enteropathy

Jennifer Larsen, DVM, PhD, DACVN, University of California, Davis

Nutrition

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Use of Hydrolyzed Diets in Cats with Enteropathy

In the literature

Kathrani A, Church DB, Brodbelt DC, Pegram C, O'Neil DG. The use of hydrolysed diets for vomiting and/or diarrhoea in cats in primary veterinary practice. J Small Anim Pract. 2020; 61(12):723-731.


FROM THE PAGE…

Although vomiting and diarrhea are frequently seen in cats, the cause is often unknown. Laboratory and fecal testing, imaging, and biopsies are recommended for definitive diagnosis.1 However, diet, antimicrobials, and/or glucocorticoids are used in many cases without a full diagnostic profile first being pursued. The outcomes in cats treated with ≥1 of these empiric therapies have not been previously reported.

This study sought to describe responses of cats with chronic vomiting and/or diarrhea of unknown etiology that were given a hydrolyzed diet with or without a concurrent antibiotic and/or glucocorticoid. Medical records of cats (n = 977) meeting the inclusion criteria were evaluated. Poor response was defined as needing antibiotics and/or glucocorticoids for vomiting and/or diarrhea at a subsequent visit after the diet was started or death associated with clinical signs within 6 months of follow-up.

Of the 977 cats, most (n = 697) were first prescribed a hydrolyzed diet only, and a small percentage of these (34%) had a poor response. Of cats initially prescribed both diet and antibiotics (n = 127), 56% had a poor response. Of cats initially prescribed both diet and glucocorticoids with or without antibiotics (n = 153), 65% had a poor response. Cats concurrently treated with either antibiotics or glucocorticoids plus diet and those given one or both (ie, antibiotics, glucocorticoids) before diet was tried had significantly increased odds of a poor response. Cats 6 years of age or older also had increased odds of having a poor response; however, other characteristics (eg, sex, neuter status, breed) were not significant.

Regardless of treatment, 42% of cats with suspected chronic inflammatory enteropathy had poor response. Due to the retrospective and uncontrolled nature of this study, it was not possible to determine efficacy of hydrolyzed diets in feline enteropathy. In addition, it is unknown if disease chronicity, severity, or exact pathophysiology (especially neoplasia2,3) could explain the higher proportion of poor response in cats prescribed nondietary therapies.


…TO YOUR PATIENTS

Key pearls to put into practice:

1

There are many potential underlying causes of vomiting and diarrhea in cats; comprehensive diagnostic testing is recommended to enable targeted therapy.

2

Efficacy of antibiotic therapy in GI disease is unknown. These drugs should be used cautiously due to concerns regarding intestinal dysbiosis and antibiotic resistance.4

 

3

Hydrolyzed diet as an initial sole therapy may be a rational approach for treatment of suspected inflammatory enteropathy in cats.

References

For global readers, a calculator to convert laboratory values, dosages, and other measurements to SI units can be found here.

All Clinician's Brief content is reviewed for accuracy at the time of publication. Previously published content may not reflect recent developments in research and practice.

Material from Digital Edition may not be reproduced, distributed, or used in whole or in part without prior permission of Educational Concepts, LLC. For questions or inquiries please contact us.


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NVA CB March 2021

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iM3 CB March 2021

Using Artificial Intelligence to Predict Risk for Chronic Kidney Disease

Taylor Gin, DVM, North Carolina State University

Craig Gin, PhD, North Carolina State University

Shelly Vaden, DVM, DACVIM, PhD, North Carolina State University

Urology & Nephrology

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Using Artificial Intelligence to Predict Risk for Chronic Kidney Disease

In the literature

Biourge V, Delmotte S, Feugier A, Bradley R, McAllister M, Elliott J. An artificial neural network-based model to predict chronic kidney disease in aged cats. J Vet Intern Med. 2020;34(5):1920-1931.


FROM THE PAGE…

Early detection of feline chronic kidney disease (CKD) can be challenging, as even the most reliable markers of kidney dysfunction can be influenced by extrarenal factors. Patient history, physical examination, and laboratory diagnostics (eg, BUN, creatinine, urine specific gravity [USG], packed cell volume, electrolytes) are typically used to determine whether kidneys are functioning properly, but evaluation of laboratory results only provides (at best) an indication of kidney dysfunction at 75% nephron loss.1 Newer diagnostics to determine risk factors or biological markers for renal dysfunction are therefore of utmost importance.

This study* used machine learning to attempt to predict whether enrolled cats would develop CKD within 12 months. The model recognized subtle combinations of laboratory tests (eg, BUN, creatinine, USG) that serve as early markers of CKD risk in cats ≥7 years of age. Two strategies to determine a cutoff between cats with high and low risk for developing CKD were considered. The first strategy maximized both sensitivity (87%) and specificity (70%) and appeared most appropriate for scenarios in which correctly identifying cats that will not develop CKD within 12 months is considered more important than correctly identifying cats that will develop CKD (ie, high negative predictive value). The second strategy maximized specificity (98%) but had lower sensitivity (42%). Because this strategy has a higher positive predictive value (87%), it is more appropriate for attempting to limit false-positive results. Clinicians should be aware of the sensitivity and specificity of the exact strategy being used when applying it to clinical practice.


…TO YOUR PATIENTS

Key pearls to put into practice:

1

The model in this study may help predict the risk for developing CKD within 12 months in cats ≥7 years of age but should not be applied to cats <7 years of age.

2

Although the model in this study does not provide a diagnosis of CKD, it is important to increase monitoring of laboratory tests (specifically BUN, creatinine, USG, electrolytes, and blood pressure) to every 3 to 4 months in cats considered at risk based on this model.

3

This study only looked at laboratory results from the patient’s most recent visit. Careful review of patient history—especially as it pertains to trends in BUN, creatinine, USG, body weight, and clinical signs—may provide more information.

*This study was funded by Royal Canin SAS, a subsidiary of Mars, Inc.

References

For global readers, a calculator to convert laboratory values, dosages, and other measurements to SI units can be found here.

All Clinician's Brief content is reviewed for accuracy at the time of publication. Previously published content may not reflect recent developments in research and practice.

Material from Digital Edition may not be reproduced, distributed, or used in whole or in part without prior permission of Educational Concepts, LLC. For questions or inquiries please contact us.


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Stelfonta CB March 2021

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Alternative Heartworm Adulticide Protocol in Dogs

Craig Datz, DVM, MS, DABVP (Canine & Feline), DACVN, University of Missouri

Parasitology

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Alternative Heartworm Adulticide Protocol in Dogs

In the Literature

Alberigi B, Fernandes JI, Paiva JP, et al. Efficacy of semi-annual therapy of an extended-release injectable moxidectin suspension and oral doxycycline in Dirofilaria immitis naturally infected dogs. Parasit Vectors. 2020;13(1):503.


FROM THE PAGE …

Canine heartworm disease caused by Dirofilaria immitis continues to be a significant problem in many areas of the world despite the availability of effective testing and preventive medications.1,2 In the United States, the only FDA-approved adulticidal treatment is melarsomine dihydrochloride, but this drug is relatively expensive and not available in all countries.3 Alternatives to melarsomine have been explored, and several studies have demonstrated that a combination of topical moxidectin and oral doxycycline can be effective in treating adult heartworms.3-5 Moxidectin is also available as a long-acting injection for the prevention of heartworm disease. In this study, researchers in Brazil aimed to determine if injectable moxidectin combined with oral doxycycline is an effective adulticidal protocol in dogs naturally infected with D immitis.

Twenty dogs with naturally occurring D immitis infection were enrolled in the study. Dogs ranged from 1 to 8 years of age (mean, 4.85 years), were clinically healthy, and had not received macrocyclic lactones or doxycycline in the 6 months prior to the study. Each dog was treated with a 12-month extended-release injectable moxidectin suspension (0.5 mg/kg SC once) and doxycycline (10 mg/kg PO twice daily for 30 days) every 6 months. Exercise was not restricted, but pet owners were instructed to help their pet avoid excessive activity.

Physical examination and diagnostic testing (ie, heartworm antigen and microfilaria [mf] count, CBC, serum chemistry profile, thoracic radiography, echocardiography) were performed at baseline and then every 6 months until 2 consecutive negative antigen tests were obtained. Eleven dogs (55%) became antigen negative on day 180, 7 dogs (35%) on day 360, 1 dog (5%) on day 540, and 1 dog (5%) on day 810. Microfilariae decreased from a geometric mean of 4,587 mf/mL at baseline to 2,584 mf/mL at day 30. All dogs were negative for microfilariae on day 150.

The number of dogs with pulmonary signs (ie, cough, dyspnea, harsh expiratory sounds) decreased significantly from baseline to the first negative antigen test. Radiographic signs of enlargement of the main and caudal pulmonary arteries also decreased over time, although no significant reductions in pulmonary bronchial and interstitial patterns were noted. In some dogs, micronodular patterns increased on the first negative antigen test, then returned to baseline on the second negative test. Echocardiography showed normal systolic right ventricular function and no worsening of pulmonary hypertension throughout the study. No adverse effects on body weight or clinical health were noted, and blood work results remained in the normal reference range.


… TO YOUR PATIENTS

Key pearls to put into practice:

1

Melarsomine is the standard recommended treatment for adult heartworms in dogs6,7; however, alternative protocols may be considered in cases in which melarsomine is unavailable or cost-prohibitive or in dogs that cannot tolerate the drug.

2

Long-acting injectable moxidectin combined with oral doxycycline administered every 6 months appears to be as safe and effective as protocols using topical moxidectin or other macrocyclic lactones. However, this study was not controlled or masked and may not be directly comparable with other studies.

3

Injectable moxidectin as used in this study is extra-label and not approved by the FDA or the drug manufacturer. Informed owner consent should be obtained before attempting this protocol in dogs with heartworm disease.

* Craig Datz is also affiliated with Royal Canin.
† This study was funded by Zoetis Brasil.

References

For global readers, a calculator to convert laboratory values, dosages, and other measurements to SI units can be found here.

All Clinician's Brief content is reviewed for accuracy at the time of publication. Previously published content may not reflect recent developments in research and practice.

Material from Digital Edition may not be reproduced, distributed, or used in whole or in part without prior permission of Educational Concepts, LLC. For questions or inquiries please contact us.


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PVD CB March 2021

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Jorvet CB March 2021

Research Note: Absorbable Fixation Straps for Total Laparoscopic Gastropexy in Dogs

Surgery, Soft Tissue

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Prophylactic gastropexy has been used to prevent occurrence or recurrence of gastric dilatation-volvulus in large- and giant-breed dogs. Various surgical techniques have been described, with incisional gastropexy being the most common. Minimally invasive gastropexy techniques, including laparoscopic-assisted gastropexy and total laparoscopic gastropexy, can have lower postoperative morbidity and faster recovery rates. Absorbable fixation straps are used for laparoscopic repair of abdominal wall hernias in humans. This cadaveric study compared load-to-failure results for absorbable fixation straps with absorbable knotless (barbed) sutures for total laparoscopic gastropexy. The authors found this technique required no intra-abdominal sutures, may be technically less demanding, and had similar loads to failure as compared with other techniques; therefore, further prospective studies with long-term follow-up are warranted.

Source

For global readers, a calculator to convert laboratory values, dosages, and other measurements to SI units can be found here.

All Clinician's Brief content is reviewed for accuracy at the time of publication. Previously published content may not reflect recent developments in research and practice.

Material from Digital Edition may not be reproduced, distributed, or used in whole or in part without prior permission of Educational Concepts, LLC. For questions or inquiries please contact us.


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Mirataz CB March 2021

Research Note: Transanal Minimally Invasive Surgery in Canine Cadavers

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This study evaluated the use of transanal minimally invasive surgery (TAMIS), which can provide an alternative approach to resection of rectal tumors, for submucosal rectal resection in 6 large-breed canine cadavers. The median length of resected rectal mucosa was 24.5 mm, and no dogs had evidence of iatrogenic full-thickness surgical penetration of the rectum (ie, a complication that could lead to septic peritonitis). Based on these results, transanal minimally invasive surgery may be a promising alternative to more invasive surgery (eg, rectal pull-through—a technique that may lead to higher incidence of complications or diminished ability to achieve clean margins). 

Source

For global readers, a calculator to convert laboratory values, dosages, and other measurements to SI units can be found here.

All Clinician's Brief content is reviewed for accuracy at the time of publication. Previously published content may not reflect recent developments in research and practice.

Material from Digital Edition may not be reproduced, distributed, or used in whole or in part without prior permission of Educational Concepts, LLC. For questions or inquiries please contact us.


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Heartgard CB March 2021

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AHS CB March 2021

Recent Updates on Brachycephalic Airway Syndrome

Susanna Hinkle Schwartz, DVM, DACVS, MedVet Medical and Cancer Center for Pets, Cincinnati, Ohio

Surgery, Soft Tissue

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Recent Updates on Brachycephalic Airway Syndrome

In the Literature

Lindsay B, Cook D, Wetzel J-M, Siess S, Moses P. Brachycephalic airway syndrome: management of post-operative respiratory complications in 248 dogs. Aust Vet J. 2020;98(5):174-180.


FROM THE PAGE…

Brachycephalic airway syndrome (BAS; ie, brachycephalic obstructive airway syndrome) is a combination of upper respiratory tract abnormalities that result in decreased air passage and typically consist of stenotic nares, elongated soft palate, everted laryngeal saccules, abnormal turbinates, and (eventually) laryngeal collapse and tonsillar protrusion from the crypt. Hypoplastic trachea is common in brachycephalic dogs and contributes to airway distress, but it is not a component of BAS. Decreased air flow as a result of these abnormalities can lead to increased upper airway resistance, hypoxia, and elevated proinflammatory cytokines.1 Affected dogs have also been found to have decreased arterial oxygen saturation, increased carbon dioxide levels, and hypertension.2 GI tract lesions (eg, gastritis) were also found in up to 98% of dogs.3 Due to the severe physiologic consequences of BAS, surgery is recommended for ideal long-term health and exercise tolerance. Staphylectomy can be performed with sharp resection (potentially resulting in more hemorrhage and swelling), a carbon dioxide laser,4 or a ligature vessel-sealing device.5 The carbon dioxide laser technique resulted in a similar prognosis as sharp resection but was much faster and easier, with potentially less hemorrhage and edema. A bipolar sealing device can be safely used and resulted in no mortalities.5

This study retrospectively reviewed medical records of 248 dogs for data on incidence and management strategies of postoperative complications following surgical correction of ≥1 components of BAS. Dogs ranged in age from 31 days to 15.8 years; Cavalier King Charles spaniels were significantly older than the rest of the study population. Other breeds were primarily brachycephalic, with pugs, Cavalier King Charles spaniels, and British bulldogs predominating. Prior to anesthesia, thoracic radiography was performed in all dogs to assess for pneumonia. Surgeries performed included vertical wedge resection, staphylectomy with sharp resection, everted saccule resection, and tonsillectomy. In this population, 23.4% of patients developed complications, including varying levels of dyspnea (25.1%), aspiration pneumonia (4%), and respiratory or cardiac arrest (2.4%). Of the 10 dogs with aspiration pneumonia, 4 had clinical evidence preoperatively. Dogs that had significant complications were older than those that did not develop complications; this differs from a previous study6 that found younger dogs developed more complications than older dogs. Overall complications (23.4%) were higher in this study than in previous studies, but overall mortality (2.4%) was similar.7,8 Vomiting and regurgitation were associated with significantly higher risk for postoperative respiratory complications. Temporary tracheostomy placement was also more common in this study and was present in 8.9% of cases; however, 5 of these dogs were presented to the referral hospital with the tracheostomy in place.


… TO YOUR PATIENTS

Key pearls to put into practice:

1

Surgical correction of BAS should be performed early for ideal long-term health and a better prognosis.

2

Preoperative radiography should be obtained to determine if pneumonia is present, and surgery should potentially be postponed until pneumonia has resolved.

 

3

Proactive postoperative supplementation with oxygen may prevent respiratory compromise and shorten time of recovery from anesthesia. Close monitoring with 24-hour care is imperative because complications are more likely to occur in the immediate postoperative period.

4

Further studies are indicated to determine whether prokinetics, antacids, or antiemetics may be beneficial in decreasing the risk for regurgitation/vomiting; this may result in a lower incidence of respiratory compromise.

References

For global readers, a calculator to convert laboratory values, dosages, and other measurements to SI units can be found here.

All Clinician's Brief content is reviewed for accuracy at the time of publication. Previously published content may not reflect recent developments in research and practice.

Material from Digital Edition may not be reproduced, distributed, or used in whole or in part without prior permission of Educational Concepts, LLC. For questions or inquiries please contact us.


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Douxo CB March 2021

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BI Duo CB March 2021

Changing Methadone Metabolism to Prolong Analgesia

Tamara Grubb, DVM, PhD, DACVAA, Washington State University

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Changing Methadone Metabolism to Prolong Analgesia

In the literature

KuKanich B, KuKanich K, Rankin DC, et al. Perioperative analgesia associated with oral administration of a novel methadone-fluconazole-naltrexone formulation in dogs undergoing routine ovariohysterectomy. Am J Vet Res. 2020;81(9):699-707.


FROM THE PAGE …

Opioids are potent analgesic drugs commonly used to control acute pain (eg, pain caused by surgery or traumatic injury). When administered orally to humans, methadone has a high bioavailability, prolonged elimination time, and results in 6 to 12 hours of analgesia.1 Opioid effects are terminated via hepatic cytochrome P450 enzymes, which is a species-specific process.2,3 In a previous study, there was no measurable plasma methadone in a majority of dogs following oral administration4; this is unlike pharmacokinetics in humans. Drugs with opioid potency, long duration of action, and efficacy following oral administration are desirable for veterinary patients but are not currently available.

As an alternative to the discovery and development of new drugs, effects of existing drugs can be modified through a variety of mechanisms, including changing the rate and/or extent of drug metabolism via manipulation of hepatic enzymes using pharmacokinetic enhancers (eg, fluconazole, ketoconazole, chloramphenicol). In dogs, enhancers coadministered with oral methadone have been shown to increase the bioavailability and prolong the elimination time of methadone.4-6 However, the clinical impact of this was previously unknown.

In this clinical study, dogs undergoing ovariohysterectomy were either given methadone (0.5 mg/kg SC every 4 hours) alone or methadone with fluconazole and naltrexone in 2 oral drug combinations (ie, methadone [0.5 mg/kg], fluconazole [2.5 mg/kg], and naltrexone [0.125 mg/kg] or methadone [1 mg/kg], fluconazole [5 mg/kg], and naltrexone [0.25 mg/kg]) PO every 12 hours.7 Pain scores (using the Glasgow Composite Measure Pain Scale Short Form) were compared among groups every 4 hours, which is the expected analgesic duration following IV administration. A significant difference in scores was identified at only one time point, and no dog required rescue analgesia, indicating adequate analgesia was provided by both protocols. All dogs also received carprofen, which may mask minor methadone insufficiency but does not change the utility of the results, as the drugs would be used together in clinical protocols.

As with all drugs, both efficacy and safety should be considered. A major safety concern of potent opioids is diversion to human use. Naltrexone, an orally administered long-duration opioid antagonist, was added to the methadone/fluconazole combination as an abuse deterrent. Although naltrexone could potentially reverse some of the analgesia provided to the patient, the drug combination was shown to be effective in this study, and opioid-mediated adverse effects (eg, vomiting) were not eliminated.

The results in this study are promising, as they demonstrate that long-duration analgesia can potentially be achieved in dogs using currently available drugs. The authors state that the efficiency of oral twice-daily administration, as compared with injectable administration every 4 hours, is expected to increase the probability patients will receive adequate analgesic treatment.

… TO YOUR PATIENTS

Key pearls to put into practice:

1

Drug metabolism is often species-specific, and the effects of drugs in humans cannot be extrapolated to veterinary species.

 

2

Orally administered methadone (2 mg/kg) without an enhancer like fluconazole is not bioavailable in dogs and should not be administered for analgesia.

 

3

As shown by pain scores in this study and others,7-9 ovariohysterectomy is painful, and adequate analgesia—along with pain scoring to assess treatment efficacy—should be a standard component of patient care.

References

For global readers, a calculator to convert laboratory values, dosages, and other measurements to SI units can be found here.

All Clinician's Brief content is reviewed for accuracy at the time of publication. Previously published content may not reflect recent developments in research and practice.

Material from Digital Edition may not be reproduced, distributed, or used in whole or in part without prior permission of Educational Concepts, LLC. For questions or inquiries please contact us.


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Endoscopy CB March 2021

Research Note: Stored Packed RBCs for Blood Transfusion

Internal Medicine

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This study evaluated the impact of storage time on canine packed RBCs over 28 days. Packed cell volume increased from 70% to 78.33%, lactate increased 627%, potassium content increased 183%, hemolysis reached 0.69%, and pH decreased 9% after 28 days. There was no determined negative effect on dogs receiving transfusions. The authors concluded that, despite alterations that occur during storage, packed RBCs stored ≤21 days are effective and safe for transfusion therapy.

Source

For global readers, a calculator to convert laboratory values, dosages, and other measurements to SI units can be found here.

All Clinician's Brief content is reviewed for accuracy at the time of publication. Previously published content may not reflect recent developments in research and practice.

Material from Digital Edition may not be reproduced, distributed, or used in whole or in part without prior permission of Educational Concepts, LLC. For questions or inquiries please contact us.


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Simparica CB March 2021

Pancytopenia & Icterus in a Cat

Alex Knetsche, DVM candidate, Kansas State University

Lisa M. Pohlman, DVM, MS, DACVP, Kansas State University

Parasitology

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Pancytopenia & Icterus in a Cat

Clinical History & Signalment

Scar, an 11-year-old, spayed domestic shorthair cat, was presented after her owner noted lethargy and vocalization outside the home. Her owners reported she had a poor appetite the previous couple days, and she refused food on the day of presentation. Scar was an indoor/outdoor cat that usually stayed close to home; however, she had reportedly started roaming more than normal after a puppy was introduced to the household ≈7 weeks prior to presentation. No previous health problems were reported. She was free-fed commercial cat food and commercial cat treats several times a week. Flea and tick preventives were up to date.

Physical Examination

Abnormal findings on physical examination included vocalization, dehydration (5%-7%), fever (105.1°F [40.6°C]), icterus, lymphadenopathy, splenomegaly, and hepatomegaly.

Diagnosis

CBC revealed pancytopenia characterized by nonregenerative anemia (hematocrit, 28%; reference interval [RI], 30%-45%), leukopenia (1,900 WBC/µL; RI, 5,500-19,000/µl) due to neutropenia (1,520 neutrophils/µL; RI, 2,500-12,500/µL), and thrombocytopenia (23,000 platelets/µL; RI, 180,000-500,000/µL). Peripheral blood smear examination revealed frequent signet-ring–shaped piroplasms within RBCs (Figure 1).

Serum chemistry profile revealed mild hyperglycemia (184 mg/dL; RI, 70-140 mg/dL) likely due to stress, as well as increased total bilirubin (4.4 mg/dL; RI, <0.2 mg/dL), alkaline phosphatase (75 U/L; RI, 15-50 U/L), and γ-glutamyl transferase (20 U/L; RI, 0-10 U/L); all of which are consistent with cholestasis. Coagulation testing was not performed in this case.

Ultrasound-guided aspirates of the spleen (Figures 2-4) and liver (Figure 5) were collected, and cytologic assessment found abundant schizonts in various stages of maturation.

DIAGNOSIS:

CYTAUXZOONOSIS

Treatment

Prognosis for cats with acute Cytauxzoon felis infection is guarded, even with supportive treatment and antiprotozoal medication.1,2 A combination of atovaquone suspension (15 mg/kg PO every 8 hours with a fatty meal3) and azithromycin (10 mg/kg PO every 24 hours) for 10 days is considered the most effective therapy for treating cytauxzoonosis in cats.3,4 Supportive care with crystalloid fluids, oxygen therapy, and analgesic medication is key to helping in recovery by improving hydration, increasing organ perfusion and oxygenation, and decreasing high pain levels.1,4 Coagulation testing is recommended, as acute cytauxzoonosis (ie, a form of sepsis) may lead to disseminated intravascular coagulation (DIC). In these cases, some clinicians advocate for heparin therapy (200 units/kg SC every 8 hours) in intensive care settings in which coagulation parameters can be monitored.4 Blood transfusion may be required during the hemolytic stage, which occurs late in the disease.4 To further aid recovery, placement of an esophageal feeding tube is often necessary for adequate nutrition and administration of medications.4 Minimal stress and handling as well as a quiet, dark environment in the cage may be helpful in achieving a positive outcome. 

TREATMENT AT A GLANCE

  • A combination of atovaquone suspension (15 mg/kg PO every 8 hours given with a fatty meal)3 and azithromycin (10 mg/kg PO every 24 hours) for 10 days is considered the most effective therapy for treating cytauxzoanosis.3,4 
  • Supportive care with crystalloid fluids, oxygen, and analgesic medication is key to helping recovery by improving hydration, increasing organ perfusion, and decreasing high pain levels.1,4
  • Blood transfusion may be necessary.4 
  • In cases in which DIC is present, heparin therapy (200 units/kg SC every 8 hours) may be indicated in intensive care settings where coagulation parameters can be monitored.4 
  • An esophageal feeding tube to administer medications and keep the cat hydrated with adequate nutrition may be indicated.1,4
  • Minimal stress and handling, as well as a quiet, dark environment in the cage, may be helpful.

Outcome

Due to the high cost of treatment and poor prognosis even with therapy, Scar’s owners elected euthanasia.

Discussion

C felis, a hemoprotozoan parasite, causes cytauxzoonosis in cats. This disease is most common when the tick vector is most active (ie, in spring to early autumn).1 Transmission of C felis occurs via Amblyomma americanum (ie, lone star tick) and Dermacentor variabilis (ie, American dog tick), with A americanum being considered the more competent vector.2 Ticks become infected with C felis when merozoite-infected erythrocytes are ingested from a reservoir species—typically bobcat and domestic cat carriers that survive infection. Replication occurs in both the salivary glands and gut of the tick to form sporozoites,1,5 which are then transmitted to the cat via tick bite. Endothelial monocytes are then infected.1 Transmission of C felis from A americanum can occur as early as 36 hours after attachment by the tick.2 Once sporozoites are present in monocytes, they undergo replication that leads to formation of schizonts.1 In the late stages of disease, schizonts rupture to release merozoites, which infect erythrocytes; these piroplasms are detectable in erythrocytes on a blood smear.1

The most consistent clinical signs of acute cytauxzoonosis are lethargy,4,6 pyrexia,4 and anorexia.4,6 Vocalization,4 lymphadenomegaly,6 icterus,4 and dyspnea4 are also frequently reported. Cats may be hypothermic late in the disease process (ie, just prior to death).4 Clinical signs are typically apparent 10 to 14 days postinfection.5 Pancytopenia, hyperbilirubinemia, bilirubinuria, and increase in liver enzymes are common1; however, pancytopenia is not always recognized, and any combination of neutropenia, lymphopenia, thrombocytopenia, and nonregenerative anemia can be consistent with C felis infection. DIC may also be seen in some cats.4

The mortality rate is high (40%-100%) and depends on whether appropriate, aggressive, and timely treatment was initiated. Even with aggressive treatment, only 60% of acutely infected cats survive.4 Cats that survive infection may be lifelong carriers of the parasite and thereby potential sources of infection for other cats.1

Most pathologic tissue damage that results in clinical signs is due to the schizogenous phase of parasitemia, which causes obstruction of small veins and capillaries of the spleen, lymph nodes, liver, lungs, and other organs, resulting in hypoxic tissue damage and copious release of inflammatory cytokines.4 As a result, lymphadenopathy, splenomegaly, and hepatomegaly are typically present.6 Piroplasms can be detected on a blood smear ≈14 days postinfection.1,6 However, because clinical signs usually precede the presence of piroplasms in the blood, visualization of schizonts on cytologic preparations of the liver, spleen, and lymph node can confirm acute disease1 when blood film analysis is equivocal.4 C felis can be fatal in as little as 1 week after clinical signs appear due to thrombosis, tissue infection, and multisystemic inflammation and organ failure caused by schizont dissemination.1,4,5

Due to the poor prognosis and short tick-attachment time required for infection, prevention is ideal; however, in outdoor cats that live in endemic areas, prevention can be difficult even with the use of preventives.2 Acaricides that minimize the time a tick is able to attach to cats, regular manual tick checks and tick removal, and keeping cats indoors in endemic areas (ie, south-central, southeastern, and mid-Atlantic United States), especially during peak tick season, can significantly decrease the likelihood of infection.2,4 Two acaricides—imidacloprid 10%/flumethrin 4.5% collar7 and selamectin/sarolaner topical solution8—have demonstrated efficacy in preventing C felis transmission by A americanum under experimental conditions.7,8

TAKE-HOME MESSAGES

  • Piroplasms within erythrocytes indicate late-stage disease.1,6
  • Detection of schizonts in cytologic preparations of the lymph node, liver, and spleen can help determine the diagnosis in earlier stages of disease, prior to piroplasmosis.1
  • Clinical signs of C felis appear 10 to 14 days postinfection, and C felis can be fatal in as little as 1 week after the appearance of clinical signs.1,5
  • C felis has a high mortality rate; without aggressive treatment, most cats with acute infection die.4
  • Even with aggressive treatment, only 60% of acutely infected cats survive.4
  • A americanum and D variabilis are vectors for C felis, so administering a tick preventive and keeping cats indoors can decrease the incidence of C felis in endemic areas.2,4
  • Two acaricides—imidacloprid 10%/flumethrin 4.5% collar7 and topical selamectin/sarolaner8—have demonstrated efficacy in preventing C felis transmission by A americanum under experimental conditions.7,8

References

For global readers, a calculator to convert laboratory values, dosages, and other measurements to SI units can be found here.

All Clinician's Brief content is reviewed for accuracy at the time of publication. Previously published content may not reflect recent developments in research and practice.

Material from Digital Edition may not be reproduced, distributed, or used in whole or in part without prior permission of Educational Concepts, LLC. For questions or inquiries please contact us.


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Blue Buffalo CB March 2021

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Merck CB March 2021

Top 5 Situations for Judicious NSAID Use

Natalie Smith, DVM, Cummings School of Veterinary Medicine at Tufts University

Claire L. Fellman, DVM, PhD, DACVIM, DACVCP, Cummings School of Veterinary Medicine at Tufts University

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Top 5 Situations for Judicious NSAID Use

NSAIDs are commonly used in veterinary medicine to control pain and inflammation and include COX inhibitors (eg, carprofen, deracoxib) and grapiprant, a newer prostaglandin-receptor antagonist. NSAIDs act by reducing the production or action of proinflammatory prostaglandins and are generally well-tolerated, although potential adverse effects may include GI upset, nephrotoxicity, and hepatotoxicity.

Following are the authors’ 5 most common uses of NSAIDs, along with important considerations for patient safety.

1

Osteoarthritis

A common application of NSAIDs is the management of osteoarthritis (OA). Because OA is characterized by both chronic and acute flare-ups of pain and inflammation secondary to joint pathology, the analgesic and anti-inflammatory properties of NSAIDs can be helpful with intermittent or continuous therapy.1,2 Numerous NSAIDs (eg, carprofen, meloxicam, firocoxib, deracoxib, grapiprant) are labeled for management of OA in dogs; however, no NSAIDs are currently FDA-approved for long-term use in cats.

Although NSAIDs are typically well-tolerated in veterinary patients, sustained use to treat OA in older patients warrants close monitoring for potential adverse effects in the GI tract, kidneys, and liver. GI adverse effects have been linked to a variety of mechanisms (eg, direct irritation of the GI mucosa, inhibition of prostaglandin E2) and potentially include ulceration, gastritis, enteritis, and perforation.3 COX expression in the kidneys can lead to production of prostaglandins, which help maintain renal homeostasis by affecting renal blood flow and glomerular filtration rate, among other functions.4 Thus, use of NSAIDs in dogs may exacerbate underlying chronic kidney disease or lead to acute kidney injury, reversible renal insufficiency, or papillary necrosis.5-8

Adverse effects in the liver are uncommon and can be attributed to idiosyncratic reactions.9 Hepatopathy has been suggested or documented with NSAID use.10-15 Idiosyncratic hepatotoxicity that occurs with carprofen administration typically involves acute hepatic necrosis, and signs of toxicosis (eg, marked increase in serum ALT) usually occur ≈2 to 4 weeks after initiation of carprofen.11

In patients receiving long-term NSAID therapy, baseline laboratory work, (ie, patient hematocrit, liver enzymes, kidney values, and urinalysis) should be performed to help determine whether the patient has underlying renal or hepatic dysfunction. In addition, ongoing clinical monitoring of renal and hepatic parameters is recommended, and the pet owner should monitor for evidence of GI intolerance (eg, inappetence, vomiting, diarrhea, melena) at home. The authors recommend blood work be rechecked ≈2 to 4 weeks after initiation of NSAID treatment, then every 3 to 6 months. In patients that develop adverse effects while receiving an NSAID, the drug should be stopped and laboratory work (minimum CBC and serum chemistry profile) repeated to assess for possible drug toxicity.

2

Management of Postoperative Pain

NSAIDs are frequently used to provide analgesia during surgical procedures (eg, ovariohysterectomy, fracture repair, mass removal) but are generally contraindicated in patients undergoing GI surgery, as there are risks for ulceration and delayed healing.16-21 COX-1 and COX-2 expression is increased in inflammatory conditions (eg, those induced during surgery). NSAIDs inhibit COX-1 and COX-2 expression, thus decreasing the production of inflammatory mediators (eg, prostaglandins, thromboxanes) responsible for peripheral and central sensitization to pain stimuli.3,22

A primary consideration in patients with postsurgical pain is the timing of NSAID administration in the perioperative period. NSAIDs have been shown to provide better postsurgical analgesia when administered prior to surgery rather than immediately following surgery.23-30 However, human and veterinary patients have frequently experienced hypotension while under anesthesia, and the kidneys are highly vulnerable to hypotensive insult.31 COX-1 and COX-2 expression play a major role in maintaining renal blood flow, particularly during hypotension, and preoperative inhibition of COX expression by NSAIDs may contribute to postoperative renal dysfunction.32 Several studies evaluating renal function after NSAID administration and anesthesia have not found evidence of significant dysfunction; however, these studies primarily included young, healthy dogs, with the oldest being 89 months of age.24-26,33,34 Accordingly, preoperative use of NSAIDs may be reasonable in healthy patients that do not have underlying renal disease or increased risk for hypotensive events; blood pressure monitoring is recommended in patients under anesthesia. Because patients with existing renal disease may be at increased risk for AKI, NSAIDs should not be used during anesthesia for these patients.

3

Fever

NSAIDs are also used to provide clinical relief from fever, as their antipyretic effects are mediated by central and peripheral thermoregulatory mechanisms. The primary antipyretic action decreases prostaglandin E2 levels in the hypothalamus by inhibiting COX.35 Fever at sites of tissue inflammation is reduced via suppression of pyrogenic cytokines, increased release of endogenous antipyretics and anti-inflammatory molecules, and decreased adhesion molecule expression to reduce endothelial cell interactions with leukocytes.35 This can allow NSAIDs to rapidly reduce fever, potentially controlling life-threatening febrile reactions and significantly improving patient comfort.

Although NSAIDs are effective at reducing fever, they usually do not treat the underlying cause. Resolution of a low- to moderate-grade fever can indicate the appropriate treatment is being used (eg, antimicrobials for system infection, glucocorticoids for immune-mediated polyarthritis). Patients with fever of unknown origin that were referred for further diagnostics and given NSAIDs, glucocorticoids, or antibiotics within 24 hours of presentation had significantly prolonged time to diagnosis as compared with patients not treated within this period.36 In addition, pyrogenic fever is a protective mechanism in patients with sepsis or fungal infections. A mild febrile response in humans with pyrogenic fever secondary to infection has been shown to improve clinical outcomes.37 Thus, NSAIDs should be used with caution in patients with fever of unknown origin, especially in cases in which infectious disease has not been ruled out or immune-mediated disease is likely and treatment with glucocorticoids may be indicated.

4

Antineoplastic Therapy

NSAIDs used in conjunction with metronomic chemotherapy are important in the management of cancer patients and can be used as a single-agent treatment for some tumors.38-40 For metronomic chemotherapy, conventional oral cytotoxic chemotherapy agents can be given at relatively low doses and regular intervals (eg, every 24-48 hours) over a sustained period. Metronomic chemotherapy agents are often delivered with other agents (eg, NSAIDs, small-molecule inhibitors).38 Therapy is aimed at altering tumor microenvironment, primarily via antiangiogenic mechanisms, rather than directly targeting the tumor cells. COX-2 inhibition via NSAIDs can decrease cell proliferation, reduce production of proangiogenic factors (eg, vascular endothelial growth factor), and increase the rate of apoptosis.41 Adjuvant metronomic chemotherapy has been explored in a variety of tumor types (eg, hemangiosarcoma, soft tissue sarcoma) and can safely be incorporated in treatment regimens for cancer patients.38

Carcinomas (eg, urothelial carcinoma, mammary carcinoma, nasal adenocarcinoma, anal sac adenocarcinoma) express COX-2.42-45 NSAIDs have activity against canine urothelial carcinoma, with several different COX inhibitors (eg, piroxicam, deracoxib, firocoxib) reported.39-40,46 NSAIDs may be recommended as part of standard therapy for carcinomas because of their potential antitumor activity and ability to provide analgesia. One study reported a median survival time of 181 days in dogs with urothelial carcinoma treated with piroxicam alone as compared with 291 days in dogs treated with piroxicam in combination with mitoxantrone.46 NSAIDs are more effective when combined with conventional chemotherapy agents for treatment of urothelial carcinoma but can be used alone when conventional chemotherapy is not possible.

The effectiveness of NSAIDs for antineoplastic therapy should be balanced against possible adverse effects. GI adverse effects may limit the use of NSAIDs, especially in patients also being treated with conventional chemotherapy agents or small-molecule inhibitors that may independently cause GI adverse effects. NSAIDs should not be used concurrently with glucocorticoids, which are often used in the treatment of round cell neoplasias (eg, lymphoma, mast cell tumors). Owners of patients treated with NSAIDs as part of antineoplastic therapy should be advised to monitor for signs of GI adverse effects. Baseline and follow-up laboratory work is also recommended (as described for OA; see Osteoarthritis).

5

Musculoskeletal Injury

NSAIDs are also frequently used in patients with acute musculoskeletal injuries. Pain associated with acute injuries persists during both the inflammatory and healing phases and may last up to 3 months before being considered chronic.17 During the inflammatory phase, prostaglandin expression may increase up to 80-fold, making COX inhibition a valuable target for therapeutic intervention.47

Patients with acute musculoskeletal injuries are typically given shorter courses of NSAID therapy, reducing the risk for potential adverse effects in the kidneys, GI tract, and liver, as compared with patients given sustained NSAID therapy. However, caution is recommended in patients with pre-existing GI disease, and screening for renal or hepatic dysfunction should be done prior to NSAID administration, especially in older patients. 

Conclusion

NSAIDs are important therapeutics because of their ability to reduce inflammation and provide effective analgesia. With appropriate monitoring for GI, renal, and hepatic adverse effects, NSAIDs can be used safely to treat a variety of conditions in small animal patients.

References

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Consistently Low Neutrophil Count in a Healthy Dog

Jenna K. Rooks, DVM, MS, University of Florida

Alex Gallagher, DVM, MS, DACVIM, University of Florida

Internal Medicine

|Peer Reviewed

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Consistently Low Neutrophil Count in a Healthy Dog

Clinical History & Signalment

Cain, a 5.5-year-old, 79.6-lb (36.2-kg), neutered male crossbreed dog, was presented for his annual examination, heartworm test, serum chemistry profile, and CBC. Clinical history was insignificant except for previously diagnosed bilateral coxofemoral degenerative joint disease.

Physical Examination

On physical examination, Cain was bright, alert, and responsive. Vital signs were within normal limits and BCS was 5/9. He had mild periodontal disease and decreased range of motion on bilateral hip extension. Remainder of the examination was unremarkable.

Table

CBC RESULTS

  Day 1 Day 16 Day 20 Day 31 Day 47 Day 61
WBC (5-13 K/µL) 4.34 4.01 3.23 3.24 4.17 5.66
Platelets (134-396 K/µL) 168 125 132 116 153 203
Fibrinogen (0.1-0.4 g/dL) 0.3 0.4 0.1 0.5 <0.1 0.3
Neutrophils (2.7-8.9 K/µL) 1.79 0.92 0.72 0.53 2.5 3.58
Lymphocytes (0.9-3.4 K/µL) 2.02 2.4 1.83 1.98 1.2 1.49
Monocytes (0.1-0.8 K/µL) 0.14 0.08 0.12 0.13 0.38 0.3
Eosinophils (0.1-1.3 K/µL) 0.37 0.56 0.54 0.6 0.13 0.27
Basophils (0-0.1 K/µL) 0.01 0 0.01 0 0 0.01
Abnormal values are indicated in italic. 

Diagnosis

Results of routine heartworm antigen testing (including associated testing for Ehrlichia spp, Anaplasma spp, and Borrelia burgdorferi antibodies) were negative. Serum chemistry profile did not indicate clinically significant abnormalities. CBC revealed mild neutropenia (1.79 K/µL; reference range, 2.7-8.9 K/µL; Table).

Neutropenia is caused by decreased production, increased destruction, increased demand, and sequestration.1,2 Common differential diagnoses include infectious disease, neoplasia, bone marrow disease, drug toxicity, and uncommon genetic disease (see Causes of Neutropenia).1-4

CBC was repeated 16 days after presentation to confirm neutropenia before additional diagnostics were performed. Moderate neutropenia (0.92 K/µL) and mild thrombocytopenia were noted.4 Because the neutrophils were <1 K/µL, prophylactic antibiotic therapy was recommended to reduce the risk for sepsis pending further testing for definitive diagnosis and therapy.1,5-9 However, the pet owner chose to routinely monitor Cain’s temperature at home and have CBC rechecked on day 20, which revealed progressive neutropenia and a normal platelet count.

Cain’s owner had recently moved to wooded property; therefore, in-house tick-borne disease testing was repeated and showed a faint positive result for Ehrlichia spp antibodies. Because antibodies indicate exposure—not necessarily infection—a vector-borne disease PCR panel (including Anaplasma spp, Babesia spp, Bartonella spp, Ehrlichia spp, Mycoplasma spp, and Rickettsia spp) was submitted to a reference laboratory to determine whether an active infection was present. Pending these results, Cain was empirically treated with doxycycline (10 mg/kg PO every 24 hours for 30 days) for possible ehrlichiosis. In addition, due to the worsening neutropenia, enrofloxacin (10 mg/kg PO every 24 hours) was administered prophylactically to reduce the risk for sepsis.1,5-9 Enrofloxacin has a better gram-negative spectrum and is bacteriocidal, whereas doxycycline is bacteriostatic.

On day 31, results of the vector-borne PCR panel were positive for Mycoplasma haematoparvum and negative for Ehrlichia spp. Cain was not anemic; thus, the positive mycoplasmal PCR was suspected to be incidental, evidence of early infection, or a false-positive result. Given the negative PCR result and no clinical signs indicating ehrlichiosis (eg, fever, lethargy, petechiae, ecchymoses, lymphadenomegaly, splenomegaly), Ehrlichia spp was excluded as a cause for Cain’s leukopenia.10 A repeat CBC indicated worsening, severe neutropenia and recurrence of mild thrombocytopenia (Table). Additional diagnostic tests for causes of neutropenia were performed. Thoracic radiographs and abdominal ultrasound revealed no abnormalities. Because no causes were found for the neutropenia or thrombocytopenia, bone marrow sampling was recommended.1,2 Presence of a persistent cytopenia or multiple cytopenias increase the possibility of bone marrow disease.2 A bone marrow aspirate for cytology and a core biopsy sample were obtained with the patient under general anesthesia.

Bone marrow cytology was consistent with myeloid hyperplasia, with an increased number of immature neutrophils, indicating an appropriate response to the peripheral neutropenia. In addition, there were adequate to increased megakaryocytes consistent with an appropriate response to the intermittent peripheral thrombocytopenia. There was no evidence of inflammation, infection, or neoplasia. Based on these cytologic findings, the core biopsy was unlikely to yield additional information and was not submitted for histopathology.

Based on cytology results and negative findings for other causes, a diagnosis of immune-mediated neutropenia (IMN) was made. In humans, flow cytometry is used to detect antineutrophil antibodies and is considered the gold standard for diagnosis of IMN; however, this test is not as specific, sensitive, or readily available in veterinary medicine.2,3,11,12 IMN is an uncommon, usually idiopathic, primary condition diagnosed by exclusion of other causes of neutropenia.1,3,11 In dogs with persistent peripheral neutropenia due to IMN, the most common finding on bone marrow cytology is myeloid hyperplasia.2,3,11,12 However, some dogs may have hypoplasia, which indicates destruction of precursor cells in the bone marrow.11

CAUSES OF NEUTROPENIA

  • Bacterial
    • Ehrlichia spp ± other rickettsial disease
    • Sepsis
    • Pneumonia
    • Dog bite infection
    • Peritonitis
  • Viral
    • Canine parvovirus
    • FeLV
    • FIV
    • Feline panleukopenia
  • Fungal
    • Histoplasma capsulatum
    • Cryptococcus neoformans
  • Marked inflammation
    • Organ torsion
    • Bile peritonitis
    • Pancreatitis
    • Hemolytic anemia
  • Neoplasia
    • Leukemia
    • Lymphoma
    • Multiple myeloma
  • Primary bone marrow disease
    • Leukemia
    • Myelodysplasia
    • Myelofibrosis
    • Aplasia
  • Drug toxicity
    • Chemotherapeutic agents
    • Estrogens
    • Trimethoprim sulfamethoxazole and other antibiotics
    • Phenobarbital
    • Methimazole
  • Immune-mediated disease
    • Primary
    • Secondary to inciting cause
  • Genetic
    • Cyclic hematopoiesis in gray-coated collies
    • Cobalamin deficiency/ malabsorption in giant schnauzers
    • Trapped neutrophil syndrome in border collies

DIAGNOSIS:

IMMUNE-MEDIATED NEUTROPENIA

Treatment & Long-Term Management

Cain was treated with prednisone (1.5 mg/kg/day; 50 mg/m2) on day 35. CBC was rechecked on days 47 and 61, and resolution of neutropenia and thrombocytopenia was noted (Table). Enrofloxacin was discontinued on day 47, as the neutrophil count was >1 K/µL. Doxycycline was continued for the remainder of the month-long treatment of M haematoparvum, as significance of the positive PCR result was uncertain.

The most common treatment of IMN is immunosuppressive doses of glucocorticoids (eg, prednisone), in which a variety of dosages have been used, with the most common being 2 mg/kg PO every 24 hours.2,3,11,12 Due to the severe adverse effects of glucocorticoids seen in large-breed dogs, recent recommendations are to consider a dose based on body surface area (50 mg/m2 in dogs >55 lb [25 kg]), as was used in this case.13 In most cases, dogs respond to corticosteroid treatment within 7 to 10 days.2,3,11,12 Once the neutrophil count is normal, prednisone can be slowly tapered over 1 to 6 months.11 Some dogs may require additional immunosuppressive medications if they are not responding well to steroids or steroids are not tolerated well. Azathioprine (initial dosage, 2 mg/kg/day or 50 mg/m2) is also commonly used.2 Serum chemistry profile should be routinely monitored, as azathioprine can cause liver toxicosis. Some dogs may require long-term or lifelong therapy.

TREATMENT AT A GLANCE

  • Prednisone should be started at an immunosuppressive dosage (2 mg/kg/day or 50 mg/m2 in dogs >55 lb [25 kg]) and CBC rechecked in 1 week.
  • If the neutrophil count is ˂1 K/µL, a broad-spectrum antibiotic to cover aerobic gram-positive and gram-negative bacteria should be considered to reduce the risk for sepsis.1,5-9
  • If the patient does not respond to prednisone alone, another immunosuppressant (eg, azathioprine [2 mg/kg/day or 50 mg/m2]) can be added.
  • If azathioprine must be discontinued due to liver toxicosis, other immunosuppressants (eg, cyclosporine, mycophenolate, leflunomide) can be attempted.

Prognosis & Outcome

CBC was repeated after Cain had been receiving prednisone for 1 month (day 61) and showed a neutrophil count of 3.58 K/µL. Prednisone was slowly tapered over the next several months, with CBC checked 1 week after each dose change. Cain continued to be healthy and was no longer receiving prednisone at the time of publication.

Prognosis for remission is good and typically fast after prednisone is instituted.2,11,12 A study of 11 dogs showed rapid remission with prednisone and no relapse as corticosteroids were tapered.12 However, in a recent study of 35 dogs, 12 developed a relapse of neutropenia when prednisone treatment was tapered or discontinued.11 Additional long-term studies are needed for more accurate assessment of relapse and to determine the number of dogs needing lifelong immunosuppressant therapy.

TAKE-HOME MESSAGES

  • IMN is an uncommon condition diagnosed based on exclusion of other causes of neutropenia. 
  • Common differential diagnoses include infectious disease, neoplasia, bone marrow disease, drug toxicity, and genetic disease.
  • The most common clinical signs are fever and lethargy; however, neutropenia may be an incidental finding on routine blood work. 
  • Physical examination should be aimed at finding any nidus for infection that could cause neutropenia, particularly a heart murmur secondary to endocarditis, abscesses, spinal pain for discospondylitis, enlarged lymph nodes, and abdominal palpation abnormalities.
  • Diagnosis involves sequential CBCs with blood smear analysis, serum chemistry profile, urinalysis, thoracic radiography, abdominal ultrasonography, tick-borne and other infectious disease testing, FeLV/FIV testing in cats, and bone marrow cytology and/or histopathology. In patients with clinical signs, urine and possibly blood cultures can be considered to rule out sources of infection.
  • Treatment should begin with prednisone; most dogs respond within 7 to 10 days.

References

For global readers, a calculator to convert laboratory values, dosages, and other measurements to SI units can be found here.

All Clinician's Brief content is reviewed for accuracy at the time of publication. Previously published content may not reflect recent developments in research and practice.

Material from Digital Edition may not be reproduced, distributed, or used in whole or in part without prior permission of Educational Concepts, LLC. For questions or inquiries please contact us.


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