September Case of the Month - Intermittent Low Grade Colic

History: “Samson” Donovan, a 10-year-old Oldenberg gelding, presented on 8/24/12 for intermittent low-grade colic consisting mostly of parking out from discomfort, with no decline in condition or performance as a low-level dressage horse.  The owners report that he has also been gassy.  Physical examination and rectal exam were within normal limits and results of a sand flotation test are pending.  His colic episodes generally self-resolve or resolve with the aid of 5cc of Banamine.  He was recently started on the Succeed Digestive Conditioning Program and he is insured.

Labwork analysis:

1.      CBC/chemistry panel: Bloodwork was unremarkable, with insignificant changes in Cl and GGT.

2.      Fecal egg count: Fecal egg count was negative for parasites.

3.      Fecal occult blood: Fecal occult blood was negative for blood.

Diagnosis: Chronic colic, open.

Common causes of chronic intermittent colic include gastric ulceration, sand impaction, and enterolithiasis. 

Gastric ulcers are prevalent in horses, with statistics ranging from 58% of showhorses and 70% of Thoroughbred broodmares to 86% of racehorses.  Due to vague clinical signs and large variation in treatment dosage and duration using GastroGard, the gold standard method of diagnosis remains gastroscopy.  Alternative methods include the Succeed fecal blood test (limited in accuracy), urine sucrose, and blood sucrose.  The procedure for urine sucrose concentration for detecting gastric ulcers is documented in the paper: Evaluation of urine sucrose concentration for detection of gastric ulcers in horses.  O'Conner MS et al. Am J Vet Res. 2004 Jan;65(1):31-9.  In this study, horses were fed 1kg concentrate (Purina Horsechow 100) and intubated with 454g sucrose (10% solution in water).  Urine sucrose was collected 2h and 4h following the intubation.  Sucrose concentration is higher in horses with gastric ulceration, with a sensitivity of 83% and specificity of 90% using a cut-off of 0.7mg/ml.  The procedure for blood glucose can be found in the paper: Sucrose concentration in blood: a new method for assessment of gastric permeability in horses with gastric ulceration.  Hewetson M, Cohen ND, Love S, Buddington RK, Holmes W, Innocent GT, Roussel AJ.  J Vet Intern Med. 2006 Mar-Apr;20(2):388-94.  In this procedure, horses are withheld from feed for 20h, intubated with 250g sucrose, and serum sucrose was significantly elevated 45min later in horses with moderate to severe gastric ulceration. 

The definitive diagnosis for sand impaction and enterolithiasis is through abdominal radiography.   If the sand flotation that was performed by the owner is negative, the test can be improved by administering psyllium (Sand Clear instructions are 5oz daily for 7 days) and performing the sand flotation during and after the treatment.  Psyllium may also have some GI benefits of aiding in mucosal repair.

Recommendation:

1.      Diagnostics: I would recommend doing additional diagnostics, including gastroscopy.  If the gastroscopy is not possible, urine/blood sucrose or empirical treatment (take note GastroGard takes 3-5 days to take effect) can be used to indicate the presence of gastric ulcers.  If he is negative for ulcers, you may wish to consider referral for abdominal radiographs and/or a trial with psyllium and repeated fecal sand flotation.

2.      Treatment: For discomfort due to bloating, you may wish to consider administration of a proven prebiotic such as Saccharomyces boulardii (10 billion organisms PO BID).  All other treatments could be pursued based on the results of additional diagnostics.

Jean-Yin Tan, DVM, DACVIM (Large Animal Internal Medicine)

Palladia (Toceranib phosphate)

by Cheryl Harris, DVM, DACVIM (Oncology and Small Animal Internal Medicine)

Palladia (toceranib phosphate) was the first FDA-approved antiangiogenic and antiproliferative cancer treatment specifically for dogs. It is manufactured by Pfizer and was released for use by veterinary oncologists in 2009 for the treatment of Patnaik grade II or III, recurrent cutaneous mast cell tumors with or without regional lymph node involvement in dogs. It has been a remarkable adjunct for the treatment of canine mast cell tumors (MCT) and is now being used for a variety of canine and even feline tumors. It is now available for widespread use by all licensed veterinarians.

Palladia is a receptor tyrosine kinase (RTK) inhibitor. Inhibition of RTKs on endothelial cells, pericytes, and tumor cells disrupts multiple processes necessary for tumor growth. Palladia inhibits the activity of VEGFR-2, an RFK expressed on endothelial cells. It inhibits the activity of PDGFR-B, an RTK expressed on pericytes and inhibits the RTK KIT on tumor cells. KIT is commonly dysregulated in canine MCT.

The original clinical field study using toceranib phosphate was a multi-center, double-blind, placebo-controlled trial conducted at 10 oncology referral centers and included 151 dogs with MCT. In dogs treated with Palladia, approximately 60% of MCT disappeared, regressed, or stabilized.

Most oncologists are no longer using the label dose of 3.25 mg/kg, but instead use dose ranges between 2.5 to 2.75 mg/kg, EOD or on a MWF basis. This appears to be associated with better tolerability while maintaining efficacy. Prednisone or NSAIDs can be used on alternate days. Many dogs are receiving Cytoxan in addition to Palladia as part of a metronomic therapy. Dogs are started on Cytoxan 10-12 mg/m2 (EOD or T/Th/Sat/Sun) and famotidine for 2 weeks prior to initiation of Palladia. Palladia should be given with food.

All dogs should have a baseline CBC, chemistry profile, urinalysis and fecal occult blood prior to starting Palladia. Owners must observe carefully for loose stools, anorexia or lethargy. For dogs that develop diarrhea, loperamide is used SID/BID and continued during therapy. For dogs with decreased appetite, add canned food to the diet and use metoclopramide, ondansetron or Cerenia.

Dogs are rechecked weekly with CBC and hemoccults for the first 2-4 weeks and body weight should be monitored very closely. It is then recommended to monitor at least monthly with hemoccult, CBC and chemistry panels. Neutropenia can occur but is tolerable as long as neutrophils stay above 1500. If they are lower than 1500, a drug holiday is recommended until the neutrophil count is normal, then the dose is modified. The same holds true for muscle cramping and lameness, an occasionally reported side effect of the drug. Newly reported side effects are elevations in ALT and ALP, protein-losing nephropathy, hypertension and pancreatitis.

The following guidelines on treatment of MCT are based on the Ohio State University treatment experience and that of Dr. Cheryl London who has participated in much of the original research using Palladia.

Palladia is usually incorporated into treatment protocols for Grade III MCT and any Grade II MCT with negative prognostic indicators (mitotic index >5, recent rapid growth, recurrence following surgery, positive lymph nodes.) In general, Palladia is part of a treatment protocol that includes surgery +/- radiation therapy and chemotherapy. It is usually not used as a single agent unless the dog has failed these modalities or it is the only treatment available. For dogs with gross disease, every attempt is made to downstage the cancer prior to initiation of Palladia therapy. If surgery is not possible, dogs can receive vinblastine/prednisone chemotherapy for 2-6 weekly treatments prior to Palladia or receive radiation therapy or a combination of chemotherapy and radiation therapy.

All MCT patients are started on famotidine and Benadryl in addition to prednisone. Any dog with positive hemoccult tests at the start of treatment is pretreated with omeprazole and sucralfate for 1-2 weeks prior to Palladia. Dogs with significant mast cell tumor burden are at high risk for developing side effects from Palladia, particularly if they are already sick. H1 and H2 blockers should always be used in dogs with gross MCT.

It is usually recommended to give Palladia for 30 days to see the full response but some responses are dramatic and seen in the first 7 days. It is unknown how long to treat dogs who are having a good response but many will have their disease recur if Palladia is discontinued. If they are tolerating the drug well, it is currently recommended to keep them on the drug on a M/W/F basis indefinitely.

Other types of tumors which have demonstrated response to Palladia include anal sac adenocarcinomas, metastatic osteosarcomas, thyroid carcinomas, nasal carcinomas, melanomas, squamous cell carcinomas, multiple myeloma and transitional cell carcinomas.

Palladia is very well tolerated in cats. The recommended starting dosage is 2.8 mg/kg EOD. Compounding is recommended to get accurate dosing. Responses have been seen in mast cell tumors, squamous cell carcinomas and vaccine-associated sarcomas. GI toxicity and myelosuppression should be monitored.

Palladia is supplied in 10, 15 and 50 mg tablets and are packaged in 30 count bottles. The tablets should not be split or crushed and should be handled with gloves. A chemical hood such as is used for administration of chemotherapy is not required. The tablets should not be handled by pregnant women.

For more information on the use of Palladia in treating tumors in dogs and cats, please feel free to call the oncologists at Veterinary Answers.

Our Consultants in Print

Mary B. Nabity, DVM, PhD, DACVP

Proteomic analysis of urine from male dogs during early stages of tubulointerstitial injury in a canine model of progressive glomerular disease.

Nabity MB, Lee GE, Dangott LJ, Ciancolo R, Suchodolski JS, Steiner JM.

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Effect of dietary protein content on the renal parameters of normal cats

Backlund B, Zoran DL, Nabity MB, Norby B, Bauer JE

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Could it be Addison’s?

Linda E. Luther, DVM

Diplomate ACVIM (SAIM)

Many cases presented for evaluation of vague symptoms end up having hypoadrenocorticism.

Can you spot the classic cases?

Can you spot the not-so-classic cases?

Hypoadrenocorticism, or “Addison’s” disease, results from atrophy of the adrenal cortex, and often presents as a diagnostic challenge. Clinical signs can vary from subtle signs to acute collapse, and the clinical course is often waxing and waning. Untreated collapsed dogs may die, so identifying dogs affected with this disease early is optimal. Types of hypoadrenocorticism include the ‘classic’ glucocorticoid & mineralocorticoid deficient patient, and the more subtle, glucocorticoid deficient patient.

Clinical signs of classic hypoadrenocorticism may include vomiting, diarrhea, lethargy, collapse, bradycardia, abdominal pain, polyuria, polydipsia, or being “just not right”. Physical examination findings are often nonspecific. Laboratory findings in a classic case may include hyponatremia, hyperkalemia, decreased Na/K ratio, azotemia (with or without an inappropriate specific gravity), hypoalbuminemia, hypoglycemia, hypercalcemia, nonregenerative anemia. The lack of a stress leukogram is common; a normal to elevated lymphocyte count, and normal to elevated eosinophil count in a sick dog are frequent, subtle findings.

The not-so-classic case will often present with more subtle clinical signs. They will have normal electrolytes, and will often have a lack of a stress leukogram. They may also have a low normal hematocrit or a non-regenerative anemia, a low to borderline albumin, hypoglycemia and hypercalcemia. These cases are commonly missed. How can you ensure that you spot these? Look at the CBC carefully. Is there a stress leukogram? Look at the albumin level. Is it decreased or in the low normal range? Consider the history. Consider the lack of other obvious disease, and don’t forget to IGNORE the normal electrolytes. If there are enough consistent findings in a dog with vague symptoms, test for hypoadrenocorticism!

Once you suspect hypoadrenocorticism, confirmation historically has been done with an ACTH stimulation test. However, a recent study showed that if a dog had a baseline cortisol level that was greater than 2.0 ug/dL, they were very unlikely to have hypoadrenocorticism. If the baseline cortisol is less than 2.0 ug/dL, hypoadrenocorticism is not ruled out, and an ACTH stimulation test should be done.

But I thought she was in renal failure…

Cases of hypoadrenocorticism can mimic acute renal failure in that clinical signs are similar, and azotemia with an inappropriate urine specific gravity may exist. How does the astute clinician differentiate the two? Questions to ask include: Is there a stress leukogram? Was the resolution of severe azotemia very rapid? Did the patient act like a ‘brand-new dog’ after just a day of fluids?

Let’s compare “Maggie”, a 7-year-old Fs Collie that presented with vomiting and lethargy, to “Bailey”, a 12-yr-old Mn Cocker that presented in lateral recumbancy (see Table 1). Both dogs had severe azotemia with an inappropriate urine specific gravity. “Maggie” lacked a stress leukogram. The electrolyte findings in both dogs were suggestive of hypoadrenocorticism, but this finding is not pathognomonic for the disease. “Maggie” turned out to have hypoadrenocorticism. “Bailey”, did not, and he was diagnosed with renal failure (see Table 3). Because “Maggie” had an abnormal ACTH stimulation test as well as abnormal electrolytes, she had glucocorticoid and mineralocorticoid deficient hypoadrenocorticism.

Therapy for “Maggie” started with intravenous fluid therapy. The hyperkalemia was treated with the fluids, as well as intravenous sodium bicarbonate therapy (1 mEq/kg, slow IV). Glucocorticoids were given, initially using dexamethasone sodium phosphate (0.1-2 mg/kg IV). Chronic glucocorticoid therapy with physiologic dose of prednisone (0.1-0.2 mg/kg/day, doubled when she was stressed) was initiated. She was also given mineralocorticoid therapy using Percorten®-V (Desoxycorticosterone pivalate or DOCP, 2.2 mg/kg IM or SQ q. 25 initially). Florinef ® (fludrocortisone acetate, 0.01-0.02 mg/kg/day initially), which also has glucocorticoid effects, could have been used instead of Percorten®.

Could he be an Addisonian?

Some Addisonian dogs have very subtle symptoms. “Max” is a 7-yr-old Mn Labrador retriever that presented for a blood panel to monitor carprofen therapy that was chronically administered to treat degenerative joint disease (see Table 2).

“Max’s” blood panel revealed significant anemia. Upon further questioning, the owner thought that he had been quieter lately. He really was not all that sick though. Besides the anemia, the blood work showed a lack of a stress leukogram, his electrolytes were normal, and there was no azotemia. An ACTH stimulation test was done (see Table 3), and “Max” indeed was an Addisonian! Since “Max” had normal electrolytes, he had glucocorticoid deficient hypoadrenocorticism, and he was not mineralocorticoid deficient. Chronic glucocorticoid therapy with a physiologic dose of prednisone (0.1-0.2 mg/kg/day, doubled when he was stressed), was started. Mineralocorticoid therapy was not indicated in this dog. Some glucocorticoid deficient cases eventually develop mineralocorticoid deficiency, thus periodic monitoring of electrolytes was indicated.

In summary, hypoadrenocorticism can be a challenging disease to diagnose. Suspicion of the disease in dogs with vague symptoms is recommended, even in dogs that have normal electrolytes.

Disclaimer: Please verify all drug dosages before administering.

References:

Scott-Moncrieff JCR. Hypoadrenocorticism. In Ettinger SJ, Feldman EC (eds.) Textbook of Veterinary Internal Medicine, 7th ed. Saunders Elsevier, St. Louis, 2010, 1847-1857.

Lennon EM, Boyce TE, Hutchins RG et al. Use of basal serum or plasma cortisol concentrations to rule out a diagnosis of hypoadrenocorticism in dogs: 123 cases (2000-2005). J Am Vet Med Assoc 2007;231:413-416.

Thompson AL, Scott-Moncrieff JC, Anderson JD. Comparison of classic hypoadrenocorticism with glucocorticoid-deficient hypoadrenocorticism in dogs: 46 cases (1985-2005). J Am Vet Med Assoc 2007;230:1190-1194.

Table 1.	“Maggie”	“Bailey”	Normal values
White blood cells, #/μL	12,880	28,290	5,500-16,900
Neutrophils, #/μL	7,670	24,750	2,000-12,000
Lymphocytes, #/μL	2,710	490	500-4,900
Monocytes, #/μL	1,550	2,370	300-2,000
Eosinophils, #/μL	890	520	100-1,490
Platelets, # x 103/μL	299	431	175-500
BUN, mg/dL	130	130	7-27
Creatinine, mg/dL	7.7	7.7	0.5-1.8
Calcium, mg/dL	13.8	5.5	7.9-12
Phosphorus, mg/dL	14.6	16.1	2.5-6.8
Na, mmol/L	136	145	144-160
K, mmol/L	9.0	9.0	3.5-5.8
Cl, mmol/L	103	111	109-122
Na/K	15.1	16.1	< 27
Urine specific gravity	1.015	1.015

Table 2.	“Max”	Normal values
Hematocrit, %	23.6	37-55
White blood cells, #/μL	2,500	5,500-16,900
Neutrophils, #/μL	1,840	2,000-12,000
Lymphocytes, #/μL	340	500-4,900
Monocytes, #/μL	110	300-2,000
Eosinophils, #/μL	190	100-1,490
Platelets, # x 103/μL	325	175-500
BUN, mg/dL	35	7-27
Creatinine, mg/dL	1.3	0.5-1.8
Albumin, mg/dL	1.2	2.3-4
Na, mmol/L	152	144-160
K, mmol/L	5.5	3.5-5.8
Cl, mmol/L	123	109-122
Na/K	27.6	< 27

Table 3.	“Maggie”	“Bailey”	“Max”	Normal values
Pre-ACTH cortisol, ug/dL	< 0.5	8.0	< 0.5	> 2.0
Post-ACTH cortisol, ug/dL	< 0.5	N/A	< 0.5	> 8.0
* Note that “Bailey’s” baseline cortisol adequately ruled out hypoadrenocorticism. “Maggie” and “max” had baseline cortisol values < 2.0 ug/dL, thus an ACTH stimulation was needed to rule in the disease.

PREGNANCY DIAGNOSIS AND TIMING ELECTIVE C-SECTIONS

C. Scott Bailey, DVM, MS, DACT

Consultant, Veterinary Answers

Veterinarians are often asked to perform pregnancy diagnosis and time a c-section with very little information from the owner. Often, the only information provided is the breeding-dates and occasionally even those are hard to come by. Consequently there is a need for veterinarians to be familiar different with methods of estimating gestational age. This is particularly important when an elective caesarean section is desirable. Elective c-sections can carry an excellent prognosis for maternal and fetal viability when timed correctly and may be less stressful to the bitch, puppies and attending veterinarian than waiting for a potential dystocia. Animals that are particularly good candidates are those with a history of dystocia or a c-section and animals that have small (less than 3 pups) or large (more than 8 pups) litter sizes. Dogs of certain breeds have a known predisposition to dystocia, such as Boxers, Bulldogs, Scottish Terriers, Great Danes and Bernese Mountain Dogs [1].

A number of factors play critical roles in the ultimate success-rate of elective c-sections, including fetal maturity, patient preparation, selection of anesthesia protocol and surgical technique as well as neonatal care of the pups. In this review we focus on only the first of these – Timing of c-section to maximize fetal maturity.

Three basic methods exist to predict parturition in the bitch:

Hormonal Assay

While the easiest methods for timing involve breeding management, breeding dates provided by owners are notoriously unreliable. Parturition may occur anywhere from 57 to 72 days after a single observed breeding [2]. On the contrary, the easiest and most accurate way to predict whelping is to diagnose or estimate the time of LH surge. Bitches reliably whelp 64-66 days post LH surge [2,3], which can be diagnosed by repeated LH assay (every 12 hours due to the short duration of the LH surge in the bitch). LH-peak may also be estimated by observing serum progesterone levels that achieve 2-3ng/ml and continue to rise thereafter [3,8]. Shortly after this period, vaginal cytology may be used to diagnose the onset of diestrus, occurring approximately 51-60 days before whelping [4].

Thereafter a variety of measures represent guides to estimate gestational stage within 2-3 days [4-6]. Further, equations have been developed to calculate gestational age in a variety of breeds [6,7].

A brief summary of useful ultrasonographic and radiographic markers of gestational age is listed below:

Ultrasonographic examination [5-8]

The fetal heartbeat is visible at approximately 22-26 days.

Limbuds, fetal movement and a fluid filled stomach may be seen on day 29, 30 and 33.

Fetal length exceeds chorionic width at approximately day 42.

Radiographic examination [5,7,9]

Pregnancy can first be reliably diagnosed radiographically day 45-48 post LH surge. More specific information is also available describing the appearance of specific structures in relation to whelping.

The scapula, humerus and femur are first detectable 17 days (15-18) prepartum.

The pelvis and 13 pairs of ribs are visible 11 days (9-13) prepartum.

Teeth are visible 4 days (3-8) prepartum.

During the final days of gestation, cortisol is produced and released from the maturing fetal adrenal gland in response to space-constraint and other physiologic stressors. This results in production of prostaglandin F2α in the placenta and endometrium, which in turn induces luteolysis and starts the cascade of events that ultimately result in fetal expulsion [10]. At the same time the cortisol also has critical effects on the fetus, resulting in rapid maturation of vital organ systems, including the musculoskeletal system, gastrointestinal system and lungs. Prior to these final maturation processes, puppy survival may be decreased due to weakness, poor mobility and respiratory distress after removal from the uterus. On the contrary, if these processes have occurred and the bitch experiences a dystocia, survival may also be decreased. Consequently, the goal of gestational timing should be to predict whelping accurately enough to intervene after final maturation has occurred but before the bitch is in active labor. To do this, repeated monitoring of hormone levels during the final week of gestation, in combination with fetal monitoring via ultrasound or tocometry, may improve fetal viability and prevent dystocias [11-13].

Progesterone [11]:

Progesterone measures below 2ng/ml indicate imminent parturition within 18-36 hours.

A temperature drop by 1-3F from previous measures occurs in 75-85% of bitches within 8-18 hours prior to parturition.

Fetal heart-rate can accurately diagnose fetal distress during late gestation [12,13]

Normal late pregnancy: 200 beats/min

Fetal Stress: 180 beats/min – Values in this range indicate readiness for parturition

Fetal distress: 150 beats/min – values of 150 or below indicate the urgent need for emergency intervention to save the puppy.

References:

1) Bergström A, Nødtvedt A, Lagerstedt AS, Egenvall A. Incidence and breed predilection for dystocia and risk factors for cesarean section in a Swedish population of insured dogs. Vet Surg 2006 Dec;35(8):786-91.

2) Concannon PW, Whaley S, Leid D, Wissler R. Canine Gestation length: vacioation related to time of mating and fertile life of sperm. Am J Vet Res 1983;44:1819-21.

3) Cohen JA, Holle DM, Meyers-Wallen VN. Accuracy of canine parturition date prediction from LH peak. Clin Theriogenology 2009;1:570

4) Holst PA, Phemister RD. Onset of diestrus in the Beagle bitch: definition and significance. Am J Vet Res 1974;35:401-6

5) Aissi A and Slimani C. Ultrasonographic appearance of the gestational structures throughout pregnancy in bitches. Am J Anim Vet Sciences 2008;3(1):32-35

6) Yeager AE and Concannon PW. Association between preovulatory LH surge and the early ultrasonographic detection of pregnancy and fetal hearteats in beagle dogs. Theriogenology 1990;34:655-665.

7) Lopate C. Estimation of gestational age and assessment of canine fetal marutation using radiology and ultrasonography: A review. Theriogenology 2008;70:397-402

8) Luvoni GC and Beccaglia M. The Prediction of Parturition Date in Canine Pregnancy. Reprod Dom Anim 2006;41:27-32.

9) Rendano VT. Radiographic evaluation of fetal development in the bitch and fetal death in the bitch and queen. In: Current veterinary therapy vol VIII. WB Saunders Co 1983; 947-52

10) Concannon PW, Butler WR, Hansel W, Knight PJ, Hamilton JM. Parturition and lactation in the bitch: serum progesterone, cortisol and prolactin. Biol Reprod 1978 Dec;19(5):1113-8.

11) Verstegen-Onclin K, Verstegen J. Endocrinology if pregnancy in the dog: A review. Theriogenology 2008;70:291-199.

12) Verstegen JP, Silvia LDM, Onclin K, Donnay I. Echocardiographic study of heart rate in dog and cat fetuses in utero. J Reprod Fertil Suppl 1993;47:174-80

13) Zone MA and Wanke MM. Diagnosis of canine fetal death by ultrasonography J. Reprod Fertil 2001;57:215-9.

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