Categories
Drugs

Amitriptyline HCL (Elavil)

Tricyclic Behavior Modifier; Anti-Pruritic; Neuropathic Pain Modifier

Highlights Of Prescribing Information

Tricyclic “antidepressant” used primarily for behavior disorders & neuropathic pain/pruritus in small animals

May reduce seizure thresholds in epileptic animals

Sedation & anticholinergic effects most likely adverse effects

Overdoses can be very serious in both animals & humans

What Is Amitriptyline HCL Used For?

Amitriptyline has been used for behavioral conditions such as separation anxiety or generalized anxiety in dogs, and excessive grooming, spraying and anxiety in cats. Amitriptyline may be useful for adjunctive treatment of pruritus, or chronic pain of neuropathic origin in dogs and cats. In cats, it potentially could be useful for adjunctive treatment of lower urinary tract disease. Amitriptyline has been tried to reduce feather plucking in birds.

Pharmacology / Actions

Amitriptyline (and its active metabolite, nortriptyline) has a complicated pharmacologic profile. From a slightly oversimplified viewpoint, it has 3 main characteristics: blockage of the amine pump, thereby increasing neurotransmitter levels (principally serotonin, but also norepinephrine), sedation, and central and peripheral anticholinergic activity. Other pharmacologic effects include stabilizing mast cells via H-l receptor antagonism, and antagonism of glutamate receptors and sodium channels. In animals, tricyclic antidepressants are similar to the actions of phenothiazines in altering avoidance behaviors.

Pharmacokinetics

Amitriptyline is rapidly absorbed from both the GI tract and from parenteral injection sites. Peak levels occur within 2-12 hours. Amitriptyline is highly bound to plasma proteins, enters the CNS, and enters maternal milk in levels at, or greater than those found in maternal serum. The drug is metabolized in the liver to several metabolites, including nortriptyline, which is active. In humans, the terminal half-life is approximately 30 hours. Half-life in dogs has been reported to be 6-8 hours.

Before you take Amitriptyline HCL

Contraindications / Precautions / Warnings

These agents are contraindicated if prior sensitivity has been noted with any other tricyclic. Concomitant use with monoamine oxidase inhibitors is generally contraindicated. Use with extreme caution in patients with seizure disorders as tricyclic agents may reduce seizure thresholds. Use with caution in patients with thyroid disorders, hepatic disorders, KCS, glaucoma, cardiac rhythm disorders, diabetes, or adrenal tumors.

Adverse Effects

The most predominant adverse effects seen with the tricyclics are related to their sedating and anticholinergic (constipation, urinary retention) properties. Occasionally, dogs exhibit hyperexcitability and, rarely, develop seizures. However, adverse effects can run the entire gamut of systems, including cardiac (dysrhythmias), hematologic (bone marrow suppression), GI (diarrhea, vomiting), endocrine, etc. Cats may demonstrate the following adverse effects: sedation, hypersalivation, urinary retention, anorexia, thrombocytopenia, neutropenia, unkempt hair coat, vomiting, ataxia, dis-orientation and cardiac conductivity disturbances.

Reproductive / Nursing Safety

Isolated reports of limb reduction abnormalities have been noted; restrict use to pregnant animals only when the benefits clearly outweigh the risks. In humans, the FDA categorizes this drug as category D for use during pregnancy (There is evidence of human fetal risk, hut the potential benefits from the use of the drug in pregnant women may he acceptable despite its potential risks.)

Overdosage / Acute Toxicity

Overdosage with tricyclics can be life-threatening (arrhythmias, cardiorespiratory collapse). Because the toxicities and therapies for treatment are complicated and controversial, it is recommended to contact a poison control center for further information in any potential overdose situation.

There were 25 exposures to amitriptyline reported to the ASPCA Animal Poison Control Center (APCC; www.apcc.aspca.org) during 2005-2006. In these cases, 21 were cats with 5 showing clinical signs. Common findings recorded in decreasing frequency included: anorexia, mydriasis and adipsia. The remaining 4 cases were dogs with no reported clinical signs.

How to use Amitriptyline HCL

Amitriptyline HCL dosage for dogs:

For adjunctive treatment of pruritus:

a) 1-2 mg/kg PO q12h ()

b) For acral pruritic dermatitis: 2.2 mg/kg PO twice daily; only occasionally effective. A 2-4 week trial is recommended ()

For behavior disorders amenable to tricyclics:

a) For separation anxiety or generalized anxiety: 1-2 mg/kg PO q12h; with behavior modification ()

b) 1-4 mg/kg PO q12h. Begin at 1-2 mg/kg PO q12h for 2 weeks, increase by 1 mg/kg up to maximum dosage (4 mg/ kg) as necessary. If no clinical response, decrease by 1 mg/kg PO q12h for 2 weeks until at initial dosage. ()

c) 2.2-4.4 mg/kg PO q12h ()

d) 0.25-1.5 mg/kg PO every 12-24h ()

For neuropathic pain:

a) 1-2 mg/kg PO ql2-24h ()

b) For adjunctive treatment of pain associated with appendicular osteosarcoma: 1-2 mg/kg PO ql2-24h ()

Amitriptyline HCL dosage for cats:

For adjunctive treatment of behavior disorders amenable to tricyclics:

a) 5-10 mgper cat PO once daily ()

b) 0.5-2 mg/kg PO ql2-24h; start at 0.5 mg/kg PO q12h ()

c) 0.5-1 mg/kg PO ql2-24h ()

d) 0.5-1 mg/kg PO ql2-24h. Allow 3-4 weeks for initial trial. ()

For self-mutilation behaviors associated with anxiety:

a) 5-10 mg per cat PO once to twice daily; with behavior modification ()

b) 1-2 mg/kg PO q12h ()

For pruritus (after other more conventional therapies have failed):

a) 5-10 mg per cat PO once daily or 2.5-7.5 mg/cat once to twice daily. When discontinuing, taper dose over 1-3 weeks. ()

For symptomatic therapy of idiopathic feline lower urinary tract disease:

a) 2.5-12.5 mg (total dose) PO once daily at night ()

b) 5-10 mg (total dose) PO once daily at night; the drug is in popular use at present and further studies are needed ()

c) Reserved for cases with severe, recurrent signs; 2.5-12.5 mg (total dose) PO at the time the owner retires for the night. Dosage is adjusted to produce a barely perceptible calming effect on the cat. If no improvement is seen within 2 months, the medication may be gradually tapered and then stopped. ()

For neuropathic pain:

a) 2.5-12.5 mg/cat PO once daily ()

b) 0.5-2 mg/kg PO once daily; may be a useful addition to NSAIDs for chronic pain. ()

Amitriptyline HCL dosage for birds:

For adjunctive treatment of feather plucking:

a) 1-2 mg/kg PO ql2-24 hours. Anecdotal reports indicate some usefulness. Barring side effects, may be worth a more prolonged course of therapy to determine efficacy. ()

Monitoring

■ Efficacy

■ Adverse effects; it is recommended to perform a cardiac evaluation, CBC and serum chemistry panel prior to therapy

■ For cats, some clinicians recommend that liver enzymes be measured prior to therapy, one month after initial therapy, and yearly, thereafter

Client Information

■ All tricyclics should be dispensed in child-resistant packaging and kept well away from children or pets.

■ Several weeks may be required before efficacy is noted and to continue dosing as prescribed. Do not abruptly stop giving medication without veterinarian’s advice.

Chemistry / Synonyms

A tricyclic dibenzocycloheptene-derivative antidepressant, amitriptyline HCL occurs as a white or practically white, odorless or practically odorless crystalline powder that is freely soluble in water or alcohol. It has a bitter, burning taste and a pKa of 9.4.

Amitriptyline may also be known as amitriptylini hydrochloridum; many trade names are available.

Storage / Stability

Amitriptyline tablets should be stored at room temperature. The injection should be kept from freezing and protected from light.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products: None

The ARCI (Racing Commissioners International) has designated this drug as a class 2 substance. See the appendix for more information.

Human-Labeled Products:

Amitriptyline HCL Tablets: 10,25, 50, 75,100,150 mg; generic; (Rx)

There are also fixed dose oral combination products containing amitriptyline and chlordiazepoxide, and amitriptyline and perphenazine.

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

Amikacin Sulfate (Amikin, Amiglyde-V)

Aminoglycoside Antibiotic

Highlights Of Prescribing Information

Parenteral aminoglycoside antibiotic that has good activity against a variety of bacteria, predominantly gram-negative aerobic bacilli

Adverse Effects: Nephrotoxicity, ototoxicity, neuromuscu-lar blockade

Cats may be more sensitive to toxic effects

Risk factors for toxicity: Preexisting renal disease, age (both neonatal & geriatric), fever, sepsis & dehydration

Now usually dosed once daily when used systemically

What Is Amikacin Sulfate Used For?

While parenteral use is only approved in dogs, amikacin is used clinically to treat serious gram-negative infections in most species. It is often used in settings where gentamicin-resistant bacteria are a clinical problem. The inherent toxicity of the aminoglycosides limit their systemic use to serious infections when there is either a documented lack of susceptibility to other, less toxic antibiotics or when the clinical situation dictates immediate treatment of a presumed gram-negative infection before culture and susceptibility results are reported.

Amikacin is also approved for intrauterine infusion in mares. It is used with intra-articular injection in foals to treat gram-negative septic arthritis.

Pharmacology/Actions

Amikacin, like the other aminoglycoside antibiotics, act on susceptible bacteria presumably by irreversibly binding to the 30S ribosomal subunit thereby inhibiting protein synthesis. It is considered a bactericidal concentration-dependent antibiotic.

Amikacin’s spectrum of activity includes: coverage against many aerobic gram-negative and some aerobic gram-positive bacteria, including most species of E. coli, Klebsiella, Proteus, Pseudomonas, Salmonella, Enterobacter, Serratia, and Shigella, Mycoplasma, and Staphylococcus. Several strains of Pseudomonas aeruginosa, Proteus, and Serratia that are resistant to gentamicin will still be killed by amikacin.

Antimicrobial activity of the aminoglycosides is enhanced in an alkaline environment.

The aminoglycoside antibiotics are inactive against fungi, viruses and most anaerobic bacteria.

Pharmacokinetics

Amikacin, like the other aminoglycosides is not appreciably absorbed after oral or intrauterine administration, but is absorbed from topical administration (not from skin or the urinary bladder) when used in irrigations during surgical procedures. Patients receiving oral aminoglycosides with hemorrhagic or necrotic enteritises may absorb appreciable quantities of the drug. After IM administration to dogs and cats, peak levels occur from ½1 hour later. Subcutaneous injection results in slightly delayed peak levels and with more variability than after IM injection. Bio availability from extravascular injection (IM or SC) is greater than 90%.

After absorption, aminoglycosides are distributed primarily in the extracellular fluid. They are found in ascitic, pleural, pericardial, peritoneal, synovial and abscess fluids; high levels are found in sputum, bronchial secretions and bile. Aminoglycosides are minimally protein bound (<20%, streptomycin 35%) to plasma proteins. Aminoglycosides do not readily cross the blood-brain barrier nor penetrate ocular tissue. CSF levels are unpredictable and range from 0-50% of those found in the serum. Therapeutic levels are found in bone, heart, gallbladder and lung tissues after parenteral dosing. Aminoglycosides tend to accumulate in certain tissues such as the inner ear and kidneys, which may help explain their toxicity. Volumes of distribution have been reported to be 0.15-0.3 L/kg in adult cats and dogs, and 0.26-0.58 L/kg in horses. Volumes of distribution may be significantly larger in neonates and juvenile animals due to their higher extracellular fluid fractions. Aminoglycosides cross the placenta; fetal concentrations range from 15-50% of those found in maternal serum.

Elimination of aminoglycosides after parenteral administration occurs almost entirely by glomerular filtration. The approximate elimination half-lives for amikacin have been reported to be 5 hours in foals, 1.14-2.3 hours in adult horses, 2.2-2.7 hours in calves, 1-3 hours in cows, 1.5 hours in sheep, and 0.5-2 hours in dogs and cats. Patients with decreased renal function can have significantly prolonged half-lives. In humans with normal renal function, elimination rates can be highly variable with the aminoglycoside antibiotics.

Before you take Amikacin Sulfate

Contraindications / Precautions / Warnings

Aminoglycosides are contraindicated in patients who are hypersensitive to them. Because these drugs are often the only effective agents in severe gram-negative infections, there are no other absolute contraindications to their use. However, they should be used with extreme caution in patients with preexisting renal disease with concomitant monitoring and dosage interval adjustments made. Other risk factors for the development of toxicity include age (both neonatal and geriatric patients), fever, sepsis and dehydration.

Because aminoglycosides can cause irreversible ototoxicity, they should be used with caution in “working” dogs (e.g., “seeing-eye,” herding, dogs for the hearing impaired, etc.).

Aminoglycosides should be used with caution in patients with neuromuscular disorders (e.g., myasthenia gravis) due to their neuromuscular blocking activity.

Because aminoglycosides are eliminated primarily through renal mechanisms, they should be used cautiously, preferably with serum monitoring and dosage adjustment in neonatal or geriatric animals.

Aminoglycosides are generally considered contraindicated in rabbits/hares as they adversely affect the GI flora balance in these animals.

Adverse Effects

The aminoglycosides are infamous for their nephrotoxic and ototox-ic effects. The nephrotoxic (tubular necrosis) mechanisms of these drugs are not completely understood, but are probably related to interference with phospholipid metabolism in the lysosomes of proximal renal tubular cells, resulting in leakage of proteolytic enzymes into the cytoplasm. Nephrotoxicity is usually manifested by: increases in BUN, creatinine, nonprotein nitrogen in the serum, and decreases in urine specific gravity and creatinine clearance. Proteinuria and cells or casts may be seen in the urine. Nephrotoxicity is usually reversible once the drug is discontinued. While gentamicin may be more nephrotoxic than the other aminoglycosides, the incidences of nephrotoxicity with all of these agents require equal caution and monitoring.

Ototoxicity (8th cranial nerve toxicity) of the aminoglycosides can manifest by either auditory and/or vestibular clinical signs and may be irreversible. Vestibular clinical signs are more frequent with streptomycin, gentamicin, or tobramycin. Auditory clinical signs are more frequent with amikacin, neomycin, or kanamycin, but either form can occur with any of these drugs. Cats are apparently very sensitive to the vestibular effects of the aminoglycosides.

The aminoglycosides can also cause neuromuscular blockade, facial edema, pain/inflammation at injection site, peripheral neuropathy and hypersensitivity reactions. Rarely, GI clinical signs, hematologic and hepatic effects have been reported.

Reproductive / Nursing Safety

Aminoglycosides can cross the placenta and while rare, may cause 8th cranial nerve toxicity or nephrotoxicity in fetuses. Because the drug should only be used in serious infections, the benefits of therapy may exceed the potential risks. 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.) In a separate system evaluating the safety of drugs in canine and feline pregnancy (), this drug is categorized as in class: C (These drugs may have potential risks. Studies in people or laboratory animals have uncovered risks, and these drugs should he used cautiously as a last resort when the benefit of therapy clearly outweighs the risks.)

Aminoglycosides are excreted in milk. While potentially, amikacin ingested with milk could alter GI flora and cause diarrhea, amikacin in milk is unlikely to be of significant concern after the first few days of life (colostrum period).

Overdosage / Acute Toxicity

Should an inadvertent overdosage be administered, three treatments have been recommended. Hemodialysis is very effective in reducing serum levels of the drug but is not a viable option for most veterinary patients. Peritoneal dialysis also will reduce serum levels but is much less efficacious. Complexation of drug with either carbenicillin or ticarcillin (12-20 g/day in humans) is reportedly nearly as effective as hemodialysis. Since amikacin is less affected by this effect than either tobramycin or gentamicin, it is assumed that reduction in serum levels will also be minimized using this procedure.

How to use Amikacin Sulfate

Note: Most infectious disease clinicians now agree that aminoglycosides should be dosed once a day in most patients (mammals). This dosing regimen yields higher peak levels with resultant greater bacterial kill, and as aminoglycosides exhibit a “post-antibiotic effect”, surviving susceptible bacteria generally do not replicate as rapidly even when antibiotic concentrations are below MIC. Periods where levels are low may also decrease the “adaptive resistance” (bacteria take up less drug in the presence of continuous exposure) that can occur. Once daily dosing may decrease the toxicity of aminoglycosides as lower urinary concentrations may mean less uptake into renal tubular cells. However, patients who are neutropenic (or otherwise immunosuppressed) may benefit from more frequent dosing (q8h). Patients with significantly diminished renal function who must receive aminoglycosides may need to be dosed at longer intervals than once daily. Clinical drug monitoring is strongly suggested for these patients.

Amikacin Sulfate dosage for dogs:

For susceptible infections:

a) Sepsis: 20 mg/kg once daily IV ()

b) 15 mg/kg (route not specified) once daily (q24h). Neutropenic or immunocompromised patients may still need to be dosed q8h (dose divided). ()

c) 15-30 mg/kg IV, IM or SC once daily (q24h) ()

Amikacin Sulfate dosage for cats:

For susceptible infections:

a) Sepsis: 20 mg/kg once daily IV ()

b) 15 mg/kg (route not specified) once daily (q24h). Neutropenic or immunocompromised patients may still need to be dosed q8h (dose divided). ()

c) 10-15 mg/kg IV, IM or SC once daily (q24h) ()

Amikacin Sulfate dosage for ferrets:

For susceptible infections:

a) 8-16 mg/kg IM or IV once daily ()

b) 8-16 mg/kg/day SC, IM, IV divided q8-24h ()

Amikacin Sulfate dosage for rabbits, rodents, and small mammals:

a) Rabbits: 8-16 mg/kg daily dose (may divide into q8h-q24h) SC, IM or IV Increased efficacy and decreased toxicity if given once daily. If given IV, dilute into 4 mL/kg of saline and give over 20 minutes. ()

b) Rabbits: 5-10 mg/kg SC, IM, IV divided q8-24h Guinea pigs: 10-15 mg/kg SC, IM, IV divided q8-24h Chinchillas: 10-15 mg/kg SC, IM, IV divided q8-24h Hamster, rats, mice: 10 mg/kg SC, IM q12h Prairie Dogs: 5 mg/kg SC, IM q12h ()

c) Chinchillas: 2-5 mg/kg SC, IM q8- 12h ()

Amikacin Sulfate dosage for cattle:

For susceptible infections:

a) 10 mg/kg IM q8h or 25 mg/kg q12h ()

b) 22 mg/kg/day IM divided three times daily ()

Amikacin Sulfate dosage for horses:

For susceptible infections:

a) 21 mg/kg IV or IM once daily (q24h) ()

b) In neonatal foals: 21 mg/kg IV once daily ()

c) In neonatal foals: Initial dose of 25 mg/kg IV once daily; strongly recommend to individualize dosage based upon therapeutic drug monitoring. ()

d) Adults: 10 mg/kg IM or IV once daily (q24h)

Foals (<30 days old): 20-25 mg/kg IV or IM once daily (q24h).

For uterine infusion:

a) 2 grams mixed with 200 mL sterile normal saline (0.9% sodium chloride for injection) and aseptically infused into uterus daily for 3 consecutive days (Package insert; Amiglyde-V — Fort Dodge)

b) 1-2 grams IU ()

For intra-articular injection as adjunctive treatment of septic arthritis in foals:

a) If a single joint is involved, inject 250 mg daily or 500 mg every other day; frequency is dependent upon how often joint lavage is performed. Use cautiously in multiple joints as toxicity may result (particularly if systemic therapy is also given). ()

For regional intravenous limb perfusion (RILP) administration in standing horses:

a) Usual dosages range from 500 mg-2 grams; dosage must be greater than 250 mg when a cephalic vein is used for perfusion and careful placement of tourniquets must be performed. ()

Amikacin Sulfate dosage for birds:

For susceptible infections:

a) For sunken eyes/sinusitis in macaws caused by susceptible bacteria: 40 mg/kg IM once or twice daily. Must also flush sinuses with saline mixed with appropriate antibiotic (10-30 mL per nostril). May require 2 weeks of treatment. ()

b) 15 mg/kg IM or SC q12h ()

c) For gram-negative infections resistant to gentamicin: Dilute commercial solution and administer 15-20 mg/kg (0.015 mg/g) IM once a day or twice a day ()

d) Ratites: 7.6-11 mg/kg IM twice daily; air cell: 10-25 mg/egg; egg dip: 2000 mg/gallon of distilled water pH of 6 ()

Amikacin Sulfate dosage for reptiles:

For susceptible infections:

a) For snakes: 5 mg/kg IM (forebody) loading dose, then 2.5 mg/kg q72h for 7-9 treatments. Commonly used in respiratory infections. Use a lower dose for Python curtus. ()

b) Study done in gopher snakes: 5 mg/kg IM loading dose, then 2.5 mg/kg q72h. House snakes at high end of their preferred optimum ambient temperature. ()

c) For bacterial shell diseases in turtles: 10 mg/kg daily in water turtles, every other day in land turtles and tortoises for 7-10 days. Used commonly with a beta-lactam antibiotic. Recommended to begin therapy with 20 mL/kg fluid injection. Maintain hydration and monitor uric acid levels when possible. ()

d) For Crocodilians: 2.25 mg/kg IM q 72-96h ()

e) For gram-negative respiratory disease: 3.5 mg/kg IM, SC or via lung catheter every 3-10 days for 30 days. ()

Amikacin Sulfate dosage for fish:

For susceptible infections:

a) 5 mg/kg IM loading dose, then 2.5 mg/kg every 72 hours for 5 treatments. ()

Monitoring

■ Efficacy (cultures, clinical signs, WBC’s and clinical signs associated with infection). Therapeutic drug monitoring is highly recommended when using this drug systemically. Attempt to draw samples at 1,2, and 4 hours post dose. Peak level should be at least 40 mcg/mL and the 4-hour sample less than 10 mcg/mL.

■ Adverse effect monitoring is essential. Pre-therapy renal function tests and urinalysis (repeated during therapy) are recommended. Casts in the urine are often the initial sign of impending nephrotoxicity.

■ Gross monitoring of vestibular or auditory toxicity is recommended.

Client Information

■ With appropriate training, owners may give subcutaneous injections at home, but routine monitoring of therapy for efficacy and toxicity must still be done

■ Clients should also understand that the potential exists for severe toxicity (nephrotoxicity, ototoxicity) developing from this medication

■ Use in food producing animals is controversial as drug residues may persist for long periods

Chemistry / Synonyms

A semi-synthetic aminoglycoside derived from kanamycin, amikacin occurs as a white, crystalline powder that is sparingly soluble in water. The sulfate salt is formed during the manufacturing process. 1.3 grams of amikacin sulfate is equivalent to 1 gram of amikacin. Amikacin may also be expressed in terms of units. 50,600 Units are equal to 50.9 mg of base. The commercial injection is a clear to straw-colored solution and the pH is adjusted to 3.5-5.5 with sulfuric acid.

Amikacin sulfate may also be known as: amikacin sulphate, amikacini sulfas, or BB-K8; many trade names are available.

Storage / Stability/Compatibility

Amikacin sulfate for injection should be stored at room temperature (15 – 30°C); freezing or temperatures above 40°C should be avoided. Solutions may become very pale yellow with time but this does not indicate a loss of potency.

Amikacin is stable for at least 2 years at room temperature. Autoclaving commercially available solutions at 15 pounds of pressure at 120°C for 60 minutes did not result in any loss of potency.

Note: When given intravenously, amikacin should be diluted into suitable IV diluent etc. normal saline, D5W or LRS) and administered over at least 30 minutes.

Amikacin sulfate is reportedly compatible and stable in all commonly used intravenous solutions and with the following drugs: amobarbital sodium, ascorbic acid injection, bleomycin sulfate, calcium chloride/gluconate, cefoxitin sodium, chloramphenicol sodium succinate, chlorpheniramine maleate, cimetidine HCl, clindamycin phosphate, colistimethate sodium, dimenhydrinate, diphenhydramine HCl, epinephrine HCl, ergonovine maleate, hyaluronidase, hydrocortisone sodium phosphate/succinate, lincomycin HCl, metaraminol bitartrate, metronidazole (with or without sodium bicarbonate), norepinephrine bitartrate, pentobarbital sodium, phenobarbital sodium, phytonadione, polymyxin B sulfate, prochlorperazine edisylate, promethazine HCL, secobarbital sodium, sodium bicarbonate, succinylcholine chloride, vancomycin HCL and verapamil HCL.

The following drugs or solutions are reportedly incompatible or only compatible in specific situations with amikacin: aminophylline, amphotericin B, ampicillin sodium, carbenicillin disodium, cefazolin sodium, cephalothin sodium, cephapirin sodium, chlorothiazide sodium, dexamethasone sodium phosphate, erythromycin gluceptate, heparin sodium, methicillin sodium, nitrofurantoin sodium, oxacillin sodium, oxytetracycline HCL, penicillin G potassium, phenytoin sodium, potassium chloride (in dextran 6% in sodium chloride 0.9%; stable with potassium chloride in “standard” solutions), tetracycline HCL, thiopental sodium, vitamin B-complex with C and warfarin sodium. Compatibility is dependent upon factors such as pH, concentration, temperature and diluent used; consult specialized references or a hospital pharmacist for more specific information.

In vitro inactivation of aminoglycoside antibiotics by beta-lac-tam antibiotics is well documented. While amikacin is less susceptible to this effect, it is usually recommended to avoid mixing these compounds together in the same syringe or IV bag unless administration occurs promptly. See also the information in the Amikacin Sulfate Interaction and Amikacin Sulfate/Lab Interaction sections.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products:

Amikacin Sulfate Injection: 50 mg (of amikacin base) per mL in 50 mL vials; Amiglyde-V (Fort Dodge), AmijectD (Butler), Amikacin K-9 (RXV), Amikacin C (Phoenix), Amtech Amimax C (IVX), Caniglide (Vedco); generic (VetTek); (Rx); Approved for use in dogs.

Amikacin Sulfate Intrauterine Solution: 250 mg (of amikacin base) per mL in 48 mL vials; Amifuse E (Butler), Amiglyde-V (Fort Dodge), Amikacin E (Phoenix), Amikacin E (RXV), Amtech Amimax E (IVX), Equi-phar Equiglide (Vedco); (Rx); Approved for use in horses not intended for food.

WARNING: Amikacin is not approved for use in cattle or other food-producing animals in the USA. Amikacin Sulfate residues may persist for long periods, particularly in renal tissue. For guidance with determining use and withdrawal times, contact FARAD (see Phone Numbers & Websites in the appendix for contact information).

Human-Labeled Products:

Amikacin Injection: 50 mg/mL and 250 mg/mL in 2 mL and 4 mL vials and 2 mL syringes; Amikin (Apothecon); generic; (Rx)

Categories
Drugs

Acepromazine Maleate (PromAce, Aceproject)

Phenothiazine Sedative / Tranquilizer

Highlights Of Prescribing Information

Negligible analgesic effects

Dosage may need to be reduced in debilitated or geriatric animals, those with hepatic or cardiac disease, or when combined with other agents

Inject IV slowly; do not inject into arteries

Certain dog breeds (e.g., giant breeds, sight hounds) may be overly sensitive to effects

May cause significant hypotension, cardiac rate abnormalities, hypo- or hyperthermia

May cause penis protrusion in large animals (esp. horses)

What Is Acepromazine Used For?

Acepromazine is approved for use in dogs, cats, and horses. Labeled indications for dogs and cats include: “… as an aid in controlling intractable animals… alleviate itching as a result of skin irritation; as an antiemetic to control vomiting associated with motion sickness” and as a preanesthetic agent. The use of acepromazine as a sedative/tranquilizer in the treatment of adverse behaviors in dogs or cats has largely been supplanted by newer, effective agents that have fewer adverse effects. Its use for sedation during travel is controversial and many no longer recommend drug therapy for this purpose.

In horses, acepromazine is labeled “… as an aid in controlling fractious animals,” and in conjunction with local anesthesia for various procedures and treatments. It is also commonly used in horses as a pre-anesthetic agent at very small doses to help control behavior.

Although not approved, it is used as a tranquilizer (see doses) in other species such as swine, cattle, rabbits, sheep and goats. Acepromazine has also been shown to reduce the incidence of halothane-induced malignant hyperthermia in susceptible pigs.

Before you take Acepromazine

Contraindications / Precautions / Warnings

Animals may require lower dosages of general anesthetics following acepromazine. Use cautiously and in smaller doses in animals with hepatic dysfunction, cardiac disease, or general debilitation. Because of its hypotensive effects, acepromazine is relatively contraindicated in patients with hypovolemia or shock. Phenothiazines are relatively contraindicated in patients with tetanus or strychnine intoxication due to effects on the extrapyramidal system.

Intravenous injections should be made slowly. Do not administer intraarterially in horses since it may cause severe CNS excitement/depression, seizures and death. Because of its effects on thermoregulation, use cautiously in very young or debilitated animals.

Acepromazine has no analgesic effects; treat animals with appropriate analgesics to control pain. The tranquilization effects of acepromazine can be overridden and it cannot always be counted upon when used as a restraining agent. Do not administer to racing animals within 4 days of a race.

In dogs, acepromazine’s effects may be individually variable and breed dependent. Dogs with MDR1 mutations (many Collies, Australian shepherds, etc.) may develop a more pronounced sedation that persists longer than normal. It may be prudent to reduce initial doses by 25% to determine the reaction of a patient identified or suspected of having this mutation.

Acepromazine should be used very cautiously as a restraining agent in aggressive dogs as it may make the animal more prone to startle and react to noises or other sensory inputs. In geriatric patients, very low doses have been associated with prolonged effects of the drug. Giant breeds and greyhounds may be extremely sensitive to the drug while terrier breeds are somewhat resistant to its effects. Atropine may be used with acepromazine to help negate its bradycardic effects.

In addition to the legal aspects (not approved) of using acepromazine in cattle, the drug may cause regurgitation of ruminal contents when inducing general anesthesia.

Adverse Effects

Acepromazine’s effect on blood pressure (hypotension) is well described and an important consideration in therapy. This effect is thought to be mediated by both central mechanisms and through the alpha-adrenergic actions of the drug. Cardiovascular collapse (secondary to bradycardia and hypotension) has been described in all major species. Dogs may be more sensitive to these effects than other animals.

In male large animals acepromazine may cause protrusion of the penis; in horses, this effect may last 2 hours. Stallions should be given acepromazine with caution as injury to the penis can occur with resultant swelling and permanent paralysis of the penis retractor muscle. Other clinical signs that have been reported in horses include excitement, restlessness, sweating, trembling, tachypnea, tachycardia and, rarely, seizures and recumbency.

Its effects of causing penis extension in horses, and prolapse of the membrana nictitans in horses and dogs, may make its use unsuitable for show animals. There are also ethical considerations regarding the use of tranquilizers prior to showing an animal or having the animal examined before sale.

Occasionally an animal may develop the contradictory clinical signs of aggressiveness and generalized CNS stimulation after receiving acepromazine. IM injections may cause transient pain at the injection site.

Overdosage / Acute Toxicity

The LD50 in mice is 61 mg/kg after IV dosage and 257 mg/kg after oral dose. Dogs receiving 20-40 mg/kg over 6 weeks apparently demonstrated no adverse effects. Dogs gradually receiving up to 220 mg/kg orally exhibited signs of pulmonary edema and hyperemia of internal organs, but no fatalities were noted.

There were 128 exposures to acepromazine maleate reported to the ASPCA Animal Poison Control Center (APCC; www.apcc.aspca.org) during 2005-2006. In these cases, 89 were dogs with 37 showing clinical signs and the remaining 39 reported cases were cats with 12 cats showing clinical signs. Common findings in dogs recorded in decreasing frequency included ataxia, lethargy, sedation, depression, and recumbency. Common findings in cats recorded in decreasing frequency included lethargy, hypothermia, ataxia, protrusion of the third eyelid, and anorexia.

Because of the apparent relatively low toxicity of acepromazine, most overdoses can be handled by monitoring the animal and treating clinical signs as they occur; massive oral overdoses should definitely be treated by emptying the gut if possible. Hypotension should not be treated with epinephrine; use either phenylephrine or norepinephrine (levarterenol). Seizures may be controlled with barbiturates or diazepam. Doxapram has been suggested as an antagonist to the CNS depressant effects of acepromazine.

How to use Acepromazine

Note: The manufacturer’s dose of 0.5-2.2 mg/kg for dogs and cats is considered by many clinicians to be 10 times greater than is necessary for most indications. Give IV doses slowly; allow at least 15 minutes for onset of action.

Acepromazine dosage for dogs:

a) Premedication: 0.03-0.05 mg/kg IM or 1-3 mg/kg PO at least one hour prior to surgery (not as reliable) ()

b) Restraint/sedation: 0.025-0.2 mg/kg IV; maximum of 3 mg or 0.1-0.25 mg/kg IM; Preanesthetic: 0.1-0.2 mg/kg IV or IM; maximum of 3 mg; 0.05-1 mg/kg IV, IM or SC ()

c) To reduce anxiety in the painful patient (not a substitute for analgesia): 0.05 mg/kg IM, IV or SC; do not exceed 1 mg total dose ()

d) 0.55-2.2 mg/kg PO or 0.55-1.1 mg/kg IV, IM or SC (Package Insert; PromAce — Fort Dodge)

e) As a premedicant with morphine: acepromazine 0.05 mg/kg IM; morphine 0.5 mg/kg IM ()

Acepromazine dosage for cats:

a) Restraint/sedation: 0.05-0.1 mg/kg IV, maximum of 1 mg ()

b) To reduce anxiety in the painful patient (not a substitute for analgesia): 0.05 mg/kg IM, IV or SC; do not exceed 1 mg total dose ()

c) 1.1-2.2 mg/kg PO, IV, IM or SC (Package Insert; PromAce — Fort Dodge)

d) 0.11 mg/kg with atropine (0.045-0.067 mg/kg) 15-20 minutes prior to ketamine (22 mg/kg IM). ()

Acepromazine dosage for ferrets:

a) As a tranquilizer: 0.25-0.75 mg/kg IM or SC; has been used safely in pregnant jills, use with caution in dehydrated animals. ()

b) 0.1-0.25 mg/kg IM or SC; may cause hypotension/hypothermia ()

Acepromazine dosage for rabbits, rodents, and small mammals:

a) Rabbits: As a tranquilizer: 1 mg/kg IM, effect should begin in 10 minutes and last for 1-2 hours ()

b) Rabbits: As a premed: 0.1-0.5 mg/kg SC; 0.25-2 mg/kg IV, IM, SC 15 minutes prior to induction. No analgesia; may cause hypotension/hypothermia. ()

c) Mice, Rats, Hamsters, Guinea pigs, Chinchillas: 0.5 mg/kg IM. Do not use in Gerbils. ()

Acepromazine dosage for cattle:

a) Sedation: 0.01-0.02 mg/kg IV or 0.03-0.1 mg/kg IM ()

b) 0.05 -0.1 mg/kg IV, IM or SC ()

c) Sedative one hour prior to local anesthesia: 0.1 mg/kg IM ()

Acepromazine dosage for horses:

(Note: ARCI UCGFS Class 3 Acepromazine)

a) For mild sedation: 0.01-0.05 mg/kg IV or IM. Onset of action is about 15 minutes for IV; 30 minutes for IM ()

b) 0.044-0.088 mg/kg (2-4 mg/100 lbs. body weight) IV, IM or SC (Package Insert; PromAce — Fort Dodge)

c) 0.02-0.05 mg/kg IM or IV as a preanesthetic ()

d) Neuroleptanalgesia: 0.02 mg/kg given with buprenorphine (0.004 mg/kg IV) or xylazine (0.6 mg/kg IV) ()

e) For adjunctive treatment of laminitis (developmental phase): 0.066-0.1 mg/kg 4-6 times per day ()

Acepromazine dosage for swine:

a) 0.1-0.2 mg/kg IV, IM, or SC ()

b) 0.03-0.1 mg/kg ()

c) For brief periods of immobilization: acepromazine 0.5 mg/ kg IM followed in 30 minutes by ketamine 15 mg/kg IM. Atropine (0.044 mg/kg IM) will reduce salivation and bronchial secretions. ()

Acepromazine dosage for sheep and goats:

a) 0.05-0.1 mg/kg IM ()

Monitoring

■ Cardiac rate/rhythm/blood pressure if indicated and possible to measure

■ Degree of tranquilization

■ Male horses should be checked to make sure penis retracts and is not injured

■ Body temperature (especially if ambient temperature is very hot or cold)

Client Information

■ May discolor the urine to a pink or red-brown color; this is not abnormal

■ Acepromazine is approved for use in dogs, cats, and horses not intended for food

Chemistry / Synonyms

Acepromazine maleate (formerly acetylpromazine) is a phenothiazine derivative that occurs as a yellow, odorless, bitter tasting powder. One gram is soluble in 27 mL of water, 13 mL of alcohol, and 3 mL of chloroform.

Acepromazine Maleate may also be known as: acetylpromazine maleate, “ACE”, ACP, Aceproject, Aceprotabs, PromAce, Plegicil, Notensil, and Atravet.

Storage / Stability/Compatibility

Store protected from light. Tablets should be stored in tight containers. Acepromazine injection should be kept from freezing.

Although controlled studies have not documented the compatibility of these combinations, acepromazine has been mixed with atropine, buprenorphine, chloral hydrate, ketamine, meperidine, oxymorphone, and xylazine. Both glycopyrrolate and diazepam have been reported to be physically incompatible with phenothiazines, however, glycopyrrolate has been demonstrated to be compatible with promazine HC1 for injection.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products:

Acepromazine Maleate for Injection: 10 mg/mL for injection in 50 mL vials; Aceproject (Butler), PromAce (Fort Dodge); generic; (Rx). Approved forms available for use in dogs, cats and horses not intended for food.

Acepromazine Maleate Tablets: 5, 10 & 25 mg in bottles of 100 and 500 tablets; PromAce (Fort Dodge); Aceprotabs (Butler) generic; (Rx). Approved forms available for use in dogs, cats and horses not intended for food.

When used in an extra-label manner in food animals, it is recommended to use the withdrawal periods used in Canada: Meat: 7 days; Milk: 48 hours. Contact FARAD (see appendix) for further guidance.

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

Human-Labeled Products: None

Categories
Horses

Bronchoalveolar Lavage

Today the use of fiberoptic bronchoscopy is a common and standard diagnostic procedure, which allows direct observation of the upper and lower conducting airways. During passage of the endoscope through the nasopharynx, trachea, and large bronchi, the quantity of mucous secretions can be assessed readily in addition to the degree of mucosal edema and bronchospasm. In addition to examination of the airway lumen, one of the greatest advantages and rewards from bronchoscopy is the ability to sample the large and small airways and the alveoli. The specimens collected are then analyzed for their cellular and noncellular constituents.

In recent years, bronchoalveolar lavage (bronchoalveolar lavage) using either an endoscope or specialized tubing has gained some popularity over more traditional sampling methods such as tracheal aspiration for most cases in which a diffuse inflammatory disorder is suspected. For many years, it has been assumed that sampling the lower trachea provides a representative impression of the alveoli and small airways because airway free cells from the peripheral lung eventually were swept toward the trachea for clearance.

However, a large clinical case survey of young athletic horses presented with poor performance attributable to the lower respiratory system has shown that the cytologic and bacteriologic results are correlated poorly between samples obtained from the tracheal aspirate versus those from bronchoalveolar lavage. The study demonstrated that tracheal aspirate and bronchoalveolar lavage cytologic cell differential counts differed greatly within the same horse, which suggests that samples from the tracheal puddle may not reflect accurately the population of cells and secretions present within the small airways and alveoli. This is relevant insofar as exercise intolerance, airway injury resulting from inflammation, and airway hyperreactivity are associated with disease in the small airways, reflected best by bronchoalveolar lavage cytology. In addition, a higher rate of positive bacterial cultures was obtained from tracheal aspirate samples versus bronchoalveolar lavage samples performed on the same occasion. Thus the lower trachea apparently harbors a normal bacterial flora that may not be present within the small airways and alveoli. For these reasons, bronchoalveolar lavage is becoming a more popular tool to assess distal (small) airway inflammation rather than the tracheal aspirate method of sampling.

To validate the relevance of bronchoalveolar lavage differential cell counts as a complementary diagnostic tool in the assessment of the respiratory system, other quantitative measurements are necessary beyond the routine clinical examination. In the last two decades, the syndrome of heaves has been studied extensively, and several research laboratories throughout the world have clearly demonstrated a high correlation between the bronchoalveolar lavage cell differential and results of pulmonary function testing and histamine bronchoprovocation in heaves-affected horses. In recent years, similarly characterized lung function in young athletic horses with noninfectious inflammatory airway disease (IAD) has paralleled these findings with respect to the diagnostic usefulness of bronchoalveolar lavage.

The purpose of this chapter is to discuss the use of the bronchoalveolar lavage technique as a tool to identify and characterize pulmonary inflammation in horses that suffer from diffuse lung pathology such as inflammatory airway disease in the young athletic horse and the heaves syndrome in mature horses. In addition viral and bacterial pulmonary conditions are discussed briefly with respect to their diagnosis by bronchoalveolar lavage.

Indications For Bronchoalveolar Lavage

Bronchoalveolar Lavage Procedure

bronchoalveolar lavage can be performed on most conscious horses with mild sedation (xylazine 0.3-0.5 mg/kg IV or romifidine 0.03-0.05 mg/kg IV) and airway desensitization by a local anesthetic (lidocaine solution 0.4% w/v, without epinephrine). The procedure can be conducted using either a bronchoscope 1.8 to 2 m in length or a specialized bronchoalveolar lavage tube (Bivona Medical Technologies, Gary, Ind.). Once the bronchoscope or bronchoalveolar lavage tube is in the trachea, reaching the tracheal bifurcation (carina) usually induces coughing. Infusing 60 to 100 ml of prewarmed lidocaine solution (0.4%, without epinephrine) is therefore beneficial at this point to desensitize cough receptors located at the carina. After this infusion step the endoscope or bronchoalveolar lavage tube is gently but securely wedged, as detected by resistance to further advancement. Prewarmed sterile saline (200-300 ml) is infused rapidly into the lung and is subsequently aspirated.

The total amount of saline should be divided into two separate boluses for infusion, with attempts to retrieve as much fluid as possible between each bolus. In general, retrieval of 40% to 60% of the total amount of infusate indicates a satisfactory bronchoalveolar lavage. In horses with advanced disease, lower volumes are recovered and a tendency exists for less foam (surfactant) to be present. The bronchoalveolar lavage fluid samples are then pooled and kept on ice if processing is not possible within 1 hour after collection. Gross examination of the fluid should be performed to detect any flocculent debris or discoloration. One or two serum or ethylenediaminetetraacetic acid (EDTA) tubes of bronchoalveolar lavage fluid are centrifuged (1500 X g for 10 min) and air-dried smears are made from the sample pellet after removal of the supernatant. In preparation of the smears, the slides must be air dried rapidly using a small bench-top fan to preserve good cellular morphology. Smears thus prepared can be kept at room temperature for up to 8 to 10 months with little cellular alterations. The air-dried smears can be stained with Diff-Quik, Wright-Giemsa, May Gruenwald, Leishman’s, or Gram’s stain for cellular and noncellular constituent interpretation. The cellular profile and morphology may serve as a guide to the nature of airway injury, inflammation, and the pulmonary immunologic response to infections or foreign antigens.

Differential Cell Counts And Their Interpretation

Conclusion

bronchoalveolar lavage is undoubtedly becoming a powerful ancillary diagnostic tool to assist in the diagnosis of clinical and sub-clinical lower airway respiratory conditions such as non-infectious inflammatory airway disease in the young athletic horse and recurrent airway obstruction, or heaves, in older horses. Using recognized, standardized procedures, the bronchoalveolar lavage differential cell count is fairly consistent for normal horses and any alteration in the cytologic profiles from normal values identifies a wide range of nonseptic inflammatory processes. Although at present, clinicians are recommending specific treatment according to cytologic findings of the bronchoalveolar lavage cell differential, a more in-depth knowledge of the various disorders in the future may allow equine practitioners to provide more accurate prognostic information to members of the horse industry with respect to respiratory diseases in athletic horses. More so, the majority of young and mature athletic horses with an excess amount of white mucopus within the airways and markedly elevated neutrophil percentage on the cell differential do not represent a septic process. Rather, these cases demonstrate nonseptic inflammatory airway disease.

Categories
Horses

Postanesthetic Upper Respiratory Tract Obstruction

Upper respiratory tract () obstruction can occur in horses recovering from general anesthesia after various surgical procedures. Postanesthetic upper respiratory tract obstruction most often results from nasal edema and/or congestion and is usually mild. Other causes include arytenoid chondritis, dorsal displacement of the soft palate, and bilateral arytenoid cartilage paralysis. Bilateral arytenoid cartilage paralysis is relatively uncommon; however, it can result in severe upper respiratory tract obstruction with the horse becoming distressed, uncontrollable, and difficult to treat. The condition may rapidly become fatal, thus postanesthetic upper respiratory tract obstruction can be a serious complication after general anesthesia and surgery.

Etiology of Postanesthetic Upper Respiratory Tract Obstruction

Nasal Edema

Nasal edema and/or congestion is most often the result of venous congestion associated with a dependent head position during a prolonged anesthesia. Horses positioned in dorsal recumbency are thought to be more prone to nasal edema than horses in lateral recumbency. Nasal and pharyngeal edema may also result from trauma during endotracheal intubation that causes local inflammation and swelling.

Dorsal Displacement of the Soft Palate

Causes of dorsal displacement of the soft palate after ex-tubation are unknown. The condition is most likely a normal consequence of orotracheal intubation and of administration of sedative and anesthetic drugs that alter upper respiratory tract neuromuscular function. If dorsal displacement persists, it is most likely the result of an underlying upper respiratory tract problem or of inflammation in the pharynx secondary to intubation.

Arytenoid Chondritis

Arytenoid chondritis is an uncommon cause of postanesthetic upper respiratory tract obstruction but can be a longer-term consequence of traumatic intubation. Although this condition will not lead to obstruction in the same anesthetic period, it may at a later time if it is not recognized. Furthermore, the presence of an abnormal arytenoid will compromise the airway and can potentiate the possibility of an obstructive crisis.

Bilateral Laryngeal Paralysis

The etiology of postanesthetic bilateral laryngeal paralysis is unknown. Proposed etiologies include inflammation and edema of the larynx and neuromuscular failure. Physical trauma from endotracheal intubation or chemical irritation from residue after endotracheal tube cleaning may result in arytenoid chondritis, laryngeal dysfunction, and laryngeal inflammation and swelling. Laryngeal edema from venous congestion associated with a dependent head position during a prolonged anesthesia may cause swelling and failure of the arytenoid cartilages to adequately adduct. Causes of neuromuscular failure that lead to bilateral arytenoid cartilage paralysis include trauma to the cervical region or jugular vein; compression of the recurrent laryngeal nerve between the endotracheal tube or cuff and noncompliant neck structures; damage to the recurrent laryngeal nerve from intraoperative hypoxia, ischemia, or hypotension; and overextension of the neck when the horse is positioned in dorsal recumbency that causes damage to the recurrent laryngeal nerve as a result of compression of its blood supply.

α2-Adrenergic agonists have been shown to increase laryngeal asynchrony and increase upper airway resistance in horses. The muscle relaxant effects of xylazine are thought to decrease the tone of the supporting airway muscles, which in combination with low head carriage may cause an increase in airway resistance. The muscle relaxant effects of xylazine may have worn off at the time the horse has recovered from anesthesia; however, one study showed that upper airway resistance increased for 30 to 40 minutes after xylazine administration and then slowly returned to normal. Impaired laryngeal function associated with xylazine administration in combination with excitement associated with recovery from anesthesia and extubation may lead to dynamic collapse of the upper respiratory tract and result in the clinical signs described. Xylazine is a commonly used preanesthetic drug; therefore although it is unlikely to be the sole cause of the upper respiratory tract obstruction, it may be a contributing factor.

Underlying upper respiratory tract disease such as laryngeal hemiplegia may also predispose horses to severe postanesthetic obstruction. A few reports exist in the literature of severe postanesthetic upper respiratory tract obstruction in horses associated with laryngeal dysfunction. In two previous reports, bilateral arytenoid cartilage paralysis was associated with surgery in the head and neck region, and the horses recovered after establishment of a patent airway. These authors have recently seen several postanesthetic upper respiratory tract obstructions in horses that have undergone surgery for a variety of reasons including arthroscopy, tarsal arthrodesis, exploratory celiotomy, ovariohysterectomy, mastectomy, and prosthetic laryngoplasty/ventriculectomy. In addition to having undergone prosthetic laryngoplasty, some of these horses had a history of laryngeal hemiplegia before surgery. This fact suggests that preexisting disease may predispose to this condition. Postanesthetic upper respiratory tract obstruction in the horses at these authors’ hospital is often associated with excitement or exertion, including standing after anesthesia and vocalization. The cause of severe obstruction therefore could be laryngospasm or dynamic adduction of both paretic arytenoid cartilages into the airway during inspiration.

In the horses at these authors’ hospital, no association exists between difficult endotracheal intubation and upper respiratory tract obstruction. In horses that developed obstruction the duration of anesthesia was 90 to 240 minutes, and horses had mild-to-moderate hypotension, hypoventilation, and hypoxemia. These authors clean their endotracheal tubes with chlorhexidine gluconate between uses. If the tubes are not rinsed adequately, mucosal irritation from residual chlorhexidine gluconate could conceivably cause upper respiratory tract irritation and lead to obstruction. Most important, however, all these horses were positioned in dorsal recumbency for at least some of the time they were under anesthesia. The horses are positioned on a waterbed from the withers caudad. This position results in hyperextension of the neck and a dependent head position, both of which may predispose to postanesthetic bilateral arytenoid paralysis.

Negative-Pressure Pulmonary Edema

Pulmonary edema can result from upper respiratory tract obstruction and has been referred to as negative-pressure pulmonary edema because the pulmonary edema occurs secondary to strong inspiratory efforts against a closed airway. In humans vigorous inspiratory efforts against a closed glottis may create a negative pressure of as low as -300 mm Hg that, obeying Starling’s laws of fluid dynamics, fluid moves from the intravascular space into the interstitium and alveoli.

Clinical Signs

Although upper respiratory tract obstruction usually occurs immediately after extubation, severe obstruction associated with bilateral arytenoid paralysis may occur within 24 to 72 hours of recovery from anesthesia. The most obvious clinical sign is upper respiratory tract dyspnea. Horses with nasal edema have a loud inspiratory snoring noise, whereas horses with dorsal displacement of the soft palate have an inspiratory and expiratory snoring noise associated with fluttering of the soft palate. Horses with severe upper respiratory tract obstruction from bilateral laryngeal paralysis have a loud, high-pitched, inspiratory stri-dor associated with exaggerated inspiratory efforts.

Treatment of Postanesthetic Upper Respiratory Tract Obstruction

Nasal Edema

The most common type of upper respiratory tract obstruction is nasal edema, which often resolves rapidly without treatment. If obstruction is severe, it is critical to create a patent airway. The horse should be reintubated with a nasotracheal or orotracheal tube or 30-cm tubing placed in the nostrils to bypass the obstruction. Phenylephrine intranasal spray (5-10 mg in 10 ml water) or furosemide (1 mg/kg) may be used to reduce the nasal edema. Edema can be prevented by atraumatic intubation, reducing surgery time, and keeping the horse’s head elevated during anesthesia and surgery.

Dorsal Displacement of the Soft Palate

Dorsal displacement of the soft palate usually resolves spontaneously when the horse swallows, however, it may be corrected through induction of swallowing by gentle manipulation of the larynx or by insertion of a nasogastric tube into the pharynx.

Bilateral Laryngeal Paralysis

Severe obstruction often develops when the horse stands after being extubated. Emergency treatment is required because the horse will rapidly become severely hypoxic, develop cardiovascular collapse, and die. Horses are often difficult to treat because obstruction may not be noticed until the horse is severely hypoxic and uncontrollable. Treatment is then delayed until the horse collapses from hypoxia, however, emergency reintubation or tracheostomy is often too late.

Immediate treatment consists of rapid reintubation or tracheostomy. Horses may be reintubated with a nasotracheal tube (14-22 mm) or an orotracheal tube (20-26 mm). The clinician performs a tracheostomy by clipping, preparing, and blocking the ventral cervical region (if time permits), making a 8-cm vertical incision on midline at the junction of the upper and middle thirds of the neck, bluntly separating the sternothyrohyoideus muscles, and then making a transverse incision between the tracheal rings. These authors recommend having a kit available with a tracheostomy tube and drugs for reinduction of anesthesia (xylazine, 1.1 mg/kg; ketamine, 2.2 mg/kg; or a paralytic agent such as succinylcholine, 330 μg/kg IM). Horses should be treated with insufflation of oxygen immediately after establishment of an airway.

Prevention of upper respiratory tract obstruction after anesthesia requires treatment of hypotension, hypoxemia, and hypoventilation, avoidance hyperextension of the neck when horses are positioned in dorsal recumbency, and thorough rinsing of endotracheal tubes. These authors recover horses with the oral endotracheal tube in place, and following extubation closely monitor air movement.

If the horse has bilateral laryngeal paralysis, it may be necessary to establish a tracheostomy while the horse is treated aggressively with antiinflammatory treatment. Recovery should occur within days.

Negative-Pressure Pulmonary Edema

Previous reports have described successful treatment of negative-pressure pulmonary edema, however, treatment may fail if a delay occurs between obstruction and treatment or if an unknown underlying disease is present. Treatment of negative-pressure pulmonary edema consists of administration of oxygen through nasal insufflation (10-15 L/min for an adult horse), a diuretic (furosemide, lmg/kg IV, and mannitol, 0.5-1.0 g/kg IV), antiinflammatory agents (flunixin meglumine, 1.1 mg/kg; dexamethasone, 0.1-0.3 mg/kg; dimethyl sulfoxide [DMSO]; lg/kg), and the positive inotrope epinephrine (2-5 μg/kg). Fluid therapy with polyionic isotonic fluids and electrolytes should be administered, however, overhydration of horses with pulmonary edema must be avoided.

Categories
Horses

Natural Colloid Therapy

Whole Blood Transfusion

When deciding if a whole blood transfusion is warranted, several factors should be considered — including the severity and cause of anemia, the short life-span of transfused red blood cells (red blood cell), and compatibility testing (cross-matching). A whole blood transfusion is indicated in horses with a packed cell volume (packed cell volume) at or below 12% secondary to acute blood loss or hemolysis. Similarly, whole blood transfusion is indicated in a patient with a packed cell volume less than or equal to 8% that results from chronic blood loss or hemolysis. Admittedly, these values are not absolute, and the patient’s overall clinical condition should be considered along with determination of whether blood loss or hemolysis is ongoing.

In addition to evaluating the severity and cause of the anemia, the short lifespan of transfused RBCs should be considered. Allogenic equine erythrocytes are removed from the circulation by the mononuclear phagocyte system within 4 days of transfusion as the result of the development of serum antibodies against nonhost erythrocyte antigens within 3 to 10 days in nearly half of horses after a single transfusion. Thus any necessary subsequent transfusions should be performed with caution if given more than 3 days after the initial transfusion.

Horses display a high degree of blood group polymorphism. At least 30 different erythrocyte antigens (alloantigens) that make up multiple blood types (A, C, D, K, P, Q, and U) account for the 400,000 or so blood phenotypes in horses. Hence identification of a perfect match between a donor and recipient is nearly impossible. However, suitable compatibility may be determined by prior blood-typing of the donor and agglutination cross-match testing. Prior knowledge of the donor’s blood type is helpful to avoid donors that are carrying the alloantigens Aa and Qa. These alloantigens are considered the most immunogenic, and transfusion of blood that contains these antigens may result in severe hemolysis. The Quarter Horse and Belgian breeds carry a low frequency of Aa and Qa alloantigens. The saline agglutination test can be divided into major and minor cross-matching. The major cross-match combines washed erythrocytes from the donor and serum from the recipient and is followed by agglutination testing. In contrast, the minor cross-match combines donor serum with erythrocytes from the recipient and is followed by testing for agglutination. Unfortunately, such testing does not provide information regarding hemolyzing antibodies (hemolysin), which, if present, will cause severe hemolysis of transfused RBCs. Testing for hemolysins requires adding exogenous complement from rabbit serum to the reaction mixture, and such testing is limited to few laboratories because of the special handling and storage required of rabbit serum. Compatibility testing should precede transfusion; however, that is not always possible. In the absence of donor blood-typing, cross-matching, or testing for hemolysins, the ideal equine blood donor is an adult gelding that is negative for equine infectious anemia virus and has never received a blood or plasma transfusion. In addition, first-time transfusion of whole blood to a patient that has not received previous blood products or cross-matched is usually well-tolerated. In cases of blood loss into a body cavity, autotransfusion of blood may be considered if the blood can be collected aseptically.

Although whole blood transfusions may significantly improve the patient’s immediate condition, they are not without complications. As previously mentioned, the short half-life of transfused RBCs and the development of alloantibodies limit the extent of long-term benefits from whole blood transfusions. In addition, blood transfusions suppress bone marrow response to anemia by reducing the production of erythropoietin by the kidneys. The normal bone marrow begins to replace lost cells within 5 days. Hence whole blood transfusions provide only temporary improvements of oxygen supply to vital tissues. Thus even after a whole blood transfusion, determination and correction of the cause of the anemia remains critical.

Whole Blood Collection

Whole blood is collected from the donor into sterile, plastic collection bags or sterile glass containers that contain acid-citrate-dextrose (anemia of chronic disease) or citrate-phosphate-dextrose (Baxter; Deerfield). The desired anemia of chronic disease-to-whole blood ratio is approximately 1:10. Depending on individual preferences, sterile glass containers may be better suited for more efficient collection of whole blood because of the negative pressure while under vacuum. However, once they are filled, they are heavy; if they are dropped, all of the contents may be lost. Regardless of the collection container, the collection procedure is aseptically performed through an intravenous catheter or a large bore needle connected to an extension set. Determination of the total blood volume to collect and transfuse depends on the size of the donor and the estimated blood loss of the recipient. An average size horse (450 kg) with a packed cell volume of 35% to 40% can provide approximately 20% (8-10 L in an adult horse) of its blood volume every 30 days. Generally, 20% to 30% of the recipient’s total blood volume (7-11 L in a 450-kg horse) is adequate to recover oxygen supply to vital tissues until bone marrow has an opportunity to respond. Alternatively, if whole blood transfusion is warranted and an estimate of blood loss is not accurate, 15 ml/kg (6-8 L in a 450-kg horse) of whole blood may be administered. Once it is collected, using whole blood immediately is best, yet it can remain stable at 4° C for 2 to 3 weeks once the anemia of chronic disease is added.

Blood Administration

Whole blood is filtered before administration and is transfused into the recipient through an aseptically placed jugular catheter. Initially (5-10 min), the administration rate should be slow (0.1 ml/kg) to observe for any signs of adverse reactions. These include tachypnea, dyspnea, restlessness, tachycardia, piloerection, muscle fasciculations, or sudden collapse. Subsequently, the transfusion rate may be increased to but not exceed 20 ml/kg/hour. If severe adverse reactions occur, the transfusion should be terminated, and epinephrine (0.01 to 0.02 ml/kg, 1:1000) along with isotonic fluids should be administered. Alternatively, if only mild reactions occur, the transfusion rate may be slowed and corticosteroids or nonsteroidal antiinflammatories administered.

Blood Component Therapy

Administering concentrates of specific equine plasma components rather than whole blood may be more appropriate for treating deficiencies of granulocytes, platelets, or erythrocytes. This is especially true for patients with a deficiency in a cell type due to destruction rather than blood loss. These horses do not have a deficiency in blood volume but rather a deficiency in the specific constituents. Hence a whole blood transfusion may predispose them to fluid overload, whereas administration of the specific components that are deficient may be more appropriate. Centrifugation apheresis provides a method for concentrating granulocytes, platelets, and erythrocytes from whole blood. In addition to these cell types, other blood components such as immunoglobins and clotting factors may be concentrated and administered. Concentrated, lyophilized immunoglobulin (Lyphomune, Diagnon Corporation, Rockville, Md.) is commercially available for treatment of failure of passive transfer in foals, selective deficiencies of immunoglobulin, and treatment of immune-mediated disorders. Cryoprecipitate — a mixture of factor VIII :C, fibrinogen, and fibronectin — is used for treatment of hemophilia in dogs and people but is not readily available or affordable for use in horses. The collection of whole blood and administration of the blood components should follow the same guidelines as discussed previously. Furthermore, aseptic handling of the blood components during the centrifugation apheresis is critical to prevent bacterial contamination before administration.

Alternatives to Blood Component Therapy

In addition to transfusion, several alternative products have been used to treat granulocytes deficiencies such as neutropenia. These products include hemopoietic growth factors such as recombinant canine and bovine granulocyte-colony stimulating factor. In one study, normal foals that were given bovine granulocyte-colony stimulating factor experienced an increase in neutrophil count without apparent adverse effects. A second study in foals found an increase in bone marrow cellularity and increased myeloid activity after treatment with canine recombinant granulocyte-colony stimulating factor. The efficacy of these products is suggested by these studies; however, more work is needed to develop a therapeutic plan for horses of all ages. Administration of human recombinant erythropoietin to horses can result in severe, sometimes fatal, anemia.

Plasma Transfusion

Horses that are suffering from declining intravascular oncotic pressure due to protein deficiency and neonatal foals that are suffering from failure of passive transfer are candidates for plasma administration. Foals require 1 to 2 L (20-40 ml/kg) of plasma to adequately increase IgG levels, and hypoproteinemic adult horses (450 kg) require 6 to 8 L of plasma to improve oncotic pressure. In general, administration of 7 L of equine plasma that contains 7 g/dl of protein will result in a 1 g/dl increase in total protein. Plasma retains several advantages over synthetic colloids as a source of functional proteins (clotting factors), immunoglobins, and complement. However, disadvantages to plasma include its poor ability to increase oncotic pressure and the expense of product. Plasma can be purchased from commercial supplier (Lake Immunogenics, Ontario, N.Y.; Veterinary Dynamics, Inc., Chino, Calif.; Immvac, Inc., Columbia, Mo.; Veterinary Immunogenics, LTD, Cumbria, England) or can be collected from whole blood that has been centrifuged or allowed to settle at room temperature for 1 to 2 hours, followed by removal of the settled RBCs by gravity flow. The collection of whole blood and administration of the plasma should follow the same guidelines discussed previously. Furthermore, aseptic handling of the blood components during plasma separation is critical to prevent bacterial contamination before administration. Because of the high risk of contaminating the plasma with large volumes of whole blood, storage of liter bags of commercially available equine plasma for future use at 0° C for up to 1 year might be ideal. In addition to normal plasma, hyperimmune plasma from horses that have been immunized against the etiologic agents responsible for diseases such as Rhodococcus pneumonia, salmonellosis, and botulism are commercially available. (Lake Immunogenics, Veterinary Dynamics, Inc., Immvac, Inc., Veterinary Immunogenics, LTD). The efficacy of these products remains unknown; however, some evidence suggests that the incidence or severity of Rhodococcus pneumonia may be lessened in foals that receive hyperimmune plasma.

Categories
Horses

Urticaria

Urticaria is a very common nodular presentation. Edema in the dermis causes a rapid onset of nodules. This condition is often referred to as “feed bumps” or “protein bumps” by the layperson. The pathogenetic mechanism is that of a type I hypersensitivity most often associated with drug administration such as antibiotics, antiinflammatory agents, or vaccines. Drugs may be administered by any route. Other causes of urticaria include allergies to pollens, foods, or insects. For a large number of cases, no specific agent is identified; these cases are then classified as idiopathic. A portion of idiopathic cases actually are likely to be a form of autoimmune disease that results from autoantibodies cross-linking the Fc receptor of mast cells.

Urticaria: Clinical Signs

Clinical signs consist of a sudden onset of localized to generalized wheals. The lesions may or may not be accompanied by pruritus. In some horses the lesions take on a serpiginous or ringlike appearance.

Diagnosis of Urticaria

Diagnosis is usually based on lesion appearance and history of rapid onset. When digital pressure is applied to a lesion, an indentation is made, which supports dermal edema rather than a cellular infiltrate as the cause of the nodule. Biopsy is indicated in cases of recurrent or chronic urticaria and, in severe cases, to rule out vasculitis as a cause for the dermal edema. Occasionally, early dermatophytosis presents with wheal formation. These lesions progress to the more classic dermatophyte lesions in a day or two.

Treatment of Urticaria

Treatment options depend on the cause and severity of the urticaria. Lesions should regress rapidly on their own on termination of exposure to the initiating antigen. Although antihistamines do not cause regression of existing lesions, they prevent further histamine-binding to receptors while the antigen is still present in the tissue and are therefore very helpful in cases of urticaria. Hydroxyzine hydrochloride (1 to 1.5 mg/kg q8-12h) is very effective for this condition. Antiinflammatory doses of corticosteroids (prednisolone 0.5 to 1.0 mg/kg/day) may be indicated in severe or chronic cases. In refractory cases, dexamethasone (at an initial dose of 0.02 to 0.1 mg/kg/day followed by oral maintenance dose of 0.01 to 0.02 mg/kg every 48 to 72 hours) may be of benefit. Lastly, epinephrine may be needed if lesions are associated with systemic signs of anaphylaxis.

In addition to treating the urticarial lesions, identification of the underlying cause is paramount. First, with a careful history, drugs should be ruled out. Insect hypersensitivity can be addressed with good fly control by using 2% permethrin. In chronic recurrent urticaria, food allergy should be investigated by placing the horse on grass hay different from the usual hay. If grain is needed, oats should be added while sweet feed and food supplements are avoided. Some horses with recurrent urticaria have positive skin test results to pollens and molds and may benefit from hyposensitization (see “Atopy”).

Urticaria: Prognosis

Prognosis depends on the underlying cause. When the case can be identified and corrected, prognosis is excellent. Chronic recurrent urticaria is usually idiopathic and therefore has a poor prognosis for cure.

Categories
Drugs

Symmetrel

Pharmacology

Animal Studies

In animals, amantadine hydrochloride caused several pharmacologic effects at relatively high doses. Signs of motor activity stimulation (increased spontaneous motor activity and antagonism of tetrabenazine- induced sedation) occurred in mice at oral doses of 35-40 mg/kg and above. A transient vasodepressor effect, cardiac arrhythmias and a weak ganglionic-blocking effect in dogs were observed following intravenous doses of 13.5 mg/kg or above. EEG activation has been reported in the rat and rabbit with high parenteral doses.

In addition, the observations summarized in the table below have afforded evidence that amantadine HCl causes norepinephrine release and blockade of norepinephrine re-uptake at peripheral autonomic neuron storage sites.

 

Amantadine
Response Species Dose (mg/kg) Route
Blockade by reserpine pre-treatment of amantadine-induced transient increase in myocardial contractile force. dog 1 to 3 intravenous
Potentiation of norepine-phrine vasopressor response. dog 40.5 intravenous
Block of phenethylamine vasopressor response. dog >13.5 intravenous
Block of norepinephrine uptake into the heart. mouse >31 intraperitoneal

Amantadine hydrochloride is well absorbed by the oral route in all species studied; the rate of excretion of the drug is first order. The metabolism of amantadine hydrochloride in the monkey and mouse is somewhat similar to that in man. The monkey and mouse metabolize the drug less than the rat, dog and rabbit. The urine appears to be the major route of elimination. The dog has been shown to convert a portion of the administered drug to its N-methyl derivative which is excreted in the urine. No other metabolites have been identified.

Toxicology

The results of acute oral, intraperitoneal and intravenous toxicity studies in several species of laboratory animals are shown in Table Acute Toxicity Of Amantadine Hydrochloride LD50 (95% confidence limits). Oral LD50 values for dogs and rhesus monkeys could not be obtained because the animals vomited. One dog, which did not vomit, died at 93 mg/kg following signs of central nervous system stimulation, including clonic convulsions. In monkeys at doses of 200-500 mg/kg, emesis always occurred and convulsions appeared irregularly. At levels near the LD50, signs of central nervous system stimulation followed by tremors and brief clonic convulsions were common to the three rodent species by all routes of administration. All deaths occurred promptly, usually within a few minutes, or at the most within a few hours after compound administration.

Table Acute Toxicity Of Amantadine Hydrochloride LD50 (95% confidence limits)

Species Sex Oral
(mg/kg)
Intraperitioneal
(mg/kg)
Intravenous
(mg/kg)
Mouse F 700 (621,779) 205 (194,216) 97 (88,106)
Rat F 890(761,1019) 223 (167,279)
Rat M 1275 (1095,1455)
Rat, neonatal M,F 150 (111,189)
Guinea pig F 360 (316,404)
Dog M,F >372*
Monkey, M >500* >37
* Emesis occurred

Chronic oral toxicity experiments were carried out with rats (88-94 weeks), dogs (2 years) and monkeys (6 months). The amantadine hydrochloride dose levels were 16, 80 and 100-160 mg/kg; 8, 40 and 40-80 mg/kg; and 10, 40 and 100 mg/kg, respectively, administered daily (5 days per week). In rats, at the high dose only, a statistically significant decrease in body weight and excess mortality was seen; signs of central nervous system stimulation after each dosing, reduced food intake, and susceptibility to infection were noted. In dogs, tremors, hyperexcitability and emesis were seen at the middle and high levels, and food intake was reduced. One dog in the middle, and three dogs in the high-level group died. In an additional dog experiment, 30 mg/kg of amantadine hydrochloride divided into two doses six hours apart, was given seven days per week for six months. No drug-related effects were seen. In the monkey experiment, stimulation was continuously evident in the high level and was seen sporadically in the middle-level group. No other effects were noted. In none of these experiments with rats, dogs and monkeys were any amantadine hydrochloride-related pathological or histomorpho-logical changes seen.

Effects on Reproduction

In rats, a 3-litter reproduction study was performed. Amantadine hydrochloride 10 mg/kg in the diet, resulted in no observed abnormality. When the dose was raised to 32 mg/kg, fertility and lactation indices were somewhat depressed. No fetal abnormalities were noted in this experiment.

In a different study virgin rats were dosed orally with amantadine hydrochloride (50 or 100 mg/kg) from 5 days prior to mating until day 6 of pregnancy. Autopsy performed on day 14 of gestation showed significant decreases in the number of implantations and number of resorptions at 100 mg/kg. Teratology studies were performed in rats by administering the drug (37, 50 or 100 mg/kg) orally on days 7-14 of gestation. Autopsy just before parturition showed increases in resorption and decreases in the number of pups per litter at 50 and 100 mg/kg. Malformation of pups occurred with a frequency of 0% at the 37 mg/kg, 4.7% at the 50 mg/kg and 17% at the 100 mg/kg level. The majority of changes were skeletal (mainly spinal column and rib deficits), but some visceral changes (edema, undescended ovaries and testes) were also mentioned.

In a teratology study carried out in Japan, pregnant rats received amantadine hydrochloride (40 or 120 mg/kg) orally on days 9 to 14 of gestation. At the higher dose the dams had a slightly decreased rate of increase in body weight, the mortality rate of the fetus was increased and the surviving pups showed decreased body weight. This difference, however, disappeared after the end of the first postnatal week. There were no malformations or skeletal abnormalities.

In a teratogenetic study mice received amantadine hydrochloride 10 or 40 mg/kg, p.o., from the 7th to the 12th day of pregnancy. The most important findings include, at the high dose level, increased fetus mortality and reduced body weight of the dams as well as of the surviving offspring. One case of exencephalia was found in the high-level group which, in the opinion of the investigators, was not drug-related.

Rabbits were mated and dosed six days later with 8 or 32 mg/kg through day 16 and sacrificed on day 28. A separate study was reported in which rabbits received amantadine hydrochloride orally, 100 mg/kg, on days 7 to 14 of gestation. No teratogenic or other adverse effects were seen in these rabbit experiments.

Categories
Diseases

Heart Failure: Treatment Strategies

Management of Acute Decompensated Congestive Heart Failure

Dogs with dilated cardiomyopathy or mitral regurgitation often present with acute onset of coughing, dyspnea, restlessness, orthopnea, and weakness subsequent to the development of severe pulmonary edema and/or low cardiac output. The immediate priorities in these patients are resolution of the pulmonary edema, maintenance of adequate tissue perfusion pressure, and adequate delivery of blood flow to vital tissues. These goals must be achieved quickly, therefore it is important that the practitioner use drugs with proven hemodynamic benefits and a rapid onset of action.

Oxygen Supplementation

As left atrial and pulmonary capillary pressures increase and the lymphatics’ capacity to remove fluid is overwhelmed, the interstitial space and alveoli become flooded. Because these flooded alveoli lack ventilation and represent areas of functional shunting, oxygen administration must be combined with agents that effectively lower pulmonary venous pressure. Oxygen can easily be administered to compromised patients by provision of an oxygen-enriched environment (i.e., oxygen cage) or by use of nasal insufflation, achieving maximal inspired oxygen concentrations of 40% to 90%, respectively.

Reduction of Pulmonary Venous Pressure

Rapid reduction of pulmonary venous pressure is most readily achieved through use of a combination of intravenous (IV) drugs that lower the circulating plasma volume and redistribute the intravascular volume. Intravenous furosemide (2 to 8 mg/kg) should be administered to dogs with severe pulmonary edema to promote natriuresis and diuresis quickly. These large doses may be repeated (initially every 1 to 2 hours) until the respiratory rate and dyspnea start to decline. After stabilization, the dose should be reduced (2 to 4 mg/kg every 8 to 12 hours), because excessive administration may lead to profound dehydration, electrolyte depletion, renal failure, low cardiac output, and circulatory collapse.

Drugs that decrease preload (to combat congestion) and afterload (to decrease myocardial work) are administered concurrently with furosemide. Intravenous sodium nitroprusside is a potent, ultrarapid, balanced vasodilator that seems to reduce pulmonary venous pressure quickly and effectively. When used in animals with congestive heart failure, nitroprusside decreases right atrial and pulmonary capillary wedge pressures and systemic vascular resistance and increases cardiac output. Although hypotension and tachycardia are reported side effects, the reduction in systemic vascular resistance (SVR) is theoretically associated with an increase in cardiac output (CO) that serves to maintain systemic arterial blood pressure (BP = SVR. x CO). Nausea, vomiting, and cyanide toxicity during prolonged administration are other reported side effects. Because of its short half-life, nitroprusside, mixed with 5% dextrose, must be administered by constant-rate infusion (CRI). After institution of an initial dose of 1 µg/kg/min, the rate is slowly titrated upward while the blood pressure is monitored. An infusion rate of 2 to 5 µg/kg/min usually is sufficient to decrease afterload, although rarely doses as high as 10 µg/kg/min may be required. If significant hypotension is encountered after administration of nitroprusside, slowing the infusion rate generally is effective at raising the blood pressure to acceptable levels.

Sodium nitroprusside Nitroprusside is an intravenous preparation with potent arteriolar and venous vasodilative properties mediated by the formation of nitric oxide and subsequently the second messenger cyclic guanosine monophosphate (cGMP). To some degree, the combination of nitroprusside and dobutamine can be considered short-term “cardiac life support,” used primarily during an attempt to rescue dogs with severe, life-threatening pulmonary edema subsequent to dilated cardiomyopathy. This drug combination’s ability to reduce afterload quickly appears to be beneficial also in patients with chronic degenerative valvular disease and pulmonary edema, although management of these cases often can be accomplished less intensively.

Unfortunately, the beneficial hemodynamic profile of nitroprusside is accompanied by a difficult administration protocol that requires intensive monitoring. Because nitroprusside produces an almost immediate and often profound reduction in systemic vascular resistance, continuous blood pressure monitoring throughout administration is recommended. The drug is light sensitive, is given by constant-rate infusion (typically 2 to 5 µg/kg/min), and should not be infused with another agent, which necessitates placement of a second intravenous catheter for administration of dobutamine. These stringent requirements may provide cause for more frequent use of intravenous bipyridines to combat life-threatening heart failure, at least until studies are able to elucidate whether either method produces better results.

If nitroprusside is unavailable, balanced vasodilatation may be attempted through administration of an arterial vasodilator (hydralazine, 0.5 to 2 mg/kg given orally) in combination with a venodilator (nitroglycerin ointment, ¼ to ¾ -inch applied cutaneously every 8 to 12 hours; or isosorbide dinitrate, 0.5 to 2 mg/kg given orally every 8 hours). Although easier to administer, this therapy seems to be less effective at quickly reducing pulmonary venous pressure compared with nitroprusside.

Potent afterload reduction in patients with severe mitral insufficiency and large regurgitant volumes serves to decrease the left ventricular to left atrial pressure gradient and hence the volume of insufficiency. Nitroprusside, or possibly hydralazine, can effectively decrease the volume of mitral regurgitation and lower left atrial pressure in cases of severe congestive heart failure subsequent to rupture of the chordae tendineae or the onset of atrial fibrillation. Despite this obvious theoretical advantage, a recent human study showed that mitral regurgitation worsened in four of nine patients with mitral valve prolapse during nitroprusside infusion. This finding highlights the point that adjustments in the therapeutic regimen may be required and should be based on patient response rather than physiologic principles.

Augmentation of Systolic Performance

Preload reducing agents, such as furosemide, cannot enhance systolic function and in fact at high doses serve only to decrease cardiac output. Therefore the use of a rapid-acting, intravenous inotropic agent is vital to the management of acute decompensated congestive heart failure in dogs with dilated cardiomyopathy. Although there is debate over whether dogs with mitral valve insufficiency have systolic dysfunction, acutely positive inotropic agents may serve to decrease the regurgitant orifice area and hence the volume of insufficiency.

The short-acting, positive inotropic agents most commonly used to manage decompensated heart failure increase cyclic adenosine monophosphate (cAMP). Dobutamine and dopamine are sympathomimetic agents that bind to beta, receptors, thereby stimulating adenylyl cyclase activity and production of cAMP. The bipyridines amrinone and milrinone increase cyclic adenosine monophosphate by preventing its degradation by phosphodiesterase. Both drug classes are capable of rapidly augmenting systolic function during constant-rate intravenous infusions. By increasing cytosolic cAMP, these agents enhance (1) calcium entry into the cell, promoting ventricular contraction; (2) diastolic calcium uptake by the sarcoplasmic reticulum, promoting ventricular relaxation; and (3) peripheral vasodilatation, reducing after-load. It should be remembered that the sympathomimetics also have alpha-agonistic properties that promote vasoconstriction. Unfortunately, both the sympathomimetics and the bipyridines may promote tachycardia and undesirable ventricular arrhythmias. Therefore careful electrocardiographs (ECG) monitoring is required during administration of these drugs, and significant or worsening ventricular arrhythmias may warrant discontinuation of the infusion and institution of antiarrhythmic therapy.

Sympathomimetics The sympathomimetics enhance cardiac contractility by complexing with myocardial beta receptors. After substrate binding to an unoccupied beta receptor, a coupled G-protein stimulates the enzyme cyclase to produce cAMP. This second-messenger “effector” system acts by means of protein kinase A to phosphorylate intracellular proteins, including the L-type calcium channel, phospholamban, and troponin I, thereby enhancing ventricular contraction and relaxation. Despite the sympathomimetics’ ability to increase cardiac contractility approximately 100% above baseline, not all drugs in this class are suitable for the management of heart failure. The specificity for beta receptor binding depends on the specific agent and dose administered. Sympathomimetics inappropriate for the management of heart failure include the pure beta agonist isoproterenol and the naturally occurring catecholamines norepinephrine and epinephrine. These agents tend to promote tachycardia, arrhythmias, and untoward alterations in systemic vascular resistance

Dobutamine and dopamine are more appropriate sympathomimetics for the management of heart failure. Although both drugs can enhance cardiac contractility, several drawbacks discourage long-term use: (1) they must be given intravenously, because successful oral administration is precluded by extensive first-pass hepatic metabolism; (2) because of their extremely short half-lives (approximately 1 to 2 minutes), they must be administered by constant-rate infusion; (3) almost any positive inotropic response tends to increase myocardial work and thus the propensity for ventricular arrhythmias; and (4) after 24 to 48 hours of constant-rate infusion, their positive inotropic response is limited by beta receptor downregulation and uncoupling. The tendency for long-term sympathomimetic administration to increase mortality, as documented in humans, appears to relegate these agents to short-term management of acute, life-threatening heart failure.

Dobutamine Dobutamine is a synthetic analog of dopamine that displays predominately betaj receptor binding (beta1 > beta2 > alpha). Dobutamine is able to increase cardiac contractility and thus cardiac output without causing a profound, concomitant increase in the heart rate. The mechanism underlying the lack of a positive chronotropic response is not well understood, but this characteristic tends to make dobutamine the most appropriate agent for short-term treatment of heart failure. It appears that complexing with vasodilative beta receptors and vasoconstrictive alpha receptors, combined with an increase in cardiac output, maintains arterial blood pressure at near baseline values. If the systolic blood pressure is normal to elevated, dobutamine infusion (slow titration up to 5 to 15 µg/kg/min in 5% dextrose) can be combined with the potent vasodilator nitroprusside in an attempt to decrease internal cardiac work and further enhance forward blood flow. Continuous ECG and blood pressure monitoring is recommended during this treatment regimen, and exacerbation of tachycardia or ventricular arrhythmias may necessitate discontinuation of dobutamine.

Dopamine A precursor of norepinephrine, dopamine can bind myocardial beta receptors in addition to peripherally located dopaminergic, beta2, and alpha receptors. Within the renal, mesenteric, coronary, and cerebral vascular beds, these dopaminergic DA2 receptors are able to promote vasodilata-tion at low infusion rates of dopamine (1 to 2 µg/kg/min). However, at higher infusion rates (10 to 20 µg/kg/min), these vasodilative properties are over-ridden by an undesirable, alpha-mediated vasoconstrictive response. Also, high doses are accompanied by increases in the heart rate, the likelihood of arrhythmogenesis, the release of norepinephrine, and the myocardial oxygen demand. Dopamine (slow titration up to 1 to 10 µg/kg/min) may be used in situations similar to those in which dobutamine is appropriate (e.g., profound myocardial failure) and may further enhance renal blood flow. For the authors, an increased propensity for the development of tachycardia relegates dopamine to the role of second-choice drug. As with dobutamine, careful ECG and blood pressure monitoring is indicated during dopamine administration.

Bipyridines Similar to the sympathomimetics, the bipyridines promote an increase in cardiac contractility by increasing cytosolic cyclic adenosine monophosphate levels. However, rather than directly enhancing the production of cAMP, they increase circulating levels by inhibiting phosphodiesterase III, the enzyme responsible for cyclic adenosine monophosphate inactivation. Unlike the sympathomimetics, the bipyridines do not rely on beta-adrenergic receptors and therefore are less affected by downregulation and uncoupling. Furthermore, because phosphodiesterase inhibitors increase vascular smooth muscle cyclic adenosine monophosphate without displaying affinity for alpha receptors, they are also vasodilators. Because of the bipyridines’ combination of positive inotropic and vasodilative properties, the term inodilators has come into use for these agents. Because they increase cytosolic calcium and myocardial work, they inherently carry the caveats of tachycardia and ventricular arrhythmias. In fact, the 28% increase in all-cause mortality identified in humans randomized to oral milrinone versus placebo has severely limited further attempts to evaluate agents that act via cAMP-dependent mechanisms.

Milrinone The phosphodiesterase inhibitor milrinone is substantially more potent than amrinone and is available in an intravenous preparation. Because of its combined positive inotropic and vasodilative properties, milrinone may be used as a substitute for the dobutamine/nitroprusside combination in the management of acute life-threatening heart failure. Despite milrinone’s ability to increase measures of fractional shortening after oral administration in dogs, this formulation is no longer available for prescription.”

There are no published reports regarding the hemodynamic effects of intravenous milrinone administered to dogs with acute myocardial failure. When administered to normal dogs at an infusion rate of 1 to 10 µg/kg/min, milrinone increased cardiac contractility 50% to 140%. Whether similar doses are efficacious in dogs with heart failure is uncertain, and dosing recommendations currently are difficult to propose. Because CRI milrinone requires 10 to 30 minutes to reach maximal peak effects in normal dogs, it may be prudent to administer a loading dose, followed by constant-rate infusion. Theoretical administration guidelines after the bolus would be to titrate the infusion rate upward slowly while monitoring the systemic blood pressure and a continuous electrocardiogram. Efficacy may be monitored clinically (e.g., reduction in the respiratory rate, alleviation of orthopnea) or echocardiographically with periodic measures of systolic function.

Amrinone The effects of amrinone are almost identical to those of milrinone except that it does not appear to be as potent. Although there are no reports of its large-scale use in the management of acute decompensated congestive heart failure, treatment recommendations have been extrapolated from studies of normal dogs. Constant-rate infusions of 10 to 100 µg/kg/min appear to be capable of increasing cardiac contractility by 10% to 80% in awake, normal dogs. Anesthetized dogs showed a 15% increase in the heart rate at an infusion rate of 30 µg/kg/min and a 20% increase at 100 µg/kg/min. This tachycardia may have been induced either directly, through cyclic adenosine monophosphate stimulation, or indirecdy, in response to a decrease in blood pressure. The 30 µg/kg/min infusion rate was associated with a 10% decrease in blood pressure, whereas the 100 µg/kg/min rate reduced blood pressure by 30%.I After institution of a CRI, amrinone requires approximately 45 minutes to reach peak effect. Therefore, similar to milrinone, it appears most appropriate to administer a slow IV bolus of 1 to 3 mg/kg, followed by a slowly up-titrated CRI of 10 to 100 µg/kg/min. Continuous ECG monitoring should be instituted to allow evaluation for excessive tachycardia or arrhythmogenesis, and the systemic blood pressure should be monitored to avoid hypotension.

Management of Acute Heart Failure Secondary to Diastolic Dysfunction

Cats with hypertrophic cardiomyopathy (HCM) often present with signs of respiratory distress subsequent to the development of pulmonary edema or pleural effusion. Impaired ventricular relaxation produces elevated atrial and venous pressures, with eventual fluid exudation into the alveoli or pleural space. The treatment goals for cats with HCM and heart failure focus on relieving congestion through preload reduction rather than augmenting systolic function or decreasing afterload.