Categories
Veterinary Medicine

Dilated cardiomyopathy in the cat

The aetiology of primary dilated cardiomyopathy in the cat is unknown. Recent work has indicated a close association between dietary taurine deficiency and dilated cardiomyopathy. In the cat, taurine is an essential amino acid which is required for the conjugation of bile acids. The premise that taurine deficiency is one of the causative factors in the pathogenesis of dilated cardiomyopathy is based on the fact that many cats on taurine-deficient diets develop myocardial failure which can be reversed with taurine supplementation.

However, not all cats on taurine-depleted diets develop dilated cardiomyopathy and some which do develop cardiomyopathy fail to respond to taurine supplementation. About 38% of cats with dilated cardiomyopathy in one study failed to respond to taurine supplementation and died within the first 30 days of treatment. Hypothermia and thromboembolism were found to increase the risk of early death.

It is also known that cats on apparently adequate diets can nevertheless become taurine deficient. The minimal concentration of taurine in the diet required to prevent signs of deficiency varies with the type of diet. For example, it has been shown that much higher concentrations (2000-2500 mg taurine / kg dry matter) of taurine are required in canned diets compared to dry cat foods since heating during the canning process produces products which increase the enterohepatic loss of taurine. Low plasma taurine levels have been reported in cats fed a taurine replete but potassium depleted diet containing 0.8% ammonium chloride as a urinary acidifier suggesting a possible association between taurine and potassium balance in cats. Dietary acidification exacerbates potassium depletion in cats by decreasing gastrointestinal absorption of potassium.

It has been suggested therefore that the aetiology of feline dilated cardiomyopathy, like that of dilated cardiomyopathy in dogs, is multifactorial. There is some evidence to show that genetic factors may play a role in feline dilated cardiomyopathy. Burmese, Siamese and Abyssinian cats appear predisposed. The incidence of dilated cardiomyopathy is higher in young to middle-aged cats; the evidence for a sex predilection is equivocal).

Pathophysiology

Impairment in myocardial contractility leads to systolic dysfunction and increased end-diastolic pressures. Progressive dilatation of the ventricles results in distortion of the atrioventricular valve apparatus and mitral regurgitation which, together with the reduction in myocardial contractility, contributes to the reduction in stroke volume and decreased cardiac output.

Clinical signs of Dilated cardiomyopathy

The clinical signs may be gradual in onset and are often rather vague (lethargy, reduced activity and decreased appetite). Many of the presenting signs are similar to those of hypertrophic cardiomyopathy making differentiation between the two diseases on a clinical basis difficult. Cats which are dyspnocic may be dehydrated and hypothermic with weak femoral pulses. There may be obvious pallor or cyanosis of the mucosae with a prolonged capillary refill time. Increased respiratory crackles in association with a gallop rhythm and systolic murmur are common findings; the presence of a large volume of pleural fluid may result in muffled heart sounds. Less frequently there is also evidence of right-sided failure (jugular distension, and hepatomegaly); ascites is a rare finding.

Electrocardiography

The electrocardiographic changes do not help differentiate dilated cardiomyopathy from the hypertrophic form of the disease. Some cats remain in a relatively slow sinus rhythm. Tall R waves and wide P waves and QRS complexes may be apparent in Lead II.

Arrhythmias, especially ventricular premature complexes, have been recorded in more than 50% of cases. The mean electrical axis is often within normal limits.

Radiographic findings

Thoracic radiographs typically show evidence of generalized cardiomegaly; enlargement of the-left atrium may be particularly marked. The cardiac silhouette is often obscured by the presence of a bilateral pleural effusion. Pulmonary venous congestion and oedema may be present but these changes are usually mild and are often masked by the presence of fluid in the pleural space. The caudal vena cava is often dilated and there may be evidence of hepatomegaly.

Echocardiography

Echocardiography offers the most reliable means of differentiating dilated cardiomyopathy from hypertrophic cardiomyopathy. The interventricular septum and left ventricular free wall appear thin and poorly contractile with a marked reduction in fractional shortening. Both ventricles and the left atrium appear dilated and left ventricular end-diastolic and end-systolic internal dimensions are increased.

Laboratory findings

Normal plasma taurine levels are greater than 60 nmol l-1 ; most cats with dilated cardiomyopathy have plasma taurine concentrations less than 20 nmol l-1 and often less than 10 nmol l-1. Taurine-defielent cats with thromboembolism may have slightly higher plasma taurine concentrations due to reperfusion hyperkalaemia. Whole blood taurine has been reported to be less sensitive to acute changes in taurine intake and provides a better indication of long-term taurine intake. Whole blood taurine concentrations greater than 280 nmol l-1 are considered adequate.

Prerenal azotaemia is a common finding in cats with dilated cardiomyopathy because of reduced renal perfusion. The pleural effusion which develops with feline dilated cardiomyopathy is typically a serosanguineous modified transudate; true chylous effusions have been reported in association with right heart failure.

Angiocardiography

Non-selective angiocardiography can be used to demonstrate dilatation of all cardiac chambers. The slow circulation time in cats with dilated cardiomyopathy increases the risk of thromboembolus formation during this procedure and decompensated cases should be stabilized beforehand.

Dilated cardiomyopathy: Treatment

Cats which are severely dyspnoeic should be given oxygen, kept warm and placed in a cage. Dyspnoeic animals, particularly those with suspected pleural effusion, should be handled with care and should not be placed in dorsal or lateral recumbency for radiography. A dorsoventral radiograph taken with the animal resting in sternal recumbency is usually sufficient to confirm the presence of pleural fluid. Thoracocentesis should be attempted before a more detailed radiographic examination is performed. Other therapeutic strategics are summarized below.

Digoxin improves myocardial contractility in some but not all cats with dilated cardiomyopathy and it has been suggested that the drug may act synergistically with taurine in this respect.The liquid form of the drug is unpalatable and is generally not well tolerated. There is considerable individual variation in the way in which cats respond to digoxin. The maintenance oral dose is 0.01 mg kg-1 every 48 h for an average 3-4 kg cat which is less than one quarter of a 62.5 μg tablet every other day. Cats with dilated cardiomyopathy are more susceptible to digoxin toxicity and tend to show toxic signs when the plasma concentration of digoxin is approximately 50% of the level which would be considered toxic in a normal healthy cat. Approximately 50% of cats given 0.01 mg kg-1 body weight every 48 h show signs of toxicity.

Other positive inotropic agents such as dopamine and dobutamine must be given by constant slow intravenous infusion and are, therefore, not used as extensively. Both drugs can be given at a rate of 1-5 μg kg-1 body weight min-1 ; with dobutamine, seizures have been reported with infusion rates as low as 5 μg kg-1 min-1 in cats.

Frusemide (initially 1.0 mg kg-1 body weight intravenously twice daily; for maintenance 1-2 mg kg-1 body weight per os once or twice daily)

Mixed arteriovenous vasodilators such as captopril (3.12-6.25 mg kg-1 body weight per os twice or three times daily; this dose equates to approximately one-eighth to one quarter of a 25 mg tablet) or venodilators such as 2% nitroglycerine ointment (1/8-1/4 inch applied three times daily to the inside of the pinna) can be given although the beneficial effects of these drugs have yet to be evaluated fully in cats with dilated cardiomyopathy. They should not be given to cats with cardiogenic shock since they may potentiate the fall in cardiac output especially if used in conjunction with diuretic agents.

Animals which are severely hydrated may require intravenous or subcutaneous fluid therapy, for example 0.45% saline with 2.5% dextrose solution may help combat the effects of circulatory failure. The recommended rate of infusion is 25-35 ml kg-1 body weight day-1 given in two or three divided doses. Care should be taken so that the rate of infusion optimizes cardiac output but minimizes the risk of exacerbating pulmonary oedema or a pleural effusion.

Aspirin (25 mg kg-1 body weight every 72 h).

Taurine supplementation (250-500 mg per os twice daily) may result in a dramatic clinical improvement within 1-2 weeks when dilated cardiomyopathy is associated with taurine deficiency although cehocardiographic evidence of improved cardiac performance is usually not evident until after at least three weeks of treatment.

Sodium restricted diet.

Prognosis

The prognosis for cats which fail to resond to taurine therapy is poor. About 93% of early deaths occur within the first two weeks; few survive longer than one month. Taurine supplementation can eventually be discontinued if adequate taurine intake is provided for in the food.

Categories
Veterinary Procedures

Oral Administration: Liquids

Without a Stomach Tube

Patient Preparation

None required. Technique is appropriate for owners to perform at home.

Technique

Small amounts of liquid medicine can be given successfully to dogs and cats by pulling the commissure of the lip out to form a pocket (). Deposit the liquid medication into the “cheek pouch,” where it subsequently flows between the teeth as the head is held slightly upward. Patience and gentleness, along with a reasonably flavored medication, contribute to the success.

Spoons are ineffective, as fluids are easily spilled. A disposable syringe can be used to measure and administer liquids orally. Depending on the liquid administered, disposable syringes can be reused several times, assuming they are rinsed after each administration. In addition, disposable syringes can be dispensed legally to clients for home administration of liquid medication. Mixing of medications in the same syringe is not recommended. However, dispensing of a separate, clearly marked syringe for each type of liquid medication prescribed for home administration is recommended.

Special Considerations

Compounding pharmacies are also available and can mix many medications into palatable flavors to help facilitate the oral administration of medications.

Dogs with swallowing disorders should not be treated at home with liquid medications because this could cause complications associated with aspiration.

With an Administration Tube

Patient Preparation

None required.

Note: This procedure is reserved for in-hospital use only. The technique should be performed only by individuals trained to perform this procedure.

Technique

Administration of medications, contrast material, and rehydrating fluids can be accomplished with the use of a well lubricated feeding tube passed through the nostrils into the stomach or distal esophagus. When a feeding tube is placed for long-term use (multiple days) and repeated use (described under Gastrointestinal Procedures later), it is generally recommended to avoid passing the tip of the tube beyond the distal esophagus. The reason for recommending nasoesophageal intubation over nasogastric intubation is based on the fact that reflex peristalsis of the esophagus against a tube passing through the cardia can result in significant mucosal ulceration within 72 hours. This is not a factor in patients receiving a single dose of medication or contrast material.

TABLE The French Catheter Scale Equivalents*

  Size
Scale Millimeters Inches
3 1 0.039
4 1.35 0.053
5 1.67 0.066
6 2 0.079
7 2.3 0.092
8 2.7 0.105
9 3 0.118
10 3.3 0.131
11 3.7 0.144
12 4 0.158
13 4.3 0.170
14 4.7 0.184
15 5 0.197
16 5.3 0.210
17 5.7 0.223
18 6 0.236
19 6.3 0.249
20 6.7 0.263
22 7.3 0.288
24 8 0.315
26 8.7 0.341
28 9.3 0.367
30 10 0.393
32 10.7 0.419
34 11.3 0.445

*Multiple types of pediatric polyurethane nasogastric feeding tubes are available in sizes ranging from 8F to 12F that easily accommodate administration of liquids medications and fluids to kittens, cats, and small dogs.

The narrow lumen of tubes passed through the nostril of small dogs and cats limits the viscosity of solutions that can be administered through a tube directly into the gastrointestinal tract. Nasoesophageal intubation can be done with a variety of tube types and sizes (Table The French Catheter Scale Equivalents). Newer polyurethane tubes, when coated with a lidocaine lubricating jelly, are nonirritating and may be left in place with the tip at the level of the distal esophagus. When placing the nasogastric tube, instill 4 to 5 drops of 0.5% proparacaine in the nostril of the cat or small dog; 0.5 to 1.0 mL of 2% lidocaine instilled into the nostril of a larger-breed dog may be required to achieve the level of topical anesthesia needed to pass a tube through the nostril. With the head elevated, direct the tube dorsomedially toward the alar fold (). Pushing dorsally on the nasal philtrum and pushing the nostril from lateral to medially will help facilitate passage of the tube into the ventrome-dial nasal meatus.

Caution: The tip of the feeding tube can be inadvertently introduced through the glottis and into the trachea. Topical anesthetic instilled into the nose can anesthetize the arytenoid cartilages, thereby blocking a cough or gag reflex.

After inserting the tip 1 to 2 cm into the nostril, continue to advance the tube until it reaches the desired length. If the turbinates obstruct the passage of the tube, withdraw the tube by a few centimeters. Then readvance the tube, taking care to direct the tube ventrally through the nasal cavity. Occasionally it will be necessary to withdraw the tube completely from the nostril and repeat the procedure. In particularly small patients or patients with obstructive lesions (e.g., tumor) in the nasal cavity, it may not be possible to pass a tube. Do not force the tube against significant resistance through the nostril.

Gavage, or gastric lavage and feeding, in puppies and kittens can be accomplished by passing a soft rubber catheter or feeding tube into the mouth, tilting the puppy’s or kittens head, and watching it swallow the tube. Most puppies or kittens will struggle and vocalize. They usually will not vocalize if the tube has been placed into the trachea. A 12F catheter is of an adequate diameter to pass freely, but it is too large for dogs and cats less than 2 to 3 weeks of age. Mark the tube with tape or a pen at a point equal to the distance from the mouth to the last rib. Merely push the tube into the pharynx and down the esophagus to the caudal thoracic level (into the stomach). Verify the placement of the tube using the same dry syringe aspiration technique to ensure that the tube is positioned in the esophagus or stomach rather than the trachea. Attach a syringe to the flared end, and slowly inject medication or food.

Depending on the feeding tube type, the end of the tube may or may not accommodate a syringe. For example, soft, rubber urinary catheters are excellent tubes for single administration use. However, the flared end may not accommodate a syringe. To affix a syringe to the outside end of a tapered feeding tube or catheter, insert a plastic adapter () into the open end of the tube.

Special Considerations

Esophageal (versus intratracheal) placement of the feeding tube can be verified with a dry, empty syringe. Attach the empty syringe to the end of the feeding tube. Rather than injecting air or water in an attempt to auscultate borborygmus over the abdomen, attempt simply to aspirate air from the feeding tube. If there is no resistance during aspiration and air fills the syringe, the tube likely has been placed in the trachea. Completely remove the tube and repeat the procedure. However, if repeated attempts to aspirate are met with immediate resistance and no air enters the syringe, the tube tip is positioned properly within the esophagus. If there is any question regarding placement, a lateral survey radiograph is indicated.

Definitive confirmation of proper tube placement can be made by diluting 1 to 2 ml of an iodinated contrast agent with sterile saline, instilling the liquid into the tube, then taking a lateral thoracoabdominal radiograph to confirm entry of the contrast material into the stomach.

Categories
Veterinary Procedures

Urine Collection Techniques

Urine can be removed from the bladder by one of four methods: (1) voided (the “free catch”), (2) manual compression of the urinary bladder (expressing the bladder), (3) catheterization, or (4) cystocentesis.

Voiding

For routine urinalysis, collection of urine by voiding (micturition) is satisfactory. The major disadvantage is risk of contamination of the sample with cells, bacteria, and other debris located in the genital tract and the perineal hair coat. The first portion of the stream is discarded, as it is most likely to contain debris. Voided urine samples are not recommended when bacterial cystitis is suspected.

Manual Compression of the Bladder

Compressing the urinary bladder is occasionally used to collect urine samples from dogs and cats. Critical: Do not use excessive pressure; if moderate digital pressure does not induce micturition, discontinue the technique. Excessive pressure can culminate in forcing contaminated urine (bladder) into the kidneys, or, worse, in patients with a urethral obstruction the urinary bladder can rupture. The technique is most difficult to accomplish in male dogs and male cats.

Urinary Catheterization

Several types of urinary catheters are currently available for use in dogs and cats. The catheter types most often used today are made of rubber, polypropylene, and latex-free silicone. Stainless steel catheters are occasionally used but unless placed with care these can cause damage to the urethra and/or urinary bladder. Generally, urinary catheters serve one of four purposes:

  1. 1. To relieve urinary retention
  2. 2. To test for residual urine
  3. 3. To obtain urine directly from the bladder for diagnostic purposes
  4. 4. To perform bladder lavage and instillation of medication or contrast material

The size of catheters (diameter) usually is calibrated in the French scale; each French unit is equivalent to roughly 0.33 mm. The openings adjacent to the catheter tips are called “eyes.” Human urethral catheters are used routinely in male and female dogs; 4F to 10F catheters are satisfactory for most dogs (Table Recommended Urethral Catheter Sizes for Routine Use in Dogs and Cats). Polypropylene catheters should be individually packaged and sterilized by ethylene oxide gas.

TABLE Recommended Urethral Catheter Sizes for Routine Use in Dogs and Cats

Animal Urethral Catheter Type Size (French Units*)
Cat Flexible vinyl, red rubber, or Tom Cat catheter (polyethylene) 3.5
Male dog (<25 lb) Flexible vinyl, red rubber, or polyethylene 3.5 or 5
Male dog (>25 lb) Flexible vinyl, red rubber, or polyethylene 8
Male dog (>75 lb) Flexible vinyl, red rubber, or polyethylene 10 or 12
Female dog (<10 lb)) Flexible vinyl, red rubber, or polyethylene 5
Female dog (10-50 lb) Flexible vinyl, red rubber, or polyethylene 8
Female dog (>50 lb) Flexible vinyl, red rubber, or polyethylene 10, 12, or 14

*The diameter of urinary catheters is measured on the French (F) scale. One French unit equals roughly 0.33 mm.

Catheterization of the Male Dog

Patient Preparation

Equipment needed to catheterize a male dog includes a sterile catheter (4F to 10F, 18 inches long, with one end adapted to fit a syringe), sterile lubricating jelly, povidone-iodine soap or chlorhexidine, sterile rubber gloves or a sterile hemostat, a 20-mL sterile syringe, and an appropriate receptacle for the collection of urine.

Proper catheterization of the male dog requires two persons. Place the dog in lateral recumbency on either side. Pull the rear leg that is on top forward, and then flex it (). Alternatively, long-legged dogs can be catheterized easily in a standing position.

Before catheter placement, retract the sheath of the penis and cleanse the glans penis with a solution of povidone-iodine 1% or chlorhexidine. Lubricate the distal 2 to 3 cm of the appropriate-size catheter with sterile lubricating jelly. Never entirely remove the catheter from its container while it is being passed because the container enables one to hold the catheter without contaminating it.

Technique

The catheter may be passed with sterile gloved hands or by using a sterile hemostat to grasp the catheter and pass it into the urethra. Alternatively, cut a 2-inch “butterfly” section from the end of the thin plastic catheter container. This section can be used as a cover for the sterile catheter, and the clinician can use the cover to grasp and advance the catheter without using gloves.

If the catheter cannot be passed into the bladder, the tip of the catheter may be caught in a mucosal fold of the urethra or there may be a stricture or block in the urethra. In small-breed dogs, the size of the groove in the os penis may limit the size of the catheter that can be passed. One also may experience difficulty in passing the catheter through the urethra where the urethra curves around the ischial arch. Occasionally a catheter of small diameter may kink and bend on being passed into the urethra. When the catheter cannot be passed on the first try, reevaluate the size of the catheter and gently rotate the catheter while passing it a second time. Never force the catheter through the urethral orifice.

Special Considerations

Effective catheterization is indicated by the flow of urine at the end of the catheter, and a sterile 20-mL syringe is used to aspirate the urine from the bladder. Walk the dog immediately after catheterization to encourage urination.

Catheterization of the Female Dog

Patient Preparation

Equipment needed to catheterize a female dog includes flexible urethral catheters identical to those used in the male dog. The following materials also should be on hand: a small nasal speculum, a 20-mL sterile syringe, lidocaine 0.5%, sterile lubricating jelly, a focal source of light, appropriate receptacles for urine collection, and 5 mL of povidone-iodine or a dilute chlorhexidine solution.

Use strict asepsis. Cleanse the vulva with a solution of povidone-iodine or dilute chlorhexidine. Instillation of lidocaine 0.5% into the vaginal vault helps to relieve the discomfort of catheterization. The external urethral orifice is 3 to 5 cm cranial to the ventral commissure of the vulva. In many instances the female dog may be catheterized in the standing position by passing the female catheter into the vaginal vault, despite the fact that the urethral papilla is not visualized directly.

Technique

In the spayed female dog, in which blind catheterization may be difficult, the use of a sterilized otoscope speculum andlight source (), vaginal speculum, or anal speculum with a light source will help to visualize the urethral tubercle on the floor of the vagina. In difficult catheterizations it may be helpful to place the animal in dorsal recumbency (). Insertion of a speculum into the vagina almost always permits visualization of the urethral papilla and facilitates passage of the catheter. Take care to avoid attempts to pass the catheter into the fossa of the clitoris because this is a blind, possibly contaminated cul-de-sac.

Catheterization of the Male Cat

Patient Preparation

Before attempting urinary bladder catheterization of the male cat, administer a short-term anesthetic (e.g., ketamine, 25 mg/kg IM), but only after a careful assessment of the cats physical, acid-base, and electrolyte status (see treatment of hyperkalemia).

In some cases, drugs to treat hyperkalemia may be required before anesthetic induction. Once the patient’s electrolyte status has been evaluated and hyperkalemia, if present, addressed appropriately, anesthesia can be induced with a combination of propofol (4 to 7 mg/kg intravenously [IV]) and diazepam (0.1 mg/kg IV); then the patient is intubated and maintained on gas anesthesia.

Technique

Place the anesthetized patient in dorsal recumbency. Gently grasp the ventral aspect of the prepuce and move it caudally in such a manner that the penis is extruded. Withdraw the penis from the sheath and gently pull the penis backward. Keeping sterile catheters in a freezer will help them become more rigid to facilitate passage into the urethra. Pass a sterile, flexible plastic or polyethylene (PE 60 to 90) catheter or 3- to 5-inch, 3.5F urethral catheter into the urethral orifice and gently into the bladder, keeping the catheter parallel to the vertebral column of the cat.

Caution: Never force the catheter through the urethra. The presence of debris within the urethral lumen may require the injection of 3 to 5 mL of sterile saline to back-flush urinary “sand” or concretions so that the catheter can be passed. In some instances the presence of cystic and urethral calculi will prevent the passage of a catheter into the urethra. For this reason a lateral radiograph of the penis, with the patients hindlimbs pulled caudally, may help document the presence of a urethral stone.

Catheterization of the Female Cat

Patient Preparation

Urinary bladder catheterization of the female cat is not a simple procedure. When indicated, and after a preanesthetic examination has been performed, attempt the technique only in the anesthetized cat. Urinary bladder catheterization can be accomplished with the use of a rubber or plastic, side-hole (blunt-ended) urinary catheter. The same catheter type used in male cats is effective in female cats. Instilling lidocaine 0.5% has been recommended as a means of decreasing sensitivity to catheter insertion in sedated (not recommended) cats. Cleanse the vulva with an appropriate antiseptic.

Technique

Catheterization can be accomplished with the cat in dorsal or ventral recumbency.

Experience and size of the cat dictate which technique works best.

After cleansing of the perineum and vaginal vault, place the patient in sternal recumbency, and gently pass the catheter along the ventral floor of the vaginal vault. Conversely, if the patient is placed in dorsal recumbency, direct the catheter dorsally along the ventral vaginal floor. If a catheter cannot be placed blindly, a small otoscopic speculum can be placed into the vagina, and the catheter pushed into the urethral papilla once it is visualized directly.

Indwelling Urethral Catheter

Patient Preparation

For continuous urine drainage in the awake, ambulatory patient, use a closed collection system to help prevent urinary tract infection. A soft urethral or Foley catheter can be used, and polyvinyl chloride tubing should be connected to the catheter and to the collection bag outside the cage. The collection bag should be below the level of the animal’s urinary bladder. Place an Elizabethan collar on the animal to discourage chewing on the catheter and associated tubing.

Technique

The urinary bladder is catheterized as described previously. Despite the quality of care of the catheter, urinary tract infection still may develop in any patient fitted with an indwelling urinary catheter. Ideally, remove the catheter as soon as it is no longer necessary, or if there are clinical signs of a urinary tract infection or previously undiagnosed fever. A urinary catheter is generally changed after it has been in place for more than 48 hours.

Special Considerations

Observe the patient for development of fever, discomfort, pyuria, or other evidence of urinary tract infection. If infection is suspected, remove the catheter and submit urine for culture and sensitivity or determination of minimum inhibitory concentration (MIC). Previously, culture of the catheter tip was recommended to diagnose a catheter-induced infection. However, culture of the catheter tip is no longer recommended, as it may not accurately reflect the type of microorganisms in a urinary tract infection. The empiric use of antibiotics to help prevent catheter-induced infection is not recommended, as their use can allow colonization of resistant nosocomial bacteria in the patient’s urinary tract.

Cystocentesis

Patient Preparation

Cystocentesis is a common clinical technique used to obtain a sample of urine directly from the urinary bladder of dogs and cats when collecting a voided, or free-catch, aliquot is not preferred. The procedure is indicated when necessary to obtain bladder urine for culture purposes. Urine that is collected by free catch has passed through the urethra and may be contaminated with bacteria, thereby making interpretation of the culture results difficult. Cystocentesis also is performed as a convenience when it is desirable to obtain a small sample of urine but the patient is not ready or cooperative.

Cystocentesis involves insertion of a needle, with a 6- or 12-mL syringe attached, through the abdominal wall and bladder wall to obtain urine samples for urinalysis or bacterial culture. The technique prevents contamination of urine by urethra, genital tract, or skin and reduces the risk of obtaining a contaminated sample. Cystocentesis also may be needed to decompress a severely overdistended bladder temporarily in an animal with urethral obstruction. In these cases, cystocentesis should be performed only if urethral catheterization is impossible. Warning: Penetration of a distended (obstructed) urinary bladder with a needle could result in rupture of the bladder.

Technique

To perform cystocentesis, palpate the ventral abdomen just cranial to the junction of the bladder with the urethra, and trap the urinary bladder between the fingers and the palm of the hand. Use one hand to hold the bladder steady within the peritoneal cavity while the other guides the needle. Next, insert the needle through the ventral abdominal wall into the bladder at a 45-degree angle (). Although this procedure is relatively safe, the bladder must have a reasonable volume of urine, and the procedure should not be performed without first identifying and immobilizing the bladder. For the procedure to be performed safely and quickly, the patient must be cooperative. If collection of a urine sample by cystocentesis is absolutely necessary, sedation may be indicated to restrain the patient adequately for the procedure.

Special Considerations

Generally, cystocentesis is a safe procedure, assuming the patient is cooperative and the bladder can be identified and stabilized throughout the procedure. However, injury and adverse reactions can occur. In addition to laceration of the bladder with the inserted needle (patient moves abruptly), the needle can be passed completely through the bladder and into the colon, causing bacterial contamination of the bladder or peritoneal cavity. There is also risk of penetrating a major abdominal bloodvessel, resulting in significant hemorrhage.

Categories
Diseases

Diseases of the Ear: General Principles Of Management

The therapeutic plan for otitis externa requires identification of the primary disease process and perpetuating factors. Ideally management is aimed at thoroughly cleaning and drying the ear canal, removing or managing the primary factors, controlling perpetuating factors, administering appropriate topical or systemic therapy (or both), and evaluating response to therapy.

Ear Cleaning

Ear cleaning serves several functions: (1) it removes material that supports or perpetuates infection; (2) it removes bacterial toxins, white blood cells (WBCs), and free fatty acids that stimulate inflammation; (3) it allows complete evaluation of the external ear canal and tympanum; (4) it allows topical therapy to contact all portions of the ear canal; and (5) it removes material that may inactivate topical medications. Significandy painful ears may benefit from initial anti-inflammatory therapy to decrease pain and swelling of the ear canal prior to cleaning. Severe cases of otitis externa often require general anesthesia to facilitate complete cleaning and evaluation of the external and middle ear.

Many different solutions are available for removing cerumen, exudate, and debris from the ear canal (Table Otic Cleaning Solutions). If the tympanic membrane cannot be visualized, only physiologic saline solution or water should be used, because many topical cleaning agents are ototoxic or incite inflammation of the middle ear. An operating otoscope, ear loops, and alligator forceps facilitate manual removal of large amounts of cerumen or debris. Debris is carefully removed under direct visualization, and care is taken deeper in the ear canal (close to the tympanic membrane). Aggressive hair removal is not advised, because inflammation and damage to the epithelium can result in secondary bacterial colonization and infection. Flushing may be performed after large accumulations of cerumen and debris are mechanically removed from the ear canal.

Otic Cleaning Solutions

Trade Name Acetic Acid Boric Acid Salicylic Acid Isopropyl Alcohol Propylene Clycol Dss Other
Ace-Otic Cleanser 2%   0.1%       Lactic acid 2.7%
Adams Pan-Otic         X X Parachlorometaxylenol, tris EDTA, methylparaben, diazolidinyl urea, popylparaben, octoxynol
Alocetic Ear Rinse X     X     Nonoxynol-12, methylparaben, alovera gel
Cerulytic Ear Ceruminolytic         X   Benzyl alcohol, butylated hydroxytoluene
Cerumene             25% Isopropyl myristate
DermaPet Ear/Skin Cleanser for Pets X X          
Docusate Solution         X X  
Earmed Boracetic Flush X X         Aloe
Earmed Cleansing Solution & Wash         X   50A 40B alcohol, cocamidopropyl phosphatidyl and PE dimonium chloride
Earoxide Ear Cleanser             Carbamide peroxide 6.5%
Epi-Otic Ear Cleanser     X   X X Lactic acid, chitosanide
Fresh-Ear X X X X X   Lidocaine hydrochloride, glycerin, sodium docusate, lanolin oil
OtiCalm     X       Benzoic acid, malic acid, oil of eucalyptus
Otic Clear X X X X X   Glycerin, lidocaine hydrochloride
Oticlean-A Ear Cleaning Lotion X X X 35% X   Lanolin oil, glycerin
Oti-Clens     X   X   Malic acid, benzoic acid
Otipan Cleansing Solution         X   Hydroxypropyl cellulose, octoxynol
Otocetic Solution 2% 2%          
Wax-O-Sol 25%             Hexamethyltetracosane

Flushing and evacuation of solution is done under direct visualization through an operating otoscope. A bulb syringe and red rubber catheter system may be used to both flush and evacuate solutions and accumulations from the ear canal. The operator, avoiding drastic pressure changes within the external ear canal that could damage the tympanum, should carefully control suction and manual evacuation of the contents of the bulb syringe from the ear canal. Other alternatives include tomcat catheters (3.5 F) or flexible, intravenous catheters (14 gauge, Teflon); stiff, narrow catheters should be used cautiously and under direct visualization deep in the external ear canal. Other reservoir systems for delivery or evacuation of solutions include a 12 mL syringe or suction tubing attached to in-house vacuum systems. In-house vacuum systems should be used cautiously and under direct visualization. Care should be taken to avoid trauma to the tympanic membrane until its integrity can be assessed. Initial flushes should be done with physiologic saline solution or water until the integrity of the tympanic membrane is established.

Other solutions may aid in the removal of wax in the ear canal. Ceruminolytics are emulsifiers and surfactants that break down ceruminocellular aggregates by causing lysis of squamous cells. A ceruminolytic agent in an alkaline pH may more effectively lyse squamous cells via cell surface protein disruption. Oil-based products soften and loosen debris to aid in their removal but do not cause cell lysis. Water-based ceruminolytics are easier to remove and dry more quickly than oil-based solutions, which are occlusive if they remain in the ear canal. Water-based products include dioctyl sodium sulfosuccinate, calcium sulfosuccinate, and carbamate peroxide, which has a foaming action with the release of urea and oxygen. Oil-based products include squalene, triethanolamine polypeptide, hexamethyltetracosane, oleate condensate, propylene glycol, glycerin, and mineral oil. In a recent study only the combination of squalene and isopropyl myristate in a liquid petrolatum base had no adverse effects on hearing, the vestibular system, and histopathologic examination. Other agents tested contained glycerin, dioctyl sodium sulfosuccinate (2% or 6.5%), parachlorometaxylenol, carbamide peroxide (6%), propylene glycol, triethanolamine polypeptide oleate condensate (10%), and chlorobutanol (0.5%).

Alcohol-based drying agents added to ceruminolytics include boric acid, benzoic acid, and salicylic acid, which decrease the pH of the ear canal, cause keratolysis, and have a mild antimicrobial effect. Drying the ear canal is important to combat increased humidity, which potentiates infection.

If the tympanum is intact, the ear canal is filled with a ceruminolytic agent for at least 2 minutes and the pinna is cleaned at the same time. The solution is flushed twice with warm water, and the canal inspected. The procedure is repeated until cleaning is complete. Other solutions commonly advocated for ear flushing include dilute chlorhexidine solution (0.05%), dilute povidone-iodine, and acetic acid (2.5%). The first two agents are potentially ototoxic or induce inflammation and should not be used if the tympanum is ruptured. A combination of propylene glycol malic, benzoic, or salicylic acid; 2% acetic acid; or dilute povidone-iodine have been suggested for use in dogs with a ruptured tympanum.

Owners may clean the ears at home with mild preparations of ceruminolytics and drying agents if mild otitis is present without severe accumulation of cerumen or exudate. Aqueous solutions are usually recommended because they are less occlusive and easier to clean from the ear, dog, and home environment.

The ear should be filled with the solution, then massaged for 40 to 60 seconds. The pet should be allowed to shake its head to remove the majority of the solution, and the excess should be wiped from the ear canal and pinna with a tissue. Daily flushing is usually recommended, followed by every other day, weekly, then as needed, depending on the solution. Ear swabs are not recommended for home use, because cerumen and debris may be forced into the horizontal ear canal and impact against the tympanic membrane

Topical Therapy

Erythematous ceruminous otitis externa is diagnosed 2.7 times more often than acute suppurative otitis according to one report. Yeast ± cocci were identified in those cases, with cocci or rods identified in suppurative otitis. Topical therapy should be based on the cytologic examination to diminish the incidence of inappropriate treatment (Table Topical Medications Used in the Treatment of Ear Disease). Many preparations combine anti-inflammatories and antimicrobials in an attempt to decrease the inflammation and combat bacterial or yeast overgrowth. All topical medications should be considered supportive, and specific treatment should be aimed at controlling the primary disease process.

Topical Medications Used in the Treatment of Ear Disease

Generic Name Trade Name Dose Frequency Description
Fluocinolone 0.01% DMSO 60% Synotic 4-6 drops; total dose<17mL q12h initially. q48-72h maintenance Potent corticosteroid anti-inflammatory
Hydrocortisone 1.0% HB101,

Burrows H,

2-12 drops, depending on ear size q12h initially. q24-48h maintenance Mild corticosteroid anti-inflammatory
Hydrocortisone 1.0%, lactic acid Epiotic HC 5-10 drops q12h for 5 days Mild corticosteroid anti-inflammatory, drying agent
Hydrocortisone 0.5%, sulfur 2%. acetic acid 2.5% Clear X Ear Treatment 2-12 drops, depending on ear size q12-24h initially. q24-48h maintenance Mild corticosteroid anti-inflammatory, astringent, germicidal
DSS 6.5%. urea (carbamide peroxide 6%) Clear X Ear Cleansing Solution 1-2 mL per ear Once per week to as necessary Ceruminolytic, lubricating agent
Chlorhexidine 2% Nolvasan Dilute 1:40 in water As necessary Antibacterial & antifungal activity
Chlorhexidine 1.5% Nolvasan Dilute 2% in

propylene glycol

q12h Antibacterial & antifungal activity
Povidone-iodine 10% Betadine solution Dilute 1:10-1:50 in water As necessary Antibacterial activity
Polyhydroxidine iodine 0.5% Xenodyne Dilute 1:1-1:5 in water As necessary, q12h, once weekly Antibacterial activity
Acetic acid 5% White vinegar Dilute 1:1-1:3 in water As necessary; q12-24h for Pseudomonas Antibacterial activity, lowers ear canal pH
Neomycin 0.25%, triamcinolone 0.1%, thiabendazole 4% Tresaderm 2-12 drops depending on ear size q12h up to 7 days Antibacterial & antifungal activity, parasiticide (mites), moderate corticosteroid anti-inflammatory
Neomycin 0.25%, triamcinolone 0.1%, nystatin 100,000 U/mL Panalog 2-12 drops depending on ear size q12h to once weekly Antibacterial & antifungal activity, moderate corticosteroid anti-inflammatory
Chloramphenicol 0.42%. prednisone 0.17%, tetracaine 2%, squalene Liquachlor, Chlora-Otic 2-12 drops depending on ear size q12h up to 7 days Antibacterial activity, mild corticosteroid anti-inflammatory
Neomycin 1.75 & polymyxin B 5000 lU/mL, penicillin C procaine 10,000 lU/mL Forte Topical 2-12 drops depending on ear size q12h Antibacterial activity
Centamicin 0.3%, betamethasone valerate 0.1% Centocin Otic Solution, Betagen Otic Solution 2-12 drops depending on ear size q12h for 7 to 14 days Antibacterial activity, potent corticosteroid anti-inflammatory
Centamicin 0.3%, betamethasone 0.1%, clotrimazole 0.1% Otomax, Obibiotic Ointment 2-12 drops depending on ear size q12h for 7 days Antibacterial & antifungal activity, potent corticosteroid anti-inflammatory
Centamicin 0.3%, betamethasone valerate 0.1%, acetic acid 2.5% Centaved Otic Solution 2-12 drops, depending on ear size q12h for 7 to 14 days Antibacterial activity, potent corticosteroid anti-inflammatory
Polymixin B 10,000 lU/mL, hydrocortisone 0.5% Otobiotic 2-12 drops, depending on ear size q12h Antibacterial activity, mild corticosteroid anti-inflammatory
Enrofloxacin 0.5%, silver sulfadiazine 1% Baytril Otic 2-12 drops, depending on ear size q12h for up to 14 days Antibacterial activity
Carbaryl 0.5%, neomycin 0.5%, tetracaine Mitox Liquid 2-12 drops, depending on ear size   Antibacterial activity, parasiticide (mites)
Pyrethrins 0.06%, piperonyl butoxide 0.6% Ear Mite and Tick Control 5 drops q12h Parasiticide (mites)
Pyrethrins 0.05%, squalene 25% Cerumite 2-12 drops, depending on ear size q24h for 7 to 10 days Parasiticide (mites), ceruminolytic
Isopropyl alcohol 90%, boric acid 2% Panodry Fill ear canal As necessary Drying agent
Acetic acid 2%, aluminum acetate Otic Domeboro Fill ear canal q12-48h Drying agent, antibacterial activity, lowers ear canal pH
Silver sulfadiazine Silvadene Dilute 1:1 with water, 1 g powder in 100 mL water q12h for 14 days Antibacterial & antifungal activity
Tris EDTA±

gentamicin 0.03%

  2-12 drops, depending on ear size q12h for 14 days 1 L distilled water, 1.2g Tris EDTA, 1 mL glacial acetic acid; antibacterial activity
Silver nitrate   Use sparingly As necessary Cauterization of

ulcerative otitis externa

Miconazole 1%; ± topical glucocorticoid (7.5 mL of dexamethasone phosphate (4 mg/mL] to10mLof1% miconazole) Conofite 2-12 drops, depending on ear size q12-24h Antifungal activity
Ivermectin 0.01% Acarexx 0.5 mL per ear Once Parasiticide (mites)
Pyrethrins 0.15%, piperonyl butoxide 1.5% Many 2-12 drops, depending on ear size Twice at 7-day interval Parasiticide (mites)
Pyrethrins 0.05%, piperonyl butoxide 0.5%, squalene 25% Cerumite 2-12 drops, depending on ear size q24h for 7 days Parasiticide (mites), ceruminolytic
Pyrethrins 0.04%, piperonyl butoxide 0.49%, DSS 1.952%, benzocaine 1.952% Aurimite 10 drops q12h  
Rotenone 0.12%, cube resins 0.16% Many 2-12 drops, depending on ear size Every other day Parasiticide (mites)

Topical glucocorticoids benefit most cases of otitis externa by decreasing pruritus, exudation, swelling, and proliferative changes of the ear canal. The most potent glucocorticoids available in topical preparations are betamethasone valerate and fluocinolone acetonide. Less potent corticosteroids include triamcinolone acetonide and dexamethasone; the least potent is hydrocortisone. Most dogs benefit from short-term therapy with topical corticosteroids at the initiation of therapy, with concurrent therapy aimed at the primary and other perpetuating factors. Long-term therapy with topical corticosteroids can be deleterious because of systemic absorption of drug. Increased serum liver enzymes and depressed adrenal responsiveness may occur; with prolonged use iatrogenic hyperadreno-corticism is possible. Glucocorticoids alone may be of benefit for short-term therapy in cases of allergic or erythematous ceruminous otitis.

Antimicrobials are important for controlling secondary bacterial or yeast overgrowth or infection. Antimicrobials are indicated in any case with cytologic evidence of bacterial overgrowth or infection, with attention paid to the morphology and gram-staining characteristics of the bacteria. Otic preparations commonly contain aminoglycoside antibiotics. Neomycin is effective against typical otitis bacteria such as Staphylococcus intermedium. Gentamicin and polymyxin B are also appropriate initial topical treatments for gram-negative bacterial otitis externa.The significant risk of bone marrow toxicity in people limits the use of chloramphenicol for treating otitis in dogs and cats despite its antibacterial spectrum and availability.

Due to the frequency of resistant gram-negative bacteria such as Pseudomonas, other topical preparations have been developed. Enrofloxacin, ophthalmic tobramycin, and topical application of injectable ticarcillin have been used to treat otitis in dogs.< Their use should be limited to cases of resistant bacteria, and culture and susceptibility testing should be performed prior to application. Other topical agents may be used to supplement treatment of resistant Pseudomonas, such as silver sulfadiazine solution and tris EDTA. Tris EDTA can render Pseudomonas susceptible to enrofloxacin or cephalosporins by enhancing membrane permeability and altering ribosome stability. Frequent ear cleaning may also assist in the treatment of resistant bacterial otitis; ceruminolytics have antimicrobial properties, and their use in clinical cases has been evaluated. Acetic acid in combination with boric acid is effective against both Pseudomonas and Staphylococcus, depending on concentration and duration of exposure. Ear cleaning removes proinflammatory products, cells, and substances that diminish the effectiveness of topical antibiotics.

Many topical preparations control yeast organisms, which may complicate erythematous ceruminous otitis and suppurative otitis. Common active ingredients include miconazole, clotrimazole, nystatin, and thiabendazole. Preparations containing climbazole, econazole, and ketoconazole have also been evaluated. Eighty percent of yeast were susceptible to miconazole and econazole, intermediately resistant to ketoconazole, and 90% were resistant to nystatin and amphotericin B in one in vitro study. Topical ear cleaning agents have some efficacy against Malassezia organisms. Other preparations (e.g. chlorhexidine, povidone-iodine, acetic acid) are also effective in the treatment of secondary yeast overgrowth.

Response to topical therapy should be gauged by re-evaluation of physical, cytologic, and otoscopic examinations every 10 to 14 days after the initiation of therapy. Any changes in the results of these examinations should be recorded. Most cases of otitis can be managed topically; failure to respond to therapy should prompt re-evaluation of the diagnosis and treatment.

Systemic Therapy

Systemic glucocorticoid administration may be beneficial in cases of severe, acute inflammation of the ear canal, chronic proliferative changes of the ear canal, and allergic otitis. Anti-inflammatory doses should be limited to 7 to 10 days. Cases of significant thickening or proliferative changes in the external ear canal benefit from systemic antimicrobial therapy. Systemic therapy should be considered if concurrent dermatologic changes of the surrounding skin, pinna, or other regions of the body are present. Long-term administration of appropriate antimicrobials based on culture and susceptibility is required in all cases of otitis media. Systemic therapy for yeast is rarely recommended in animals with otitis alone. One study evaluated oral itraconazole therapy, and in ear samples evaluated on cytology and culture, no change in cytology score was found.

 

Categories
Diseases

Therapy For Specific Diseases Of The External Ear Canal

Ectoparasites

Thorough cleaning of the external ear canal, treatment of all household pets, and whole-body therapy should be considered in the treatment regimen for ear mites. Pets with no clinical signs may be asymptomatic carriers and a reservoir for reinfestation. Otic parasiticides such as pyrethrins, rotenone, amitraz, and carbaryl must be administered every 24 hours throughout the 20-day mite life cycle because they do not kill mite eggs. Thiabendazole eliminates all mite stages, but it must be applied every 12 hours for 14 days. Ivermectin (0.3 to 0.5 mg/kg) may be applied topically once weekly for 5 weeks. Otic administration of medication does not affect mites on adjacent or distant skin locations, and systemic or other total-body parasiticide may be indicated. Alternatively, ivermectin administered subcutaneously (0.2 to 0.3 mg/kg) 2 to 3 times at 10- to 14-day intervals or orally (0.3 mg/kg) every week for four treatments eliminates otic mites and those found elsewhere on the body. Other topicals proven safe and effective for ear mite treatment include selamectin (6 mg/kg) applied to the skin between the shoulder blades and fipronil spray. Selamectin administered once in cats and two times, 30 days apart in dogs gave results similar to topical pyrethrin therapy.

Idiopathic Inflammatory or Hyperplastic Otitis in Cocker Spaniels

Treatment is aimed at decreasing the secondary ear canal changes associated with this condition. Anti-inflammatory doses of corticosteroids administered orally may be useful. Topical corticosteroid preparations in combination with antimicrobials decrease the soft tissue mass affecting the ear canal but may not be as effective as oral administration. Maintenance therapy may be required both topically and orally; however, low doses of corticosteroids should be used. Re-evaluation should include attention to the potential side effects of corticosteroid therapy. Intermittent treatment of secondary bacterial or yeast overgrowth and infection may be required. Surgery is often indicated due to the severe secondary changes within the ear canal.

Excessive Moisture (Swimmer’s Ear)

Other primary disease conditions such as allergic otitis should be ruled out in any dog with erythematous ceruminous otitis. Dogs with frequent exposure to water, however, may require ear cleaning and drying agents to diminish the humidity of the ear canal. Many cleaning and drying agents also posses antimicrobial effects. Products that combine a drying agent and corticosteroid decrease the ear canal humidity and inflammation associated with allergic otitis complicated by swimming. Care should be taken to control primary disease (i.e. allergic otitis), however, and intermittendy manage the predisposing factor (i.e. excessive moisture) as necessary. The dog’s ears should be cleaned and dried the day of water exposure and for 2 to 5 days after. For continued frequent exposure, maintenance cleaning may be required every other day to twice weekly.

Chronic Bacterial Otitis

Resistant bacteria play an important role in the development of chronic otitis externa. Any dog not responding to initial therapy should be re-evaluated for primary and perpetuating conditions such as allergic disease, foreign body, neoplasia, otitis media, and secondary anatomic changes of the ear canal. Primary disease processes identified in one study included hypothyroidism, atopy, food allergy, and immune-mediated disease. Infection with Pseudomonas species frequently occurs with repeated treatment of otitis extema, and acquired resistance is common. Culture and susceptibility testing is imperative to guide therapy. Oral antimicrobials combined with topical therapy are used in severe cases with secondary changes of the ear canal. Identification of otitis media is vital to remove the middle ear as a source of otitis extema. Otitis media requires long-term treatment.

Ear cleaning prior to the application of topical medication may increase the efficacy of the agent by decreasing exudate in the ear canal that inactivates antimicrobial drugs such as polymyxin. In cases that fail to respond to first-line drug treatments such as polymyxin or gentamicin, other topical antimicrobial agents should be tried. Ophthalmic tobramycin and injectable amikacin have been described for use as topical antimicrobials in ear disease. The integrity of the tympanic membrane should be known prior to use; the clinician should avoid these medications if the tympanic membrane cannot be proven intact. Enrofloxacin or ticarcillin injectable preparations diluted in saline or water may be applied topically for resistant Pseudomonas. Parenteral ticarcillin was used in cases with a ruptured tympanic membrane until healing was observed, at which time topical therapy was instituted; clinical response occurred in 11 of 12 cases. Enrofloxacin and silver sulfadiazine combination is also available in an otic preparation (Baytril Otic, Bayer Shawne Mission, KS).

Other topical therapy may assist in eliminating resistant Pseudomonas from the ear canal.

Decreasing the pH of the ear canal with 2% acetic acid is lethal to Pseudomonas; diluted vinegar in water (1:1 to 1:3) may be used to flush the ear canal. Acetic acid combined with boric acid is lethal to Pseudomonas and Staphylococcus, depending on the concentration of each agent. Increasing the concentration of acetic acid may broaden its spectrum of activity but causes irritation of the external and middle ear. Silver sulfadiazine in a 1% solution exceeds the minimum inhibitory concentration of Pseudomonas and may be instilled into the ear canal. One gram of silver sulfadiazine powder mixed in 100 mL of water may be used for topical therapy and is also effective against Proteus species, enterococci, and Staphylococcus intermedium. Dilute acetic acid (2%) and silver sulfadiazine (1%) have not caused adverse effects in cases with a ruptured tympanic membrane.I Tris EDTA may be applied after thorough ear cleaning to increase the susceptibility of Pseudomonas to antimicrobial agents. It must be mixed, pH adjusted, and autoclaved prior to use or is available in an otic preparation (TrizEDTA, DermaPet ®, Potomac, MD), which is used to clean the ears prior to instillation of topical antibiotic. Topical antiseptics such as chlorhexidine and povidone-iodine solutions may be helpful, but ototoxicity is an issue, particularly in cases in which the tympanum is ruptured or cannot be evaluated.

Re-evaluation of the pet is important for monitoring response to therapy. Evaluation of the ear canal for progressive secondary changes and cytologic examination will allow alterations in therapy as needed. Significant narrowing of the ear canal is an indication for surgical intervention. Yeast overgrowth may occur with aggressive medical management of bacterial otitis and should be identified to maintain proper medical management.

Refractory or Recurrent Yeast Infection

Malassezia infection is a common perpetuating factor with erythematous ceruminous otitis and alterations in the otic microenvironment. Primary causes of the otitis should be identified and treated. Cytologic examination, not culture, should be relied upon for the diagnosis of yeast infection. If a case becomes refractory to therapy, reassessment of the primary condition and perpetuating factors should be done. Miconazole, clotrimazole, cuprimyxin, nystatin, and amphotericin B have all been described for treating Malassezia otitis. Climbazole had better in vitro activity against isolates of Malassezia pachydermatis in one study. Yeast were more susceptible to azole antifungals than polyene antifungals; however, oral ketoconazole, itraconazole, or fluconazole have been recommended for refractory cases. Long-term therapy may require topical antibacterial and antifungal combinations.

Ear cleaning may aid in the elimination of yeast organisms by removing cerumen, debris, or exudate and altering the microenvironment of the ear canal. Cleaning with antimicrobial agents such as chlorhexidine, povidone-iodine, and acetic acid may be beneficial; but as always the integrity of the tympanum should be established prior to use. Ear cleaning solutions may also have some efficacy against yeast organisms both in vitro and in clinical cases of otitis.

Neoplasia

Chronic otitis externa may be the result of otic neoplasia, or otitis may be a predisposing factor in the development of neoplasia. Cocker spaniels are over-represented for benign and malignant neoplasia and otitis extema. Tumors of the skin and adenexal structures of the ear predominate. Benign tumors in dogs include sebaceous gland adenoma, basal cell tumor, polyp, ceruminous gland adenoma, and papilloma. Cats are more frequendy diagnosed with malignant neoplasms, but benign conditions include inflammatory polyps, ceruminous gland adenomas, ceruminous gland cysts, and basal cell tumors. Malignant neoplasms in both species include ceruminous gland adenocarcinoma, undifferentiated carcinoma, and squamous cell carcinoma. Ceruminous gland adenocarcinomas are the most frequendy diagnosed tumors of the ear canal in dogs and cats; however, one report stated that squamous cell carcinoma occurs with equal incidence in the cat.

The biologic behavior of otic tumors cannot be judged by their gross appearance; however, benign masses are usually nodular and pedunculated. Ulceration can be secondary to otitis associated with mass lesions, but malignant masses ulcerate more frequendy than benign masses. The tympanic bulla is involved in up to 25% of aural neoplasms, and neurologic signs occur in 10% of dogs and 25% of cats with otic neoplasia. The biologic behavior of malignant neoplasms tends to be local invasion with a low metastatic rate (e.g. 10% in dogs) to draining lymph nodes or lung.

Surgery is the mainstay treatment of otic neoplasia. Conservative excision may be possible for benign lesions, depending on the location of the tumor. Malignancies should be removed by total ear canal ablation and lateral bulla osteotomy. Incomplete excision results in recurrence of the mass and secondary otitis externa. Malignant neoplasia is associated with a median survival time (MST) of more than 58 months in dogs and 11.7 months in cats. Extensive tumor involvement and lack of aggressive management are associated with a poor prognosis in dogs. In cats a poor prognosis is associated with neurologic signs, squamous cell carcinoma or undifferentiated carcinoma, vascular or lymphatic invasion, and lack of aggressive therapy. Ceruminous gland adenocarcinoma has a median disease free interval of more than 36 months and 42 months in dogs and cats, respectively. The MST associated with squamous cell carcinoma and undifferentiated carcinoma in cats is 4 to 6 months.

Categories
Diseases

Otitis Media

Otitis media may result from extension of otitis extema through the tympanic membrane, aspiration of pharyngeal contents up the auditory tube (e.g. a sequela to upper respiratory tract (URT] infection in cats), or from hematogenous spread. Extension from otitis externa is the most common cause of otitis media, but otitis media may serve as a perpetuating factor for otitis extema. Developmental abnormalities of the external ear canal and pharynx may also result in otitis media due to the accumulation of secretions in the middle ear. Neoplasia, inflammatory polyps, and middle ear trauma may be associated with secondary otitis media or result in similar clinical signs.

Cholesteatoma is commonly associated with otitis media and chronic otitis extema. A cholesteatoma is a mass of keratinized squamous cells that accumulate within a structure lined with stratified squamous epithelium. The lesion is presumed to develop when a pocket of tympanic membrane becomes adhered to inflamed middle ear mucosa. Significant narrowing of the external ear canal is usually present. Radiographic signs of increased density and bony changes of the tympanic bulla predominate with loss of the air-filled lumen of the external ear canal and concurrent calcification. Treatment is usually limited to total ear canal ablation and lateral bulla osteotomy due to the changes of the external ear canal and mass or accumulation of debris in the tympanic bulla.

The clinical signs associated with middle ear disease often reflect concurrent otitis extema (e.g. head shaking, lethargy, exudate, otic malodor). Significant otic pain, lethargy, inappetence, and pain upon opening the mouth are more suggestive of middle ear involvement. Neurologic signs may be present due to the course of the facial nerve and sympathetic innervation of the eye. Facial nerve paresis or paralysis result in facial asymmetry (i.e. uneven position of the lip commissures, unequal ear carriage, unilateral ptyalism) and abnormal cranial nerve reflexes on neurologic examination (e.g. menace response, palpebral and corneal reflexes, abnormal ear canal, and concave pinnal sensation). Homer’s syndrome, or loss of sympathetic innervation to the eye, can also be complete or partial (i.e. ptosis, miosis, enophthalmia, prolapse of the third eyelid). Otitis interna is usually evidenced by head tilt, abnormal nystagmus, and ataxia and should be differentiated from central vestibular disease based on careful neurologic examination. Otitis interna is not usually associated with ipsilateral hemiparesis or abnormalities in level of consciousness.

Cases of paraaural abscessation usually have concurrent otitis media. The primary cause may be trauma to the external ear canal, severe otitis externa, extension of otic neoplasia, or total ear canal ablation. Signs of middle or external ear disease and soft tissue swelling in the parotid area may be accompanied by draining tracts. A head tilt and pain upon palpation of the area are usually present.

The diagnosis of otitis media is based on a thorough history and physical, neurologic, and otoscopic examinations. A ruptured tympanum strongly suggests otitis media. The pharynx should also be evaluated on physical examination; identification of specific conditions may require general anesthesia due to anatomic location (eg. inflammatory polyps) or pain associated with examination (e.g. otitis media causing temporomandibular joint (TMJ) pain, severe otitis externa). General anesthesia may also be required to perform a complete otoscopic examination in cases of severe otitis externa in which thorough cleaning of the ear is necessary for therapy and diagnosis (i.e. visualization of the tympanum). Significant otitis externa is commonly associated with otitis media; the tympanic membrane is ruptured in up to 50% of dogs with otitis externa, although 70% of dogs with otitis media had an intact tympanic membrane in one study. The tympanic membrane in dogs with otitis extema may be difficult to examine due to secondary changes of the external ear canal, pain associated with otoscopic examination, and accumulation of exudate, cerumen, and debris. Treatment to diminish the severity of otitis externa and general anesthesia may increase the ability to evaluate the tympanum in these cases.

Any case that has significant cerumen, exudate, or debris should undergo careful cleaning of the ear canal to allow evaluation of the integrity and character of the tympanic membrane The presence of a “false middle ear” occurs when large accumulations of debris lodge against the tympanic membrane, causing it to deviate medially into the middle ear. This makes the external ear canal appear elongated and leads to misdiagnosis of a ruptured tympanic membrane.

Gende probing of the tympanic membrane with a red rubber catheter under direct visualization may assist in the diagnosis of small tears in the membrane. If the catheter tip is consistently visible, rupture is unlikely. Alternatively, an aliquot of 1 mL of physiologic saline placed in the horizontal canal should remain stationary; disappearance suggests an opening in the tympanum, allowing the fluid to drain into the middle ear. Movement of the fluid may be blocked by large amounts of debris in the middle ear, even in the presence of a tear in the tympanum.

If the tympanic membrane is visible, its character should be recorded in the medical record for comparison upon re-evaluation. Bulging, increased opacity, and hyperemia may be present with otitis media. If otitis media is suspected, radiographs of the bullae may be made. Lateral oblique and open-mouth views are most helpful for evaluating the tympanic bulla, but positioning for comparison of left and right sides is difficult and requires general anesthesia. Ventrodorsal or dorsoventral views allow evaluation of the air-filled lumen and calcification of the external ear canal. Abnormalities of the bulla include increased opacity, sclerosis, and lysis. Fluid cannot be differentiated from increased soft tissue density (e.g. neoplasia), and absence of radiographic changes does not rule out otitis media. Radiographic changes were absent in 33% of the middle ears in one study of dogs with otitis media confirmed by surgical exploration. Otitis media or neoplasia and otitis interna can cause radiographic evidence of lysis of the petrosal bone.

Other diagnostic tools are available to evaluate patients with otitis media interna. Contrast introduced into the external ear canal followed by radiography, termed canalography, is used to diagnose tympanic membrane perforations. The method is useful for acute tympanic membrane rupture and increases the frequency of diagnosing tympanic membrane rupture with concurrent otitis externa and media beyond that of otoscope alone Advanced imaging with CT and MRI have been studied in normal dogs and dogs with otitis media. CT is considered superior to MRI for bony changes, whereas MRI is better for detection of soft tissue abnormalities in both dogs and cats.

If the tympanic membrane is intact in a dog with otitis media, a myringotomy is performed to obtain samples for culture and susceptibility testing and cytologic examination. Affected dogs are often more comfortable after collection of samples due to decreased pressure in the middle ear after myringotomy. The procedure must be performed with general anesthesia and is usually done after radiography or advanced imaging of the ear. The external ear canal should be thoroughly cleaned and dried prior to myringotomy to avoid contamination with external ear canal debris. Direct otoscopic visualization is used for the procedure. A 20-gauge spinal needle is used to penetrate the tympanic membrane through the caudoventral aspect of the pars tensa. Suction is applied and samples collected — culture and susceptibility takes priority over cytologic examination because cytology is frequently negative, and cultures of the external ear canal do not reflect the middle ear bacteria in the majority of cases. If fluid cannot be aspirated direcdy from the middle ear, 0.5 to 1 mL of warm, sterile saline can be infused through the needle into the middle ear cavity and aspirated. Alternatively, an open-ended tomcat catheter or small, sterile culture swab may be passed into the middle ear cautiously under otoscopic visualization. Pseudomonas species and Staphylococcus intermedium are most commonly isolated, followed by yeast, β-hemolytic Streptococcus, Corynebacterium species, Proteus species, and Enterococcus species. Surgical exploration is rarely required for the diagnosis of otitis media.

Medical therapy of otitis media should be guided by culture and susceptibility results. The external ear canal is flushed and dried as necessary to treat concurrent otitis extema. Flushing is usually performed under the same general anesthetic episode used for diagnostic testing. If the tympanic membrane is ruptured, the middle ear should be gendy lavaged with warm saline. Cytology results, when available, should be used to guide initial therapy. The integrity of the tympanic membrane must be considered when using topical agents to treat concurrent otitis extema: ototoxic medications and vehicles should be avoided if the tympanic membrane is ruptured.

Newly diagnosed cases of otitis media may be started on empiric therapy based on cytology. First-choice antimicrobials include cephalosporins, amoxicillin and clavulonic acid, and fluoroquinolones. Definitive therapy consists of administration of antibiotics based on culture and susceptibility results for a minimum of 4 to 6 weeks. Primary and perpetuating factors of otitis externa should be identified and treated or controlled. Topical medication and flushing of the external ear canal should continue until resolution of clinical signs and normalization of cytology. Gradual improvement of the otitis media is expected within 14 days. The ear canal and tympanic membrane should be evaluated prior to and after discontinuation of therapy. Small tears in the tympanic membrane after myringotomy heal rapidly with appropriate therapy within 2 to 3 weeks.Hs However, re-evaluation of the tympanic membrane in dogs with otitis externa media should precede alteration of the topical agents in the therapeutic plan.

Failure to respond to therapy or chronic or recurrent otitis media warrant re-evaluation for surgical intervention. Total ear canal ablation and lateral bulla osteotomy should be considered in cases with severe secondary changes of the external ear canal and concurrent otitis media. If the external ear canal is not affected, a ventral bulla osteotomy may be performed to remove gross exudate and establish drainage from the middle ear of dogs and cats with chronic or recurrent otitis media. Caution should be taken in considering lateral ear resection and ventral bulla osteotomy in the treatment of concurrent otitis externa and media because lateral ear resection is only an adjunct to medical management of otitis externa.

Categories
Drugs

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based (Abelcet, Fungizone)

Antifungal

Highlights Of Prescribing Information

Systemic antifungal used for serious mycotic infections

Must be administered IV

Nephrotoxicity is biggest concern, particularly with the deoxycholate form; newer lipid based products are less nephrotoxic & penetrate into tissues better, but are more expensive

Renal function monitoring essential

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based interactions

What Is Amphotericin B Desoxycholate, Amphotericin B Lipid-Based Used For?

Because the potential exists for severe toxicity associated with this drug, it should only be used for progressive, potentially fatal fungal infections. Veterinary use of amphotericin has been primarily in dogs, but other species have been treated successfully. For further information on fungal diseases treated, see the Pharmacology and Dosage sections.

The liposomal form of amphotericin B can be used to treat Leishmaniasis.

Pharmacology / Actions

Amphotericin B is usually fungistatic, but can be fungicidal against some organisms depending on drug concentration. It acts by binding to sterols (primarily ergosterol) in the cell membrane and alters the permeability of the membrane allowing intracellular potassium and other cellular constituents to “leak out.” Because bacteria and rickettsia do not contain sterols, amphotericin B has no activity against those organisms. Mammalian cell membranes do contain sterols (primarily cholesterol) and the drug’s toxicity may be a result of a similar mechanism of action, although amphotericin binds less strongly to cholesterol than ergosterol.

Amphotericin B has in vitro activity against a variety of fungal organisms, including Blastomyces, Aspergillus, Paracoccidioides, Coccidioides, Histoplasma, Cryptococcus, Mucor, and Sporothrix. Zygomycetes is reportedly variable in its response to amphotericin. Aspergillosis in dogs and cats does not tend to respond satisfactorily to amphotericin therapy. Additionally, amphotericin B has in vivo activity against some protozoa species, including Leishmania spp. and Naegleria spp.

It has been reported that amphotericin B has immunoadjuvant properties but further work is necessary to confirm the clinical significance of this effect.

Pharmacokinetics

Pharmacokinetic data on veterinary species is apparently unavailable. In humans (and presumably animals), amphotericin B is poorly absorbed from the GI tract and must be given parenterally to achieve sufficient concentrations to treat systemic fungal infections. After intravenous injection, the drug reportedly penetrates well into most tissues but does not penetrate well into the pancreas, muscle, bone, aqueous humor, or pleural, pericardial, synovial, and peritoneal fluids. The drug does enter the pleural cavity and joints when inflamed. CSF levels are approximately 3% of those found in the serum. Approximately 90-95% of amphotericin in the vascular compartment is bound to serum proteins. The newer “lipid” forms of amphotericin B have higher penetration into the lungs, liver and spleen than the conventional form.

The metabolic pathways of amphotericin are not known, but it exhibits biphasic elimination. An initial serum half-life of 24-48 hours, and a longer terminal half-life of about 15 days have been described. Seven weeks after therapy has stopped, amphotericin can still be detected in the urine. Approximately 2-5% of the drug is recovered in the urine in unchanged (biologically active) form.

Before you take Amphotericin B Desoxycholate, Amphotericin B Lipid-Based

Contraindications / Precautions / Warnings

Amphotericin is contraindicated in patients who are hypersensitive to it, unless the infection is life-threatening and no other alternative therapies are available.

Because of the serious nature of the diseases treated with systemic amphotericin, it is not contraindicated in patients with renal disease, but it should be used cautiously with adequate monitoring.

Adverse Effects

Amphotericin B is notorious for its nephrotoxic effects; most canine patients will show some degree of renal toxicity after receiving the drug. The proposed mechanism of nephrotoxicity is via renal vasoconstriction with a subsequent reduction in glomerular filtration rate. The drug may directly act as a toxin to renal epithelial cells. Renal damage may be more common, irreversible and severe in patients who receive higher individual doses or have preexisting renal disease. Usually, renal function will return to normal after treatment is halted, but may require several months to do so.

Newer forms of lipid-complexed and liposome-encapsulated amphotericin B significantly reduce the nephrotoxic qualities of the drug. Because higher dosages may be used, these forms may also have enhanced effectiveness. A study in dogs showed that amphotericin B lipid complex was 8-10 times less nephrotoxic than the conventional form.

The patient’s renal function should be aggressively monitored during therapy. A pre-treatment serum creatinine, BUN (serum urea nitrogen/SUN), serum electrolytes (including magnesium if possible), total plasma protein (TPP), packed cell volume (PCV), body weight, and urinalysis should be done prior to starting therapy. BUN, creatinine, PCV, TPP, and body weight are rechecked before each dose is administered. Electrolytes and urinalysis should be monitored at least weekly during the course of treatment. Several different recommendations regarding the stoppage of therapy when a certain BUN is reached have been made. Most clinicians recommend stopping, at least temporarily, amphotericin treatment if the BUN reaches 30-40 mg/dL, serum creatinine >3 mg/dL or if other clinical signs of systemic toxicity develop such as serious depression or vomiting.

At least two regimens have been used in the attempt to reduce nephrotoxicity in dogs treated with amphotericin desoxycholate. Mannitol (12.5 grams or 0.5-1 g/kg) given concurrently with amphotericin B (slow IV infusion) to dogs may reduce nephrotoxicity, but may also reduce the efficacy of the therapy, particularly in blasto-mycosis. Mannitol treatment also increases the total cost of therapy. Sodium loading prior to treating has garnered considerable support in recent years. A tubuloglomerular feedback mechanism that induces vasoconstriction and decreased GFR has been postulated for amphotericin B toxicity; increased sodium load at the glomerulus may help prevent that feedback. One clinician (Foil 1986), uses 5 mL/kg of normal saline given in two portions, before and after amphotericin B dosing and states that is has been “… helpful in averting renal insufficiency….”

Cats are apparently more sensitive to the nephrotoxic aspects of amphotericin B, and many clinicians recommend using reduced dosages in this species (see Dosage section).

Adverse effects reported in horses include: tachycardia, tachyp-nea, lethargy, fever, restlessness, anorexia, anemia, phlebitis, polyuria and collapse.

Other adverse effects that have been reported with amphotericin B include: anorexia, vomiting, hypokalemia, distal renal tubular aci-dosis, hypomagnesemia, phlebitis, cardiac arrhythmias, non-regenerative anemia and fever (may be reduced with pretreatment with NSAIDs or a low dosage of steroids). Calcinosis cutis has been reported in dogs treated with amphotericin B. Amphotericin B can increase creatine kinase levels.

Reproductive / Nursing Safety

The safety of amphotericin B during pregnancy has not been established, but there are apparently no reports of teratogenicity associated with the drug. The risks of therapy should be weighed against the potential benefits. In humans, the FDA categorizes this drug as category B for use during pregnancy (Animal studies have not yet demonstrated risk to the fetus, hut there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, hut adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters.) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: A (Prohahly safe. Although specific studies may not have proved the safety of all drugs in dogs and cats, there are no reports of adverse effects in laboratory animals or women.)

Overdosage / Acute Toxicity

No case reports were located regarding acute intravenous overdose of amphotericin B. Because of the toxicity of the drug, dosage calculations and solution preparation procedures should be double-checked. If an accidental overdose is administered, renal toxicity maybe minimized by administering fluids and mannitol as outlined above in the Adverse Effects section.

How to use Amphotericin B Desoxycholate, Amphotericin B Lipid-Based

All dosages are for amphotericin B desoxycholate (regular amphotericin B) unless specifically noted for the lipid-based products.

Note: Some clinicians have recommended administering a 1 mg test dose (less in small dogs or cats) IV over anywhere from 20 minutes to 4 hours and monitoring pulse, respiration rates, temperature, and if possible, blood pressure. If a febrile reaction occurs some clinicians recommend adding a glucocorticoid to the IV infusion solution or using an antipyretic prior to treating, but these practices are controversial.

A published study () demonstrated less renal impairment and systemic adverse effects in dogs who received amphotericin BIV slowly over 5 hours in 1 L of D5W than in dogs who received the drug IV in 25 mL of D5W over 3 minutes.

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for dogs:

For treatment of susceptible systemic fungal infections:

a) Two regimens can be used; after diluting vial (as outlined below in preparation of solution section), either:

1) Rapid-Infusion Technique: Dilute quantity of stock solution to equal 0.25 mg/kg in 30 mL of 5% dextrose. Using butterfly catheter, flush with 10 mL of D5W. Infuse amphotericin B solution IV over 5 minutes. Flush catheter with 10 mL of D5W and remove catheter. Repeat above steps using 0.5 mg/kg 3 times a week until 9-12 mg/kg accumulated dosage is given.

2) Slow IV Infusion Technique: Dilute quantity of stock solution to equal 0.25 mg/kg in 250-500 mL of D5W. Place indwelling catheter in peripheral vein and give total volume over 4-6 hours. Flush catheter with 10 mL of D5W and remove catheter. Repeat above steps using 0.5 mg/kg 3 times a week until 9-12 mg/kg accumulated dosage is given. ()

b) In dehydrated, sodium-depleted animals, must rehydrate before administration. Dosage is 0.5 mg/kg diluted in D5W. In dogs with normal renal function, may dilute in 60-120 mL of D5W and give by slow IV over 15 minutes. In dogs with compromised renal function, dilute in 500 mL or 1 liter of D5W and give over slowly IV over 3-6 hours. Re-administer every other day if BUN remains below 50 mg/dl. If BUN exceeds 50 mg/dl, discontinue until BUN decreases to at least 35 mg/dl. Cumulative dose of 8 -10 mg/kg is required to cure blastomycosis or histoplasmosis. Coccidioidomycosis, aspergillosis and other fungal diseases require a greater cumulative dosage. ()

c) For treating systemic mycoses using the lipid-based products: AmBisome, Amphocil or Abelcet Give test dose of 0.5 mg/ kg; then 1-2.5 mg/kg IV q48h (or Monday, Wednesday, Friday) for 4 weeks or until the total cumulative dose is reached. Use 1 mg/kg dose for susceptible yeast and dimorphic fungi until a cumulative dose of 12 mg/kg is reached; for more resistant filamentous fungal infections (e.g., pythiosis) use the higher dose 2-2.5 mg/kg until a cumulative dose of 24-30 mg/kg is reached. ()

d) For treating systemic mycoses using the amphotericin B lipid complex (ABLC; Abelcet) product: 2-3 mg/kg IV three days per week for a total of 9-12 treatments (cumulative dose of 24-27 mg). Dilute to a concentration of 1 mg/mL in dextrose 5% (D5W) and infuse over 1-2 hours ()

e) For systemic mycoses using amphotericin B lipid complex (Abelcet): Dilute in 5% dextrose to a final concentration of 1 mg/mL and administer at a dosage of 2-3 mg/kg three times per week for 9-12 treatments or a cumulative dosage of 24-27 mg/kg ()

For blastomycosis (see general dosage guidelines above):

a) Amphotericin B 0.5 mg/kg 3 times weekly until a total dose of 6 mg/kg is given, with ketoconazole at 10-20 mg/kg (30 mg/kg for CNS, bone or eye involvement) divided for 3-6 months ()

b) Amphotericin B 0.15-0.5 mg/kg IV 3 times a week with ketoconazole 20 mg/day PO once daily or divided twice daily; 40 mg/kg divided twice daily for ocular or CNS involvement (for at least 2-3 months or until remission then start maintenance). When a total dose of amphotericin B reaches 4-6 mg/kg start maintenance dosage of amphotericin B at 0.15-0.25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or ketoconazole at 2.5-5 mg/kg PO once daily. If CNS/ocular involvement use ketoconazole at 20-40 mg/kg PO divided twice daily ()

c) For severe cases, using amphotericin B lipid complex (Abelcet): 1-2 mg/kg IV three times a week (or every other day) to a cumulative dose of 12-24 mg/kg ()

For cryptococcosis (see general dosage guidelines above):

a) Amphotericin B 0.5 – 0.8 mg/kg SC 2 – 3 times per week. Dose is diluted in 0.45% NaCl with 2.5% dextrose (400 mL for cats, 500 mL for dogs less than 20 kg and 1000 mL for dogs greater than 20 kg). Concentrations greater than 20 mg/L result in local irritation and sterile abscess formation. May combine with flucytosine or the azole antifungals. ()

For histoplasmosis (see general dosage guidelines above):

a) Amphotericin B 0.15 – 0.5 mg/kg IV 3 times a week with ketoconazole 10-20 mg/day PO once daily or divided twice daily (for at least 2-3 months or until remission then start maintenance). When a total dose of amphotericin B reaches 2-4 mg/kg, start maintenance dosage of amphotericin B at 0.15-0.25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or at 2.5-5 mg/kg PO once daily ()

b) As an alternative to ketoconazole treatment: 0.5 mg/kg IV given over 6-8 hours. If dose is tolerated, increase to 1 mg/ kg given on alternate days until total dose of 7.5-8.5 mg/kg cumulative dose is achieved ()

For Leishmaniasis:

a) Using the liposomal form of Amphotericin B: 3-3.3 mg/kg IV 3 times weekly for 3-5 treatments)

b) Using AmBisome (lipid-based product): Give initial test dose of 0.5 mg/kg, then 3-3.3 mg/kg IV every 72-96 hours until a cumulative dose of 15 mg/kg is reached. May be possible to give the same cumulative dose with a lower level every 48 hours. ()

For gastrointestinal pythiosis:

a) Resect lesions that are surgically removable to obtain 5 – 6 cm margins. Follow-up medical therapy using the amphotericin B lipid complex (ABLC; Abelcet) product: 1-2 mg/kg IV three times weekly for 4 weeks (cumulative dose 12-24 mg). May alternatively use itraconazole at 10 mg/kg PO once daily for 4-6 months. ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for cats:

For treatment of susceptible systemic fungal infections: a) Rapid-Infusion Technique: After diluting vial (as outlined below in preparation of solution section), dilute quantity of stock solution to equal 0.25 mg/kg in 30 mL of 5% dextrose. Using butterfly catheter, flush with 10 mL of D5W Infuse amphotericin B solution IV over 5 minutes. Flush catheter with 10 mL of D5W and remove catheter. Repeat above steps using 0.25 mg/kg 3 times a week until 9-12 mg/kg accumulated dosage is given. ()

For cryptococcosis (see general dosage guidelines above):

a) As an alternative therapy to ketoconazole: Amphotericin B: 0.25 mg/kg in 30 mL D5WIV over 15 minutes q48h with flucytosine at 200 mg/kg/day divided q6h PO. Continue therapy for 3-4 weeks after clinical signs have resolved or until BUN >50 mg/dl. (Legendre 1989)

b) Amphotericin B 0.15-0.4 mg/kg IV 3 times a week with flucytosine 125-250 mg/day PO divided two to four times a day. When a total dose of amphotericin B reaches 4-6 mg/ kg, start maintenance dosage of amphotericin B at 0.15-0.25 mg/kg IV once a month with flucytosine at dosage above or with ketoconazole at 10 mg/kg PO once daily or divided twice daily ()

c) Amphotericin B 0.5-0.8 mg/kg SC 2-3 times per week. Dose is diluted in 0.45% NaCl with 2.5% dextrose (400 mL for cats, 500 mL for dogs less than 20 kg and 1000 mL for dogs greater than 20 kg). Concentrations greater than 20 mg/L result in local irritation and sterile abscess formation. May combine with flucytosine or the azole antifungals. ()

d) For treating systemic mycoses using the amphotericin B lipid complex (ABLC; Abelcet) product: 1 mg/kg IV three days per week for a total of 12 treatments (cumulative dose of 12 mg). Dilute to a concentration of 1 mg/mL in dextrose 5% (D5W) and infuse over 1-2 hours ()

For histoplasmosis (see general dosage guidelines above):

a) Amphotericin B: 0.25 mg/kg in 30 mL D5WIV over 15 minutes q48h with ketoconazole at 10 mg/kg q12h PO. Continue therapy for 4-8 weeks or until BUN >50 mg/dl. If BUN increases greater than 50 mg/dl, continue ketoconazole alone. Ketoconazole is used long-term (at least 6 months of duration. ()

b) Amphotericin B 0.15-0.5 mg/kg IV 3 times a week with ketoconazole 10 mg/day PO once daily or divided twice daily (for at least 2-3 months or until remission, then start maintenance). When a total dose of amphotericin B reaches 2-4 mg/ kg, start maintenance dosage of amphotericin B at 0.15-0.25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or at 2.5-5 mg/kg PO once daily ()

For blastomycosis (see general dosage guidelines above):

a) Amphotericin B: 0.25 mg/kg in 30 mL D5WIV over 15 minutes q48h with ketoconazole: 10 mg/kg q12h PO (for at least 60 days). Continue amphotericin B therapy until a cumulative dose of 4 mg/kg is given or until BUN >50 mg/dl. If renal toxicity does not develop, may increase dose to 0.5 mg/ kg of amphotericin B. ()

b) Amphotericin B 0.15-0.5 mg/kg IV 3 times a week with ketoconazole 10 mg/day PO once daily or divided twice daily (for at least 2-3 months or until remission then start maintenance). When a total dose of amphotericin B reaches 4-6 mg/ kg start maintenance dosage of amphotericin B at 0.15-0.25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or ketoconazole at 2.5 – 5 mg/kg PO once daily. If CNS/ocular involvement, use ketoconazole at 20-40 mg/kg PO divided twice daily. ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for rabbits, rodents, and small mammals:

a) Rabbits: 1 mg/kg/day IV ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for horses:

For treatment of susceptible systemic fungal infections:

a) For fungal pneumonia: Day 1: 0.3 mg/kg IV; Day 2: 0.4 mg/kg IV; Day 3: 0.6 mg/kg IV; days 4-7: no treatment; then every other day until a total cumulative dose of 6.75 mg/kg has been administered ()

b) For phycomycoses and pulmonary mycoses: After reconstitution (see below) transfer appropriate amount of drug to 1L of D5W and administer using a 16 g needle IV at a rate of 1 L/ hr. Dosage schedule follows: Day 1: 0.3 mg/kg IV; Day 2: 0.45 mg/kg IV; Day 3: 0.6 mg/kg IV; then every other day for 3 days per week (MWF or TTHSa) until clinical signs of either improvement or toxicity occur. If toxicity occurs, a dose may be skipped, dosage reduced or dosage interval lengthened. Administration may extend from 10-80 days. ()

For intrauterine infusion: 200-250 mg. Little science is available for recommending doses, volume infused, frequency, diluents, etc. Most intrauterine treatments are commonly performed every day or every other day for 3-7 days. ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for Llamas:

For treatment of susceptible systemic fungal infections: a) A single case report. Llama received 1 mg test dose, then initially at 0.3 mg/kg IV over 4 hours, followed by 3 L of LRS with 1.5 mL of B-Complex and 20 mEq of KC1 added. Subsequent doses were increased by 10 mg and given every 48 hours until reaching 1 mg/kg q48h IV for 6 weeks. Animal tolerated therapy well, but treatment was ultimately unsuccessful (Coccidioidomycosis). ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for birds:

For treatment of susceptible systemic fungal infections:

a) For raptors and psittacines with aspergillosis: 1.5 mg/kg IV three times daily for 3 days with flucytosine or follow with flucytosine. May also use intratracheally at 1 mg/kg diluted in sterile water once to 3 times daily for 3 days in conjunction with flucytosine or nebulized (1 mg/mL of saline) for 15 minutes twice daily. Potentially nephrotoxic and may cause bone marrow suppression. ()

b) 1.5 mg/kg IV q12h for 3-5 days; topically in the trachea at 1 mg/kg q12h; 0.3-1 mg/mL nebulized for 15 minutes 2-4 times daily ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for reptiles:

For susceptible fungal respiratory infections: a) For most species: 1 mg/kg diluted in saline and given intratracheally once daily for 14-28 treatments ()

Client Information

■ Clients should be informed of the potential seriousness of toxic effects that can occur with amphotericin B therapy

■ The costs associated with therapy

Chemistry / Synonyms

A polyene macrolide antifungal agent produced by Streptomyces nodosus, amphotericin B occurs as a yellow to orange, odorless or practically odorless powder. It is insoluble in water and anhydrous alcohol. Amphotericin B is amphoteric and can form salts in acidic or basic media. These salts are more water soluble but possess less antifungal activity than the parent compound. Each mg of amphotericin B must contain not less than 750 micrograms of anhydrous drug. Amphotericin A may be found as a contaminant in concentrations not exceeding 5%. The commercially available powder for injection contains sodium desoxycholate as a solubilizing agent.

Newer lipid-based amphotericin B products are available that have less toxicity than the conventional desoxycholate form. These include amphotericin B cholesteryl sulfate complex (amphotericin B colloidal dispersion, ABCD, Amphotec), amphotericin B lipid complex (ABLC, Abelcet), and amphotericin B liposomal (ABL, L-AMB, Ambisome).

Amphotericin B may also be known as: amphotericin; amphotericin B cholesteryl sulfate complex, amphotericin B lipid complex, amphotericin B liposome, amphotericin B phospholipid complex, amphotericin B-Sodium cholesteryl sulfate complex, anfotericina B, or liposomal amphotericin B; many trade names are available.

Storage / Stability / Compatibility

Vials of amphotericin B powder for injection should be stored in the refrigerator (2-8°C), protected from light and moisture. Reconstitution of the powder must be done with sterile water for injection (no preservatives — see directions for preparation in the Dosage Form section below).

After reconstitution, if protected from light, the solution is stable for 24 hours at room temperature and for 1 week if kept refrigerated. After diluting with D5W (must have pH >4.3) for IV use, the manufacturer recommends continuing to protect the solution from light during administration. Additional studies however, have shown that potency remains largely unaffected if the solution is exposed to light for 8-24 hours.

Amphotericin B deoxycholate is reportedly compatible with the following solutions and drugs: D5W, D5W in sodium chloride 0.2%, heparin sodium, heparin sodium with hydrocortisone sodium phosphate, hydrocortisone sodium phosphate/succinate and sodium bicarbonate.

Amphotericin B deoxycholate is reportedly incompatible with the following solutions and drugs: normal saline, lactated Ringer’s, D5-normal saline, Ds-lactated Ringer’s, amino acids 4.25%-dextrose 25%, amikacin, calcium chloride/gluconate, carbenicillin disodium, chlorpromazine HCL, cimetidine HCL, diphenhydramine HCL, dopamine HCL, edetate calcium disodium (Ca EDTA), gentamicin sulfate, kanamycin sulfate, lidocaine HCL, metaraminol bitartrate, methyldopate HCL, nitrofurantoin sodium, oxytetracycline HCL, penicillin G potassium/sodium, polymyxin B sulfate, potassium chloride, prochlorperazine mesylate, streptomycin sulfate, tetracycline HCL, and verapamil HCL. Compatibility is dependent upon factors such as pH, concentration, temperature and diluent used; consult specialized references or a hospital pharmacist for more specific information.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products: None

Human-Labeled Products:

Amphotericin B Desoxycholate Powder for Injection: 50 mg in vials; Amphocin (Gensia Sicor); Fungizone Intravenous (Apothecon); generic (Pharma-Tek); (Rx)

Directions for reconstitution/administration: Using strict aseptic technique and a 20 gauge or larger needle, rapidly inject 10 mL of sterile water for injection (without a bacteriostatic agent) directly into the lyophilized cake; immediately shake well until solution is clear. A 5 mg/mL colloidal solution results. Further dilute (1:50) for administration to a concentration of 0.1 mg/mL with 5% dextrose in water (pH >4.2). An in-line filter may be used during administration, but must have a pore diameter >1 micron.

Amphotericin B Lipid-Based Suspension for Injection: 100 mg/20 mL (as lipid complex) in 10 mL & 20 mL vials with 5 micron filter needles: Abelcet (Enzon); (Rx)

Amphotericin B Lipid-Based Powder for Injection: 50 mg/vial (as cholesteryl) in 20 mL vials; 100 mg (as cholesteryl) in 50 mL vials; Amphotec (Sequus Pharmaceuticals); 50 mg (as liposomal) in single-dose vials with 5-micron filter; AmBisome (Fujisawa; (Rx)

Amphotericin B is also available in topical formulations: Fungizone (Apothecon); (Rx)

Categories
Drugs

Ammonium Chloride (Uroeze)

Acidifying Agent

Highlights Of Prescribing Information

Urinary acidifier; treatment of metabolic alkalosis

Contraindicated in patients with hepatic failure or uremia

Potential adverse effects are primarily GI distress; IV use may lead to metabolic acidosis

May increase excretion of quinidine; decrease efficacy of erythromycin or aminoglycosides in urine

What Is Ammonium Chloride Used For?

The veterinary indications for ammonium chloride are as a urinary acidifying agent to help prevent and dissolve certain types of uroliths (e.g., struvite), to enhance renal excretion of some types of toxins (e.g., strontium, strychnine) or drugs (e.g., quinidine), or to enhance the efficacy of certain antimicrobials (e.g., chlortetracycline, methenamine mandelate, nitrofurantoin, oxytetracycline, penicillin G or tetracycline) when treating urinary tract infections. Ammonium chloride has also been used intravenously for the rapid correction of metabolic alkalosis.

Because of changes in feline diets to restrict struvite and as struvite therapeutic diets (e.g., s/d) cause aciduria, ammonium chloride is not commonly recommended for struvite uroliths in cats.

Pharmacology / Actions

The acidification properties of ammonium chloride are caused by its dissociation into chloride and ammonium ions in vivo. The ammonium cation is converted by the liver to urea with the release of a hydrogen ion. This ion combines with bicarbonate to form water and carbon dioxide. In the extracellular fluid, chloride ions combine with fixed bases and decrease the alkaline reserves in the body. The net effects are decreased serum bicarbonate levels and a decrease in blood and urine pH.

Excess chloride ions presented to the kidney are not completely reabsorbed by the tubules and are excreted with cations (principally sodium) and water. This diuretic effect is usually compensated for in the kidneys after a few days of therapy.

Pharmacokinetics

No information was located on the pharmacokinetics of this agent in veterinary species. In humans, ammonium chloride is rapidly absorbed from the GL

Before you take Ammonium Chloride

Contraindications / Precautions / Warnings

Ammonium chloride is contraindicated in patients with severe hepatic disease as ammonia may accumulate and cause toxicity. In general, ammonium chloride should not be administered to uremic patients since it can intensify the metabolic acidosis already existing in some of these patients. As sodium depletion can occur, ammonium chloride should not be used alone in patients with severe renal insufficiency and metabolic alkalosis secondary to vomiting hydrochloric acid. In these cases, sodium chloride repletion with or without ammonium chloride administration should be performed to correct both sodium and chloride deficits. Ammonium chloride is contraindicated in patients with urate calculi or respiratory acidosis and high total CO2 and buffer base. Ammonium chloride alone cannot correct hypochloremia with secondary metabolic alkalosis due to intracellular potassium chloride depletion; potassium chloride must be administered to these patients.

Do not administer subcutaneously, rectally or intraperitoneally Use ammonium chloride with caution in patients with pulmonary insufficiency or cardiac edema.

Adverse Effects

Development of metabolic acidosis (sometimes severe) can occur unless adequate monitoring is performed. When used intravenously, pain at the injection site can develop; slow administration lessens this effect. Gastric irritation, nausea and vomiting may be associated with oral dosing of the drug. Urinary acidification is associated with an increased risk for calcium oxalate urolith formation in cats.

Overdosage / Acute Toxicity

Clinical signs of overdosage may include: nausea, vomiting, excessive thirst, hyperventilation, bradycardias or other arrhythmias, and progressive CNS depression. Profound acidosis and hypokalemia maybe noted on laboratory results.

Treatment should consist of correcting the acidosis by administering sodium bicarbonate or sodium acetate intravenously. Hypokalemia should be treated by using a suitable oral (if possible) potassium product. Intense acid-base and electrolyte monitoring should be performed on an ongoing basis until the patient is stable.

Reproductive / Nursing Safety

In humans, the FDA categorizes this drug as category B for use during pregnancy (Animal studies have not yet demonstrated risk to the fetus, hut there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, hut adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters.) In a separate system evaluating the safety of drugs in canine and feline pregnancy (), this drug is categorized as in class: B (Safe for use if used cautiously. Studies in laboratory animals may have uncovered some risk, hut these drugs appear to he safe in dogs and cats or these drugs are safe if they are not administered when the animal is near term.)

How to use Ammonium Chloride

Ammonium Chloride dosage for dogs:

For urine acidification:

a) As adjunctive therapy for struvite uroliths: 20 mg/kg PO three times daily ()

b) To enhance the renal elimination of certain toxins/drugs: 200 mg/kg/day divided four times daily ()

c) To enhance elimination of strontium: 0.2-0.5 grams PO 3-4 times a day (used with calcium salts) ()

For ATT (ammonia tolerance testing):

a) 2 mL/kg of a 5% solution of ammonium chloride deep in the rectum, blood sampled at 20 minutes and 40 minutes; or oral challenge with ammonium chloride 100 mg/kg (maximum dose = 3 grams) either in solution: dissolved in 20-50 mL warm water or in gelatin capsules, blood sampled at 30 and 60 minutes. Test may also be done by comparing fasting and 6-hour postprandial samples without giving exogenous ammonium chloride. (Center 2004)

Ammonium Chloride dosage for cats:

For urine acidification:

a) In struvite dissolution therapy if diet and antimicrobials do not result in acid urine or to help prevent idiopathic FUS in a non-obstructed cat: 20 mg/kg PO twice daily ()

b) As adjunctive therapy for struvite uroliths: 20 mg/kg PO twice daily ()

c) 800 mg per day given in the food once daily (if diet and antimicrobials do not reduce pH) ()

Ammonium Chloride dosage for horses:

a) 4-15 grams PO ()

b) Ammonium chloride as a urinary acidifier: 60-520 mg/kg PO daily. Ammonium salts are unpalatable and will have to be dosed via stomach tube or dosing syringe. Alternatively, ammonium sulfate at 165 mg/kg PO per day is more palatable and may be accepted when mixed with grain or hay. ()

c) As a urinary acidifier to enhance renal excretion of strychnine: 132 mg/kg PO ()

Ammonium Chloride dosage for cattle:

For urolithiasis prevention:

a) 200 mg/kg PO ()

b) 15-30 grams PO ()

Ammonium Chloride dosage for sheep and goats:

For urolithiasis prevention:

a) 200 mg/kg PO ()

b) 1-2 grams PO ()

Client Information

■ Contact veterinarian if animal exhibits signs of nausea, vomiting, excessive thirst, hyperventilation or progressive lethargy

■ Powders may have a bitter taste and patients may not accept their food after mixing

Chemistry / Synonyms

An acid-forming salt, ammonium chloride occurs as colorless crystals or as white, fine or course, crystalline powder. It is somewhat hygroscopic, and has a cool, saline taste. When dissolved in water, the temperature of the solution is decreased. One gram is soluble in approximately 3 mL of water at room temperature; 1.4 mL at 100°C. One gram is soluble in approximately 100 mL of alcohol.

One gram of ammonium chloride contains 18.7 mEq of ammonium and chloride ions. The commercially available concentrate for injection (26.75%) contains 5 mEq of each ion per mL and contains disodium edetate as a stabilizing agent. The pH of the concentrate for injection is approximately 5.

Ammonium chloride may also be known as muriate of ammonia and sal ammoniac.

Storage / Stability / Compatibility

Ammonium chloride for injection should be stored at room temperature; avoid freezing. At low temperatures, crystallization may occur; it may be resolubolized by warming to room temperature in a water bath.

Ammonium chloride should not be titrated with strong oxidizing agents etc. potassium chlorate) as explosive compounds may result.

Ammonium chloride is reported to be physically compatible with all commonly used IV replacement fluids and potassium chloride. It is incompatible with codeine phosphate, dimenhydrinate, methadone HCL, nitrofurantoin sodium, sulfisoxazole diolamine, and warfarin sodium. It is also reportedly incompatible with alkalis and their hydroxides.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products:

Ammonium Chloride Tablets: 200 mg, 400 mg; UriKare 200, 400 Tablets (Neogen); (Rx). Approved for use in cats and dogs.

Ammonium Chloride Granules: 200 mg per V4 teaspoonful powder; Uroeze200 (Virbac), UriKare 200 (Neogen); (Rx) Approved for cats and dogs.

Ammonium Chloride Granules: 400 mg per V4 teaspoonful powder; Uroeze (Virbac), UriKare 400 (Neogen); (Rx) Approved for cats and dogs.

Ammonium chloride is also found in some veterinary labeled cough preparations e.g., Spect-Aid Expectorant Granules (7% guaifenesin, 75% ammonium chloride, potassium iodide 2%) and in some cough syrups (also containing guaifenesin, pyrilamine and phenylephrine).

When used in large animals, feed grade ammonium chloride can be obtained from feed mills.

Human-Labeled Products:

Ammonium Chloride Injection: 26.75% (5 mEq/mL) in 20 mL (100 mEq) vials. Must be diluted before infusion; generic; (Rx). Preparation of solution for IV administration: Dilute 1 or 2 vials (100-200 mEq) in either 500 or 1000 mL of sodium chloride 0.9% for injection. Do not administer at a rate greater than 5 mL/min (human adult).

Categories
Drugs

Aminophylline Theophylline

Phosphodiesterase Inhibitor Bronchodilator

Highlights Of Prescribing Information

Bronchodilator drug with diuretic activity; used for bronchospasm & cardiogenic pulmonary edema

Narrow therapeutic index in humans, but dogs appear to be less susceptible to toxic effects at higher plasma levels

Therapeutic drug monitoring recommended

Many drug interactions

What Is Aminophylline Theophylline Used For?

The theophyllines are used primarily for their broncho dilatory effects, often in patients with myocardial failure and/or pulmonary edema. While they are still routinely used, the methylxanthines must be used cautiously due to their adverse effects and toxicity.

Pharmacology/Actions

The theophyllines competitively inhibit phosphodiesterase thereby increasing amounts of cyclic AMP which then increase the release of endogenous epinephrine. The elevated levels of cAMP may also inhibit the release of histamine and slow reacting substance of anaphylaxis (SRS-A). The myocardial and neuromuscular transmission effects that the theophyllines possess maybe a result of translocating intracellular ionized calcium.

The theophyllines directly relax smooth muscles in the bronchi and pulmonary vasculature, induce diuresis, increase gastric acid secretion and inhibit uterine contractions. They have weak chronotropic and inotropic action, stimulate the CNS and can cause respiratory stimulation (centrally-mediated).

Pharmacokinetics

The pharmacokinetics of theophylline have been studied in several domestic species. After oral administration, the rate of absorption of the theophyllines is limited primarily by the dissolution of the dosage form in the gut. In studies in cats, dogs, and horses, bioavail-abilities after oral administration are nearly 100% when non-sustained release products are used. One study in dogs that compared various sustained-release products (), found bioavailabilities ranging from approximately 30-76% depending on the product used.

Theophylline is distributed throughout the extracellular fluids and body tissues. It crosses the placenta and is distributed into milk (70% of serum levels). In dogs, at therapeutic serum levels only about 7-14% is bound to plasma proteins. The volume of distribution of theophylline for dogs has been reported to be 0.82 L/kg. The volume of distribution in cats is reported to be 0.46 L/kg, and in horses, 0.85-1.02 L/kg. Because of the low volumes of distribution and theophylline’s low lipid solubility, obese patients should be dosed on a lean body weight basis.

Theophylline is metabolized primarily in the liver (in humans) to 3-methylxanthine which has weakbronchodilitory activity. Renal clearance contributes only about 10% to the overall plasma clearance of theophylline. The reported elimination half-lives (mean values) in various species are: dogs = 5.7 hours; cats = 7.8 hours, pigs = 11 hours; and horses = 11.9 to 17 hours. In humans, there are very wide interpatient variations in serum half-lives and resultant serum levels. It could be expected that similar variability exists in veterinary patients, particularly those with concurrent illnesses.

Before you take Aminophylline Theophylline

Contraindications / Precautions / Warnings

The theophyllines are contraindicated in patients who are hypersensitive to any of the xanthines, including theobromine or caffeine. Patients who are hypersensitive to ethylenediamine should not take aminophylline.

The theophyllines should be administered with caution in patients with severe cardiac disease, seizure disorders, gastric ulcers, hyperthyroidism, renal or hepatic disease, severe hypoxia, or severe hypertension. Because it may cause or worsen preexisting arrhythmias, patients with cardiac arrhythmias should receive theophylline only with caution and enhanced monitoring. Neonatal and geriatric patients may have decreased clearances of theophylline and be more sensitive to its toxic effects. Patients with CHF may have prolonged serum half-lives of theophylline.

Adverse Effects

The theophyllines can produce CNS stimulation and gastrointestinal irritation after administration by any route. Most adverse effects are related to the serum level of the drug and may be symptomatic of toxic blood levels; dogs appear to tolerate levels that may be very toxic to humans. Some mild CNS excitement and GI disturbances are not uncommon when starting therapy and generally resolve with chronic administration in conjunction with monitoring and dosage adjustments.

Dogs and cats can exhibit clinical signs of nausea and vomiting, insomnia, increased gastric acid secretion, diarrhea, polyphagia, polydipsia, and polyuria. Side effects in horses are generally dose related and may include: nervousness, excitability (auditory, tactile, and visual), tremors, diaphoresis, tachycardia, and ataxia. Seizures or cardiac dysrhythmias may occur in severe intoxications.

Reproductive / Nursing Safety

In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, hut there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans.)

Overdosage / Acute Toxicity

Clinical signs of toxicity (see above) are usually associated with levels greater than 20 mcg/mL in humans and become more severe as the serum level exceeds that value. Tachycardias, arrhythmias, and CNS effects (seizures, hyperthermia) are considered the most life-threatening aspects of toxicity. Dogs appear to tolerate serum levels higher than 20 mcg/mL.

Treatment of theophylline toxicity is supportive. After an oral ingestion, the gut should be emptied, charcoal and a cathartic administered using the standardized methods and cautions associated with these practices. Patients suffering from seizures should have an adequate airway maintained and treated with IV diazepam. The patient should be constantly monitored for cardiac arrhythmias and tachycardia. Fluid and electrolytes should be monitored and corrected as necessary. Hyperthermia may be treated with phenothiazines and tachycardia treated with propranolol if either condition is considered life threatening.

How to use Aminophylline Theophylline

Note: Theophyllines have a low therapeutic index; determine dosage carefully. Because of aminophylline/theophylline’s pharmacokinet-ic characteristics, it should be dosed on a lean body weight basis in obese patients. Dosage conversions between aminophylline and theophylline can be easily performed using the information found in the Chemistry section below. Aminophylline causes intense local pain when administered IM and is rarely used or recommended via this route.

Aminophylline Theophylline dosage for dogs:

a) Using Theochron Extended-Release Tablets or Theo-Cap Extended-Release Capsules: Give 10 mg/kg PO every 12 hours initially, if no adverse effects are observed and the desired clinical effect is not achieved, give 15 mg/kg PO q12h while monitoring for adverse effects. ()

b) For adjunctive medical therapy for mild clinical signs associated with tracheal collapse (<50% collapse): aminophylline: 11 mg/kg PO, IM or IV three times daily. ()

c) For adjunctive therapy of severe, acute pulmonary edema and bronchoconstriction: Aminophylline 4-8 mg/kg IV or IM, or 6-10 mg/kg PO every 8 hours. Long-term use is not recommended. ()

d) For cough: Aminophylline: 10 mg/kg PO, IV three times daily ()

e) As a broncho dilator tor collapsing trachea: 11 mg/kg PO or IV q6- 12h ()

Aminophylline Theophylline dosage for cats:

a) Using Theo-Dur 20 mg/kg PO once daily in the PM; using Slo-Bid 25 mg/kg PO once daily in the PM (Johnson 2000) [Note: The products Theo-Dur and Slo-Bid mentioned in this reference are no longer available in the USA. Although hard data is not presently available to support their use in cats, a reasonable alternative would be to cautiously use the dog dose and products mentioned above in the reference by Bach et al — Plumb]

b) Using aminophylline tablets: 6.6. mg/kg PO twice daily; using sustained release tablets (Theo-Dur): 25-50 mg (total dose) per cat PO in the evening ()

c) For adjunctive medical therapy for mild clinical signs associated with tracheal collapse (<50% collapse): aminophylline: 5 mg/kg PO, two times daily. ()

d) For adjunctive therapy for bronchoconstriction associated with fulminant CHF: Aminophylline 4-8 mg/kg SC, IM, IV q8-12h. ()

e) For cough: Aminophylline: 5 mg/kg PO twice daily ()

Aminophylline Theophylline dosage for ferrets:

a) 4.25 mg/kg PO 2-3 times a day ()

Aminophylline Theophylline dosage for horses:

(Note: ARCI UCGFS Class 3 Aminophylline Theophylline)

NOTE: Intravenous aminophylline should be diluted in at least 100 mL of D5W or normal saline and administered slowly (not >25 mg/min). For adjunctive treatment of pulmonary edema:

a) Aminophylline 2-7 mg/kg IV q6- 12h; Theophylline 5-15 mg/kg PO q12h ()

b) 11 mg/kg PO or IV q8-12h. To “load” may either double the initial dose or give both the oral and IV dose at the same time. IV infusion should be in approximately 1 liter of IV fluids and given over 20-60 minutes. Recommend monitoring serum levels. ()

For adjunctive treatment for heaves (RAO):

a) Aminophylline: 5-10 mg/kg PO or IV twice daily. ()

b) Aminophylline: 4-6 mg/kg PO three times a day. ()

Monitoring

■ Therapeutic efficacy and clinical signs of toxicity

■ Serum levels at steady state. The therapeutic serum levels of theophylline in humans are generally described to be between 10-20 micrograms/mL. In small animals, one recommendation for monitoring serum levels is to measure trough concentration; level should be at least above 8-10 mcg/mL (Note: Some recommend not exceeding 15 micrograms/mL in horses).

Client Information

■ Give dosage as prescribed by veterinarian to maximize the drug’s benefit

Chemistry / Synonyms

Xanthine derivatives, aminophylline and theophylline are considered to be respiratory smooth muscle relaxants but, they also have other pharmacologic actions. Aminophylline differs from theophylline only by the addition of ethylenediamine to its structure and may have different amounts of molecules of water of hydration. 100 mg of aminophylline (hydrous) contains approximately 79 mg of theophylline (anhydrous); 100 mg of aminophylline (anhydrous) contains approximately 86 mg theophylline (anhydrous). Conversely, 100 mg of theophylline (anhydrous) is equivalent to 116 mg of aminophylline (anhydrous) and 127 mg aminophylline (hydrous).

Aminophylline occurs as bitter-tasting, white or slightly yellow granules or powder with a slight ammoniacal odor and a pKa of 5. Aminophylline is soluble in water and insoluble in alcohol.

Theophylline occurs as bitter-tasting, odorless, white, crystalline powder with a melting point between 270-274°C. It is sparingly soluble in alcohol and only slightly soluble in water at a pH of 7, but solubility increases with increasing pH.

Aminophylline may also be known as: aminofilina, aminophyllinum, euphyllinum, metaphyllin, theophyllaminum, theophylline and ethylenediamine, theophylline ethylenediamine compound, or theophyllinum ethylenediaminum; many trade names are available.

Theophylline may also be known as: anhydrous theophylline, teofillina, or theophyllinum; many trade names are available.

Storage / Stability/Compatibility

Unless otherwise specified by the manufacturer, store aminophylline and theophylline oral products in tight, light-resistant containers at room temperature. Do not crush or split sustained-release oral products unless label states it is permissible.

Aminophylline for injection should be stored in single-use containers in which carbon dioxide has been removed. It should also be stored at temperatures below 30°C and protected from freezing and light. Upon exposure to air (carbon dioxide), aminophylline will absorb carbon dioxide, lose ethylenediamine and liberate free theophylline that can precipitate out of solution. Do not inject aminophylline solutions that contain either a precipitate or visible crystals.

Aminophylline for injection is reportedly compatible when mixed with all commonly used IV solutions, but may be incompatible with 10% fructose or invert sugar solutions.

Aminophylline is reportedly compatible when mixed with the following drugs: amobarbital sodium, bretylium tosylate, calcium gluconate, chloramphenicol sodium succinate, dexamethasone sodium phosphate, dopamine HCL, erythromycin lactobionate, heparin sodium, hydro cortisone sodium succinate, lidocaine HCL, mephentermine sulfate, methicillin sodium, methyldopate HCL, metronidazole with sodium bicarbonate, pentobarbital sodium, phenobarbital sodium, potassium chloride, secobarbital sodium, sodium bicarbonate, sodium iodide, terbutaline sulfate, thiopental sodium, and verapamil HCL

Aminophylline is reportedly incompatible (or data conflicts) with the following drugs: amikacin sulfate, ascorbic acid injection, bleomycin sulfate, cephalothin sodium, cephapirin sodium, clindamycin phosphate, codeine phosphate, corticotropin, dimenhydrinate, dobutamine HCL, doxorubicin HCL, epinephrine HCL, erythromycin gluceptate, hydralazine HCL, hydroxyzine HCL, insulin (regular), isoproterenol HCL, levorphanol bitartrate, meperidine HCL, methadone HCL, methylprednisolone sodium succinate, morphine sulfate, nafcillin sodium, norepinephrine bitartrate, oxytetracycline, penicillin G potassium, pentazocine lactate, procaine HCL, prochlorperazine edisylate or mesylate, promazine HCL, promethazine HCL, sulfisoxazole diolamine, tetracycline HCL, vancomycin HCL, and vitamin B complex with C. Compatibility is dependent upon factors such as pH, concentration, temperature, and diluent used and it is suggested to consult specialized references for more specific information.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products: None

The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information.

Human-Labeled Products:

The listing below is a sampling of products and sizes available; consult specialized references for a more complete listing.

Aminophylline Tablets: 100 mg (79 mg theophylline) & 200 mg (158 mg theophylline); generic; (Rx)

Aminophylline Injection: 250 mg (equiv. to 197 mg theophylline) mL in 10 mL & 20 mL vials, amps and syringes; generic; (Rx)

Theophylline Time Released Capsules and Tablets: 100 mg, 125 mg 200 mg, 300 mg, 400 mg, 450 mg, & 600 mg. (Note: Different products have different claimed release rates which may or may not correspond to actual times in veterinary patients; Theophylline Extended-Release (Dey); Theo-24 (UCB Pharma); Theophylline SR (various); Theochron (Forest, various); Theophylline (Able); Theocron (Inwood); Uniphyl (Purdue Frederick); generic; (Rx)

Theophylline Tablets and Capsules: 100 mg, 200 mg, & 300 mg; Bronkodyl (Winthrop); Elixophyllin (Forest); generic; (Rx)

Theophylline Elixir: 80 mg/15 mL (26.7 mg/5 mL) in pt, gal, UD 15 and 30 mL, Asmalix (Century); Elixophyllin (Forest); Lanophyllin (Lannett); generic; (Rx)

Theophylline & Dextrose Injection: 200 mg/container in 50 mL (4 mg/mL) & 100 mL (2 mg/mL); 400 mg/container in 100 mL (4 mg/ mL), 250 mL (1.6 mg/mL), 500 mL (0.8 mg/mL) & 1000 mL (0.4 mg/mL); 800 mg/container in 250 mL (3.2 mg/mL), 500 mL (1.6 mg/mL) & 1000 mL (0.8 mg/mL); Theophylline & 5% Dextrose (Abbott & Baxter); (Rx)

Categories
Drugs

Aminopentamide Hydrogen Sulfate (Centrine)

Anticholinergic/Antispasmodic

Highlights Of Prescribing Information

Anticholinergic/antispasmodicfor GI indications in small animals

Typical adverse effect profile (“dry, hot, red”); potentially could cause tachycardia

Contraindicated in glaucoma; relatively contraindicated in tachycardias, heart disease, GI obstruction, etc.

What Is Aminopentamide Hydrogen Sulfate Used For?

The manufacturer states that the drug is indicated “in the treatment of acute abdominal visceral spasm, pylorospasm or hypertrophic gastritis and associated nausea, vomiting and/or diarrhea” for use in dogs and cats.

Pharmacology/Actions

Aminopentamide is an anticholinergic agent that when compared to atropine has been described as having a greater effect on reducing colonic contractions and less mydriatic and salivary effects. It reportedly may also reduce gastric acid secretion.

Pharmacokinetics

No information was located.

Before you take Aminopentamide Hydrogen Sulfate

Contraindications / Precautions / Warnings

The manufacturer lists glaucoma as an absolute contraindication to therapy and to use the drug cautiously, if at all, in patients with pyloric obstruction. Additionally, aminopentamide should not be used if the patient has a history of hypersensitivity to anticholinergic drugs, tachycardias secondary to thyrotoxicosis or cardiac insufficiency, myocardial ischemia, unstable cardiac status during acute hemorrhage, GI obstructive disease, paralytic ileus, severe ulcerative colitis, obstructive uropathy or myasthenia gravis (unless used to reverse adverse muscarinic effects secondary to therapy).

Antimuscarinic agents should be used with extreme caution in patients with known or suspected GI infections, or with autonomic neuropathy. Atropine or other antimuscarinic agents can decrease GI motility and prolong retention of the causative agent(s) or toxin(s) resulting in prolonged clinical signs.

Antimuscarinic agents should be used with caution in patients with hepatic disease, renal disease, hyperthyroidism, hypertension, CHF, tachyarrhythmias, prostatic hypertrophy, esophageal reflux, and in geriatric or pediatric patients.

Adverse Effects

Adverse effects resulting from aminopentamide therapy may include dry mouth, dry eyes, blurred vision, and urinary hesitancy. Urinary retention is a symptom of too high a dose and the drug should be withdrawn until resolved.

Overdosage / Acute Toxicity

No specific information was located regarding acute overdosage clinical signs or treatment for this agent. The following discussion is from the Atropine monograph that could be used as a guideline for treating overdoses:

If a recent oral ingestion, emptying of gut contents and administration of activated charcoal and saline cathartics may be warranted. Treat clinical signs supportively and symptomatically. Do not use phenothiazines as they may contribute to the anticholinergic effects. Fluid therapy and standard treatments for shock may be instituted.

The use of physostigmine is controversial and should probably be reserved for cases where the patient exhibits either extreme agitation and is at risk for injuring themselves or others, or for cases where supraventricular tachycardias and sinus tachycardias are severe or life threatening. The usual dose for physostigmine (human) is: 2 mg IV slowly (for average sized adult), if no response, may repeat every 20 minutes until reversal of toxic antimuscarinic effects or cholinergic effects takes place. The human pediatric dose is 0.02 mg/kg slow IV (repeat q10 minutes as above) and may be a reasonable choice for treatment of small animals. Physostigmine adverse effects (bronchoconstriction, bradycardia, seizures) may be treated with small doses of IV atropine.

How to use Aminopentamide Hydrogen Sulfate

Aminopentamide Hydrogen Sulfate dosage for dogs:

a) May be administered every 8-12 hours via IM, SC or oral routes. If the desired effect is not attained, the dosage maybe gradually increased up to 5 times those listed below: Animals weighing: 10 lbs or less: 0.1 mg; 11-20 lbs: 0.2 mg; 21-50 lbs: 0.3 mg; 51 -100 lbs: 0.4 mg; over 100 lbs: 0.5 mg (Package Insert; Centrine — Fort Dodge)

b) To decrease tenesmus in malabsorption/maldigestion syndromes: 0.1-0.4 mg SC, or IM twice daily-three times daily ()

c) As an antiemetic: 0.1-0.4 mg SC, or IM two to three times daily ()

Aminopentamide Hydrogen Sulfate dosage for cats:

a) As in “a” above in dogs

b) As an antiemetic: 0.1-0.4 mg SC, or IM two to three times daily ()

c) As second-line adjunctive therapy for refractory IBD: 0.1-0.4 mg/kg SC two to three times daily ()

Client Information

■ Contact veterinarian if animal has difficulty urinating or if animal is bothered by dry eyes or mouth

Chemistry / Synonyms

An antispasmodic, anticholinergic agent, aminopentamide hydrogen sulfate has a chemical name of 4-(dimethylamino)-2,2-diphenylvaleramide.

Aminopentamide hydrogen sulfate may also be known as dimevamid or Centrine.

Storage / Stability

Store aminopentamide tablets and injection at controlled room temperature (15-30°C; 59-86°F).

Dosage Forms / Regulatory Status

Veterinary-Labeled Products:

Aminopentamide Hydrogen Sulfate Tablets: 0.2 mg; Centrine (Fort Dodge); (Rx). Approved for use in dogs and cats only.

Aminopentamide Hydrogen Sulfate Injection: 0.5 mg/mL in 10 mL vials; Centrine (Fort Dodge); (Rx). Approved for use in dogs and cats only.

Human-Labeled Products: None