Shock

Shock reflects a state in which tissue perfusion is inadequate to meet tissue metabolic needs.²⁶⁸ Tissue perfusion may be inadequate because of low or unevenly distributed blood flow.²⁶⁹ Selection of the most appropriate therapy is facilitated by categorizing shock first as to the functional disturbance and second as to primary cause.

Classification Of Shock

Hypovolemic Shock

Hypovolemic shock is one of the more common causes of shock in small animals.²⁶⁸ Causes include but are not limited to hemorrhage, trauma, and severe dehydration such as that which accompanies renal dysfunction, vomiting, or hypoadrenocorticism.²⁶⁹ Physiologically, hypovolemic shock can present in three stages. The earliest stage is accompanied by compensatory mechanisms (e.g., increased heart rate, increased vascular resistance) designed to maintain blood pressure. As volume loss progresses, the second or middle stage is characterized by tachycardia with low systemic blood pressure and hypothermia. Capillary refill time is prolonged, and pulse pressure is poor. Blood is shunted away from less vital organs to the brain and heart, and blood clotting abnormalities may be accompanied by increased capillary permeability. Urine output decreases. If hypovolemia persists, the final stage of decompensation occurs. This stage is largely irreversible²⁶⁸ and is characterized by vascular dilation and pooling of blood in peripheral tissues. Poor cardiac filling leads to insufficient cardiac and brain perfusion. Death reflects myocardial failure, cardiac arrhythmias, respiratory failure associated with pulmonary edema, and cardiopulmonary arrest.²⁶⁸

Cardiogenic Shock

Cardiogenic shock is a state of low cardiac output associated with diastolic or systolic dysfunction. The heart is unable to function as a pump, and blood delivery to organs is insufficient. Causes include myocardial failure (acquired or congenital) and cardiac arrhythmias. Iatrogenic cardiogenic shock also can be drug induced.²⁶⁹ Clinically, because the underlying cause of shock is inadequate blood flow, cardiogenic shock presents similarly to hypovolemic shock, with the primary difference of increased atrial filling pressures accompanied by pulmonary edema.²⁶⁹

Distributive Shock

Distributive shock occurs when blood flow is distributed improperly to tissues. Improper distribution reflects a rapid, marked increase in peripheral vasodilation, vascular capacitance, and peripheral pooling of blood.²⁶⁹ Causes generally include those associated with the release of vasoactive mediators, most notably endotoxemia (see Chapter 8) or other causes of sepsis and anaphylaxis or anaphylactoid reactions. Injured and ischemic tissues (e.g., due to hypovolemic or cardiogenic shock) also lead to the release of vasoactive and procoagulant mediators. Vascular occlusive diseases such as saddle thrombi and pulmonary thromboembolism (e.g., dirofilariasis) also cause distributive shock.²⁶⁹ For example, with sepsis distributive shock might initially be “warm” in that blood flow is increased in peripheral tissues. As shock progresses and venous pooling continues, fluid is lost from the vascular space, venous return decreases, cardiac output decreases, and tissues become underperfused or “cool.”

Pathophysiology

Ideally, treatment of shock should focus on early reversal based on the underlying cause. As shock progresses, the underlying pathophysiology is the same, and treatment is oriented toward prevention and reversal of inadequate tissue perfusion. Some type of damage is likely to occur in any tissue subjected to a period of hypotension (mean arterial blood pressure <50 mm Hg). These include cell ischemia, inadequate oxygen delivery, and the generation of proinflammatory/procoagulant mediators.²⁶⁹

Sequelae of cellular ischemia

Tissues suffer damage from inadequate tissue oxygenation in 5 to 10 minutes, and the damage is irreversible at 15 to 20 minutes.²⁶⁹ Mitochondrial dysfunction accompanies ATP depletion, leading to anaerobic metabolism and lactic acid accumulation. Cell membrane (ATPase) pumps become disrupted, and intracellular destructive enzymes are released. Accumulation of intracellular calcium leads to the activation of enzymes that disrupt cellular homeostasis. Intracellular sodium and chloride increase, and magnesium and potassium decrease. ATP breakdown yields hypoxanthine and generation of xanthine oxidase (converted from xanthine dehydrogenase), which produces oxygen free radicals.²⁶⁹ With reperfusion, hyperemia occurs once blood flow is reestablished if the period of impaired oxygenation or poor tissue perfusion is short. The duration of hyperemia is determined by the extent of mediator release (potassium, hydrogen, NO, adenosine, adrenomedullin, the latter a hypotensive peptide first discovered in pheochromocytomas). On the other hand, if blood flow is less than 20% of normal for longer than 5 minutes, reperfusion after perfusion failure leads to reoxygenation injury. Injury reflects the production of self-destructive enzymes and metabolites and derangements in blood clotting.²⁶⁹ Together the consequences of reperfusion injury include uneven distribution of blood flow and focal ischemia (perhaps exacerbated by inappropriate thrombosis), swelling of capillary endothelial cells and subsequent plugging by leukocytes migrating to the area, and increased microvascular viscosity and interstitial edema.²⁶⁹

Oxygen free radicals

The generation of oxygen free radicals by mitochondria, macrophages, and neutrophils sets the stage for reperfusion injury should blood flow be reestablished after a sufficiently long period of poor perfusion, causing perhaps the most detrimental sequelae of shock.²⁶⁹ Xanthine oxidase metabolizes molecular oxygen into radicals such as superoxide anion, hydrogen peroxide, and the hydroxyl radical (see Chapter 29). Enzymes that normally scavenge oxygen free radicals (e.g., superoxide dismutase, catalase, and glutathione) are overwhelmed as tissues reperfuse. Production of oxygen free radicals is exacerbated by mediators released in response to oxygen free radicals, including cytokines (including TNF), interleukins (which also induce procoagulant activity), and prostaglandins.²⁶⁹

Role of nitric oxide

NO can be either protective or detrimental in the patient with sepsis and endotoxemia. Under basal physiologic conditions, NO serves as a free oxygen radical scavenger, limiting toxicity associated with superoxide and other radicals. Inhibition of platelet aggregation and leukocyte adhesion limits ischemia–reperfusion injuries.²¹ During shock large amounts of iNOS are formed; as such, NO becomes a major contributor to the pathophysiology of shock.^21,²⁶⁹ Peroxynitrous acid, generated from the reaction of NO with oxygen free radicals, destroys cellular macromolecules, causing mitochondrial and cell membrane dysfunction, production of prostaglandins, and programmed cell death (apoptosis). The coagulation cascade is activated, ultimately leading to disseminated intravascular coagulation. Arteriovenous shunting (possibly caused by iNOS) contributes to maldistribution of blood flow, particularly in endotoxic and other septic shock, and may be a cause of irreversibility.²⁶⁹

Thus, although the initial responses of the body to iNOS might lead to important compensatory responses, ultimately the responses may prove to be detrimental. Nevertheless, inhibition of NOS is undesirable because systemic vascular resistance is improved only at the cost of loss of blood flow to vital organs. Platelet aggregation increases, along with the risk of thrombus formation and disseminated intravascular coagulation.²⁶⁹ Analogs of L-arginine, such as L-NAME (N-nitro-L-arginine methyl ester) competitively inhibit NO production by either cNOS or iNOS from L-arginine. Treatment of human patients in septic shock with L-NAME, however, led to pulmonary hypertension and reduced cardiac output.²⁷⁰ Drugs that selectively inhibit iNOS but not cNOS may be a more appropriate focus of investigation.

Gastrointestinal barrier

The sequelae of ischemia and hypoxia in the gut have profound clinical implications for the patient undergoing shock. Potent vasoconstrictors (endothelins), cytokines, and other mediators act in concert with leukocyte migration and epithelial necrosis to increase capillary permeability, transcapillary fluid filtration, and interstitial edema. Diarrhea is a common clinical complication of resuscitation from shock and may indicate the loss of the protective mucosal barrier in the gastrointestinal tract. Bacterial translocation and endotoxin absorption result in release of massive quantities of proinflammatory mediators, predisposing the patient to septicemia and, ultimately, to the systemic inflammatory response syndrome (see Chapter 29).²⁶⁹ This syndrome is characterized by multiorgan dysfunction.

The compensatory mechanisms implemented to counter the pathophysiologic sequelae (decreased tissue perfusion and oxygen delivery) of shock involve the neural, hormonal, and renal reflexes previously described for cardiovascular diseases. Vasoconstriction maintains arterial blood pressure and redistributes blood flow to vital organs (cerebral and coronary vessels). Cardiac output is increased by increasing heart rate and a fluid shift from interstitial to intravascular sites. Although compensatory mechanisms support the patient during the initial stages of shock, increased vascular resistance and myocardial oxygen demand ultimately will contribute to the demise of the patient.

Treatment

Successful therapy for shock focuses on reestablishing blood flow, blood pressure, and blood volume to normal or above normal (see Table 14-4).²⁶⁹ Monitoring response to therapy can, however, be difficult. Muir²⁶⁹ recommends that response to therapy and a good prognosis be based on frequent monitoring of behavior, level of consciousness, arterial blood pressure, tissue oxygenation, heart and respiratory rate and rhythm, mucous membrane color, capillary refill time, and urine output. Clinical pathology data should focus on packed cell volume, total protein, and serum lactate.

Table 14-4 Crash Cart Drugs

KEY POINT 14-59

Successful therapy for shock focuses on reestablishing blood flow, blood pressure, and blood volume to normal or above normal.

Treatment of shock should maximize tissue perfusion and oxygen delivery to and consumption by peripheral tissues and minimize the effects of proinflammatory and procoagulant mediators. For septic shock (discussed more extensively in Chapter 8) therapy also focuses more aggressively on prevention of endotoxin release and its effects. Regardless of the cause of shock, appropriate therapy is summarized by the acronym VIP: Ventilation to facilitate blood oxygenation, Infusion of fluids to restore blood volume, and support of the myocardial Pump to facilitate blood delivery (flow) to tissues.²⁶⁹

Fluid therapy

Fluid therapy should be aggressive but not overzealous. Care should be taken not to reduce packed cell volume and total protein to less than 20% and 3.5 g/dL, respectively, to minimize the risk of pulmonary or interstitial edema. Administration of hypertonic saline provides rapid but short-term (30 to 120 minutes) hemodynamic improvement in hypovolemic or endotoxic shock; duration of improvement can be extended if hypertonic saline is combined with a colloid.

Blood and blood substitutes

Treatment of hypotensive shock secondary to hemorrhage in which 25 mL/kg or more of blood is lost should include whole blood or packed red blood cells. Blood substitutes should be used when blood products are not available or for animals for which the risk of a transfusion reaction is too great.

Pressor drugs

Positive inotropic drugs are indicated to maintain arterial blood pressure and regional blood flow in patients whose myocardial function does not improve sufficiently after administration of fluids. Pressor drugs also are indicated for patients whose cardiac contractile activity is compromised. Dopamine and dobutamine have been the preferred pressor drugs; dopamine may be preferred for bradycardic animals. ²²⁹ Improved blood flow to the gastrointestinal tract will help minimize the risk of gastrointestinal mucosal damage and subsequent multiorgan failure.²²⁹ Volume replacement must occur before either drug can be used successfully. Refractory hypotension is often associated with septic shock. Underlying mechanisms include vasopressin deficiency, activation of ATP-sensitive K⁺ channels (in response to accumulation of lactate and hydrogen), and overproduction of NO (which precludes vascular smooth muscle contraction). Activation of K⁺ channels causes hyperpolarization, precluding interaction of vasoconstrictors with smooth muscle receptors. Among the current therapies is treatment with vasopressin. ^269a In patients with septic or hypovolemic shock, vasopressin is released biphasically. Osmotic overstimulation may cause rapid release of endogenous vasopressin. However, only 20% of the total pool is available for rapid release. Slower release results in relative deficiency by 1 hour of sustained hypovolemic shock in humans. Whereas arterial pressure is minimally affected in healthy subjects, patients in vasodilatory shock express an exaggerated response to exogenous vasopressin therapy. Mechanisms include replacement of endogenous stores, inhibition of K⁺ channels, and decreased synthesis of nitric acid. Treatment at physiologic doses (0.01-0.04 units [70-kg human adult]) has been described as the best vasopressor drug; doses of first-line vasoproessors can be reduced, thus reducing the risk of adverse effects with these drugs. The drug can be given intratracheally.^269b Yoo^269c described a vasopressin dose determination study in dogs with experimentally-induced hemorrhagic shock. A dose of 0.4 IU/kg was the most effective dose, providing more hemodynamic response in decompensated shock compred to 1.6 IU/kg. Treatment ideally occurs when endogenous concentrations are lowest. Other benefits of vasopressin include increase urine output; improved cerebral, coronary, and pulmonary blood flow; and increased serum cortisol. Side effects occurring at nonphysiologic doses include platelet aggregation and renal, mesenteric, pulmonary, and coronary vasoconstriction. Vasopressin should be used only with caution in patients with cardiovascular disease. The use of glucocorticoids may be indicated in patients non-responsive to pressor agents as a result of functional adrenocorticodeficiency (See Chapter 30).

Miscellaneous drugs

The use of drugs intended to minimize the damage of oxygen free radicals has not been well established in animals such that a standard protocol can be followed. The use of glucocorticoids is controversial (see Chapter 30). Their potential benefits to the endotoxic shock patient have been delineated. In general, the efficacy of these products to limit vascular response to vasoactive compounds depends on the time of administration. Efficacy is greatest when administered before or within several hours of the onset of the pathophysiologic response to shock. Although survival (several hours) has been documented after use of glucocorticoids (compared with placebo) in human and animal clinical trials, long-term survival (beyond several days) has not been documented. Use of glucocorticoids in human patients with endotoxic or septic shock has been associated with an increased risk of infection in some studies but no increased risk in others. The use of glucocorticoids in veterinary medicine remains controversial. Of the drugs to be used, methylprednisolone may be preferred in most causes of shock because of its potential ability to scavenge oxygen free radicals. Administration should be short term.

KEY POINT 14-60

The use of drugs intended to minimize the damage of oxygen free radicals has not been well established in animals.

A number of NSAIDs have been studied for their ability to block response to mediators of endotoxic shock. Indomethacin and ibuprofen have shown efficacy in human patients. Flunixin meglumine has been studied in dogs. As with glucocorticoids, however, the effects of NSAIDs must be realized within the first 2 hours of the onset of endotoxic shock (i.e., before mediators have been able to stimulate response). Prolonged therapy with NSAIDs is not advised because of toxic effects. Although gastrointestinal toxicity is the major concern in most animals, the patient suffering from endotoxic shock may be more predisposed.

Despite the lack of scientific data to support clinical response to drugs that scavenge oxygen free radicals, their use should be strongly considered, particularly if there is little risk of toxicity (See Chapter 29).

The use of antimicrobials in patients suffering from or predisposed to endotoxic or septic shock is discussed elsewhere (see Chapter 8). Patients that have suffered vascular compromise are at risk of suffering the consequences of translocation of enteric pathogens. Prophylactic therapy should be oriented toward minimization of gastric erosion or ulceration (see Chapter 19) and selective decontamination of the digestive tract (targeting gram-negative aerobic pathogens). In humans oral antimicrobials that are not absorbed are recommended: a paste containing 2% polymyxin, 2% tobramycin, and 2% amphotericin (to target fungal organisms) for the oral cavity and a solution of polymixin (100 mg), tobramycin (80 mg), and amphotericin B (500 mg) for the gastrointestinal tract (about 0.1 mL/kg every 6 hours) have been recommended.²⁷¹ However, this therapy is intended to reduce the incidence of nosocomial infections in the intensive care environment. The incidence of pneumonia, urinary tract infections, and catheter-related septicemia can be decreased. The role of selective digestive decontamination in patients subject to shock (with the exception of endotoxic shock) is less clear.

Cardiopulmonary Cerebrovascular Resuscitation

Generally, the goal of cardiopulmonary cerebrovascular resuscitation (CPCR) is to maintain or preserve neurologic function. It is beyond the scope of this chapter to discuss the causes of and recognition of the need for CPCR. Obviously, prevention is the key to success, and treatment of underlying diseases likely to cause cardiopulmonary arrest should be reviewed. Success is more likely if the cardiopulmonary arrest is associated with reversible conditions (e.g., anesthetic overdose, upper airway obstruction, hemorrhage, electrolyte imbalances). The focus of this discussion is on drugs used in CPCR. Which drugs are proper and when their use is indicated in the patient are controversial. Cardiac rather than respiratory arrest is discussed. The pharmacologic effects, side effects, and other pertinent clinical pharmacologic data for each of the drugs have been discussed elsewhere; discussion here is limited to the use of the drugs during or immediately after CPCR.

“Crash Cart” Drugs

Drugs that should be carried in a crash cart include epinephrine, atropine, magnesium chloride, naloxone, lidocaine, sodium bicarbonate, and bretylium tosylate.²⁷²

Epinephrine remains the mainstay of acute cardiac life support. It is intended to promote systemic vasoconstriction such that blood flow is diverted to the coronary and cerebral circulation. It is indicated for pulseless ventricular tachycardia, ventricular fibrillation, electromechanical dissociation (pulseless electrical activity), and ventricular asystole. The standard dose is 10 to 20 μg/kg (1 mg in humans) or 10 mL of a 1:10,000 solution repeated every 3 to 5 minutes. The optimal dose may be very high, ranging from 0.45 to 2 mg/kg (Table 14-4). For humans the American Heart Association has recommended a fivefold increase in the dose to 5 mg if there is no response to the initial 1 mg dose.²⁶⁷

KEY POINT 14-61

Epinephrine remains the mainstay of acute cardiac life support.

Atropine has little indication in CPCR with the exception of bradycardia, pulseless electrical activity, and ventricular asystole. The dose for electromechanical dissociation and asystole is 1 mg intravenously, repeated every 3 to 5 minutes. In humans complete vagal blockade occurs at 0.04 mg/kg (3 mg); this dose is discouraged. Likewise, a total dose below 0.5 mg can cause parasympathomimetic effects and also is discouraged.²⁶⁷

Isoproterenol is a pure, nonselective β-agonist drug. As such, it is a positive inotrope but can also cause peripheral vasodilation. It will increase myocardial oxygen demand. Currently, its use is limited to bradyarrhythmias that do not respond to atropine.²⁷²

Bicarbonate provides little benefit and may in fact harm patients in metabolic acidosis. Acidosis associated with cardiac arrest is best treated with ventilatory and circulatory support. Potentially harmful effects of bicarbonate include arrhythmogenic alkalemia; increased generation of CO₂; hyperosmolarity; hypokalemia; paradoxical central nervous system and myocardial intracellular acidosis; and a leftward shift in the oxyhemoglobin dissociation curve, limiting delivery of O₂ to tissues.²⁶⁷ When used, bicarbonate therapy ideally should be guided by blood gas analysis (pH <7.15 to 7.2).²⁶⁷ Indications or situations in which bicarbonate may prove beneficial for humans requiring CPCR include hyperkalemia; tricyclic antidepressant overdose; prolonged cardiac arrest (protracted hypoperfusion-induced acidosis); and postresuscitation, bicarbonate-responsive, and anaerobic lactic acidoses.²⁶⁷ Sodium bicarbonate (1 mEq/kg intravenously) may be used after epinephrine in patients suffering from a prolonged cardiac arrest who have shown improvement in cardiovascular or cerebral recovery. It should be followed by correction of any deficit (monitored) that is greater than 5 mEq/kg. The bicarbonate-induced hypercarbia tends to be transient and generally harmless to the heart if used in conjunction with epinephrine.²⁷²

KEY POINT 14-62

Bicarbonate provides little benefit and may in fact harm patients in metabolic acidosis.

Calcium administration does not appear to enhance cardiac performance during CPCR. Ischemia associated with cardiac arrest causes intracellular accumulation of calcium, which can disrupt membranes and uncouple oxidative phosphorylation. Calcium can cause coronary vasospasm and will exacerbate the arrhythmic tendency of the unstable myocardium and impair relaxation.^267,²⁷² It will also exacerbate digoxin toxicity. Calcium causes precipitation when combined with sodium bicarbonate. Calcium is not recommended except in cases of prolonged cardiac arrest or absent or ineffective pump activity. Calcium chloride (10% solution contains 100 mg/mL Ca²⁺) is associated with the longest and most predictable increase in plasma ionized calcium.²⁷² In human patients 1 g of calcium chloride (approximately 15 mg/kg) is generally sufficient, although toxicity may occur at this dose. Other indications for calcium include hyperkalemia, ionized hypocalcemia, and CCB overdose.²⁶⁷

Crystalloids (including hypertonic resuscitation and balanced electrolyte solutions) are indicated if the cause of cardiac arrest is hypovolemia. Inappropriate fluid load can, however, contribute to decreased cerebral blood flow and decreased coronary blood flow.²⁷² The production of lactic acid will be enhanced in critically ill hyperglycemic patients, which can lead to or contribute to cell injury. Dextrose infusions are considered by the American Heart Association to be harmful to humans.²⁶⁷ As such, dextrose-containing fluids should be avoided. Isotonic saline or Ringer’s lactate is preferred as the resuscitation fluid.

KEY POINT 14-63

If crystalloid therapy is indicated in the shock patient, isotonic saline containing fluids free of dextrose is indicated.

Several routes of drug administration can be used to support resuscitation. Central venous catheter placement is ideal for immediate drug delivery to the heart. A sufficient bolus of a compatible isotonic fluid should follow any drug administered through peripheral tubing. Intracardiac injections probably offer no increased benefit compared with central intravenous administration. Potential complications include cardiac tamponade, coronary vessel laceration, and pneumothorax. Intracardiac bolus may destabilize the electrical properties of the heart.

Alternative routes of administration can be considered in the absence of venous access. Intratracheal administration is an effective alternative route to central intravenous administration for selected drugs during CPCR.²⁷² In general, the dose is doubled and the drug is administered through a catheter in 10 to 20 mL of liquid for the drugs to reach the alveoli, where they will be subsequently absorbed. Insufflation will facilitate drug absorption. Doses of all drugs administered intratracheally should be increased by twofold to 2.5-fold. The duration of action of the drugs may be longer after intratracheal administration than after intravenous administration. Drugs shown to be effective after intratracheal administration include epinephrine, lidocaine, atropine, and naloxone. There are several drugs that should not be given via intratracheal administration because of the risk of tissue damage. Examples include sodium bicarbonate (depletes surfactant), norepinephrine, and calcium chloride.²⁶⁷ Drugs should not be mixed in the same syringe before intratracheal administration. Intraosseous administration is another alternative to intravenous use in small animals. The bone marrow provides a large venous access; the most common sites during CPCR are either the trochanteric fossa of the femur or distal cranial femur.²⁷²

Specific Conditions

Cardiac asystole refers to the complete absence of electrical activity. Therapy is oriented toward stimulating any electrical activity and then modifying the activity to generate a rhythm with a pulse.²⁶⁷ Epinephrine generally remains the drug of choice for cardiac arrest. Doses should be sufficient (> 0.01 mg/kg) to cause positive inotropic and peripheral vasoconstrictive effects yet low enough (<0.2 mg/kg) to avoid ventricular fibrillation. In an experimental model of cardiac arrest in dogs, declining renal function was positively correlated with the amount of epinephrine administered and the energy required for defibrillation.²⁷³ Because of its short duration of action, epinephrine should be administered every 3 minutes. Longer-term inotropic support should be provided with a less effective pressor drug such as dopamine or dobutamine. Electrolyte imbalance should be treated with the appropriate electrolyte. Bicarbonate is useful only in the previously described indications.

Ventricular fibrillation is best converted to a normal rhythm by electrical defibrillation. Potassium chloride, bretylium, and magnesium chloride have been used to pharmacologically treat defibrillation in the dog. Among these, magnesium chloride (5 to 10 mL of a 2% solution administered intravenously) may be best. Once an organized rhythm has been established, epinephrine may be beneficial for increasing vascular tone and improving blood flow to the brain. The initial dose should be low (0.02 mg/kg) and increased tenfold (0.2 mg/kg) in nonresponsive patients. Very high doses may, however, excessively increase myocardial oxygen demand. Lidocaine may prove useful for “coarsening” fibrillation, rendering it more amenable to electroconversion. In addition, it may increase vascular tone response to epinephrine.²⁶⁷ Bretylium has proved useful in some human cases of refractory ventricular fibrillation. The drug is administered immediately (1 minute) before electrical defibrillation. Refractory cases also may require correction of severe acidosis. Precaution is, however, taken to ensure that the pH is increased to no higher than 7.5 because of increased resistance to defibrillation.²⁶⁷

Ventricular tachycardia also is most amenable to electrical shock. Lidocaine is the drug of choice for control of ventricular tachycardia. Alternatives include procainamide (and, for humans, bretylium). Magnesium sulfate (25 to 40 mg/kg intravenously over 5 minutes) may be useful in refractory cases or in cases of ventricular flutter; constant-rate infusion over 4 to 8 hours is indicated if the patient responds.

Electromechanical dissociation (EMD; pulseless electrical activity) generally is fatal when caused by myocardial diseases. Treatable causes in humans include hypovolemia (e.g., acute blood loss, which should be treated with volume replacers), pericardial tamponade, and tension pneumothorax.²⁶⁷ Epinephrine or atropine (0.04 to 0.08 mg/kg intravenously) may be useful when EMD is associated with hypotension or pleural or pericardial disorders. Pulseless electrical activity is likewise accompanied by a poor prognosis, although naloxone, dexamethasone sodium phosphate, and calcium have been recommended. Calcium is most likely to be of benefit with hypocalcemia or extreme hyperkalemia.²⁶⁷

Bradyarrhythmias are most amenable to nondrug therapy. The slower the rate and the wider the ventricular complex on the electrocardiogram, the more ineffective will be the cardiac contractility.²⁶⁷ Atropine is most useful with narrow complex bradyarrhythmias. However, atropine should be used cautiously such that potentially lethal tachycardia might be prevented in hypoxic patients. A low dose (0.022 mg/kg) is indicated unless vagolytic arrest is present. Dopamine and epinephrine may be helpful for inotropic support. Isoproterenol is controversial because of peripheral vasodilation.

Anesthetic or narcotic overdoses should be reversed if posssible. Naloxone (0.02-0.04 mg/kg intravenously) is indicated for any narcotic. Yohimbine or atipamezole (0.1 to 0.2 mg/kg intravenously) is indicated in the presence of α-2 antagonists and may be effective for other chemical restraining agent, including ketamine or barbiturates.^267a,^b Flumazenil (0.02 mg/kg intravenously) is indicated for reversal of diazepine depressant effects.

Postresuscitation monitoring and care are critical to successful CPCR. Dobutamine is preferred to dopamine by many clinicians for postresuscitation inotropic support. SBP should be maintained above 90 mm Hg. Urine formation should be maintained at 1 to 2 mL/kg per hour. Furosemide may be indicated in the face of decreasing urine output. Neurologic function should be assessed along with the need for iron chelators, CCBs, or oxygen free radical scavengers. Vasopressin (0.04 to 0.8 units/kg intravenously or 0.001 units/kg/hr) may be indicated in patients whose vasculature remains nonresponsive to epinephrine.

Hyperlipidemia

The metabolic pathway of lipid formation and metabolism is complex,^274,²⁷⁵ offering several targets of pharmacologic control. Although coronary artery disease associated with atherosclerotic plaques is not a disease of dogs and cats, drug therapies for the disease play role in the treatment of hyperlipidemias in animals. As such, an in-depth discussion of lipid metabolism is warranted. Lipoproteins are macromolecules consisting of lipids (cholesterols, triglycerides, phospholipids) and proteins (apolipoproteins or apoproteins; e.g., apo-A [I-V], apo-B, apo-C [II and III], and apo-E). Together, cholesterol and triglycerides comprise the major lipid particles in the body, with each having important functions. Cholesterol provides stability to cell membranes, facilitates membrane transport, and serves as a basis for the synthesis of steroids and bile acids. Triglycerides serve as a source of energy storage, being lightweight compared to glycogen. Cardiac and skeletal muscle extract triglycerides from circulating proteins and, through lipolysis, convert them to fatty acids as an energy source (Kreb’s cycle for ATP production and gluconeogenesis in selected tissues) and glycerol.

Both cholesterol and triglycerides are insoluble in water, and as such they circulate as lipoproteins, with apoproteins providing structural rigidity to lipoproteins. However, the proteins also serve as ligands or cofactors in lipoprotein metabolism. Spherical lipoproteins are structured such that the most water-soluble components (apoproteins, phospholipids, and unesterified cholesterol) face outward and surround the most lipid-soluble core components (cholesterol esters, triglycerides). In addition to transport, apoproteins facilitate recognition of enzymes that remove or process the lipids within the lipoprotein. Several classes of lipoproteins have been classified according to their density, lipid content, and surface protein. These include in order of density chylomicrons (least dense at ≤ 0.95g/mL), very low-density lipoprotein (VLDL) cholesterol, intermediate-density lipoprotein (IDL) cholesterol, low-density lipoprotein (LDL) cholesterol (“bad” cholesterol), and high-density lipoprotein (HDL) cholesterol (“good cholesterol”) (most dense at 1.06g/mL). Generally, total cholesterol, triglycerides, and HDL are measured directly, with VLDL and LDL estimated though calculation.

Three pathways exist for formation of lipoproteins. The exogenous pathway of lipoprotein formation begins with digestion and absorption of dietary fat. Dietary cholesterol must be esterified, a process mediated by acyl coenzyme A cholesterol acyltransferase (ACAT-2,) located in both the intestinal epithelial cell and liver. In the epithelial cell, cholesterol and triglyceride are packaged into chylomicrons. Chylomicrons contain the largest proportion of triglycerides (fat) of any of the lipoproteins, with a triglyceride to cholesterol ratio of 10:1 (i.e., more than 90% triglycerides). Therefore, although chylomicrons are very large, their fat content renders them the least dense of the lipoproteins. The high fat content of chylomicrons also provides the buoyancy necessary for their accumulation at the top of undisturbed (>12 hours) plasma. Formation of chylomicrons depends on microsomal triglyceride transfer protein (MTP), which acts to transfer the triglyceride to an apolipoprotein. The apolipoproteins will form the outside surface of chylomicrons and are synthesized in intestinal epithelial cells or are acquired from HDLs once the chylomicron is secreted into lymph. Chylomicrons enter plasma at the thoracic duct. Once in circulation, fatty acids are released from the triglycerides in chylomicrons in tissue that produce lipoprotein lipase (LPL); insulin provides a permissive effect. Its absence in humans is associated with severe hypertriglyceridemia and pancreatitis. Tissues that contain LPL are exemplified by adipose tissue and skeletal and cardiac muscles. Fatty acids released from triglycerides are either immediately used as a source of energy by surrounding tissues or stored for future energy needs in adipocytes. The chylomicron remnants that remain once triglycerides have been removed contain dietary cholesterol and they are rapidly metabolized by the liver.

The endogenous pathway for generation of lipoproteins reflects hepatic synthesis of VLDLs and subsequent uptake of circulating VLDLs by tissues. Triglyceride synthesis is regulated in the liver and other tissues through coenzyme A (CoA) diacylglycerol acyltransferase enzymes that catalyze the final step. Triglycerides intended for lipoprotein synthesis are transferred (along with other lipids) to the endoplasmic reticulum, where they, along with cholesterol, will combine with newly synthesized apoB-100 to form VLDLs. Transfer cannot occur without MTP, and its absence (or the absence of triglycerides) prevents formation of VLDLs and subsequent lipoproteins. Like chylomicrons, VLDLs are very large, containing a large amount of core triglyceride (ratio of triglycerides: cholesterol of 5:1). Although VLDLs contribute to plasma turbidity, they do not float with chylomicrons on the surface of undisturbed plasma. The VLDLs are synthesized in the liver endoplasmic reticulum in response to increased free fatty acids.

The VLDLs are released into circulation, taken up by tissues that produce LPL, and processed by LPL to yield fatty acids, glycerol, and a VLDL remnant or IDLs. The free fatty acids are either used as an energy source or stored in the cell as fat (Box 14-1).

The IDLs either are removed by the liver in response to LPL or are metabolized by way of hepatic triglyceride lipase to form LDLs. The LDLs are composed primarily of cholesterol esters and contain essentially no triglycerides. Because they have a longer half-life than other lipoproteins, LDLs accumulate to a higher plasma concentration compared with either VLDLs or IDLs. Hence the LDLs carry the majority of cholesterol (the “bad” cholesterol) in the body. The LDLs also are removed from circulation primarily by the liver in proportion to LDL receptor expression, with a smaller amount taken up by LDL receptors in tissues. Tissue uptake results in the release of free cholesterol, which is subsequently esterified such that it accumulates in cells. Most clearance occurs in the liver. Increased expression of LDL receptor expression is a major means by which cells regulate free cholesterol content. A number of signals increase LDL receptor expression, thereby decreasing circulating LDL, including thyroxin and estrogen, decreased consumption of saturated fats and cholesterol, and pharmacologic anticholesterol drugs (statins).

Among LDLs, densities vary, with the smaller, denser, less buoyant particles potentially more amenable to oxidation.²⁷⁴ Oxidized (radical) lipoproteins damage vascular endothelium and are scavenged by a receptor mediated process in macrophages (forming foam cells). It is the inflammatory and immunologic response to oxidized LDL and at the vascular endothelium of coronary vessels that contributes to atherosclerosis and its subsequent morbidity in humans. Although it is cholesterol that is considered “bad”, it appears that it is the fatty acids, not cholesterol, that are oxidized to atherogenic metabolites. As such, triglycerides, not cholesterol, are the source of atherosclerotic mediators, and thus the lipoproteins containing the largest component of triglycerides should be considered the greatest risk. What is not clear is why transport of cholesterol by HDL would decrease this risk.

HDLs facilitate the transport of cholesterol from peripheral tissues (including atherogenic plaques) to the liver. As such, HDLs contain more cholesterol (as ester) than triglyceride in their core compared with other lipoproteins and are of higher density than the other lipoproteins. This mechanism of “reverse cholesterol transport,” the third pathway of lipid metabolism, is complex and not well understood.²⁷⁴

Box 14-1 Fatty Acids

Fatty acids contain variable lengths of carbons that may or may not include double bonds. Nomenclature of fatty acids involves an ending with “oic” [or simply “ic”] acid [the acid referring to the carboxylic acid that each contains] with the number of carbons followed by the number of double bonds [e.g., arachidonic acid, C 20:0, contains 20 carbons and no double bonds, whereas arachidonic acid C20:4 contains 4 double bonds]. A saturated fat contains carbons with as many hydrogens as possible, meaning it contains no double bonds or functional groups. Such fats are straight and as such, can be packed very tightly, thus allowing storage of a lot of energy in a small space. Such fats also offer no opportunity for lipid peroxidation. Unsaturated fats contain variable numbers of functional groups or, more commonly, (alkene) carbon double bonds. The more double bonds, the greater the risk of oxygen radical formation (peroxidation). The fatty acid that extends on either side of each double bond can exist in one of two configurations: cis, for which both ends are on the same side of the double bond, or trans, for which each end is on a different side. Steric hindrance presented with fatty acid ends being on the same side of the bond as in cis fatty acids causes the molecule to bend or kink. However, the ends of a trans fat are on opposite sides, do not compete for space and thus remain largely straight, such as might occur with saturated fats. Most naturally occurring unsaturated fatty acids contain only three double bonds, each in the cis position. The few naturally occurring trans fatty acids are generally found in the meat and dairy products of ruminant animals (originating from the rumen). Saturated fats and trans unsaturated fats tend to be solid at room temperature and are less amenable to oxidation. The term trans is used when referring to fats because it is the common name used to refer to all unsaturated fats. This probably reflects the fact that most fats that are consumed are unsaturated plant fats that are artificially partially hydrogenated such that a trans configuration is produced. Because they are more saturated, they are less conducive to oxidation (degradation) into smaller fatty acids, ketones, and aldehydes, and because they are less likely to become rancid, their shelf-life is prolonged. Presumably, fats that contain unsaturated (oxidizable) double bonds should be less safe than the fats whose carbon bonds are “saturated” with hydrogen. However, because unsaturated fats might also be considered more fluid, thus allowing flexibility in cell membranes, polyunsaturated fats have also been considered safer, although absorption of unsaturated dietary fats that are oxidized during the cooking of food may increase their atherogenecity. Despite the fact that trans, partially hydrogenated (unsaturated) fats are less oxidizable, the amount of trans fats in the diet correlates with the advent of atherosclerosis. Although the mechanism is not well understood, it may simply reflect increased total unsaturated fat content. Coronary heart disease in humans correlates with the amount of both saturated and unsaturated fat; however, saturated fats appear to be less atherogenic than disproportionate carbohydrates in the diet [the latter perhaps contributing to increased formation of saturated fat formation in the body]; fish also decreases the risk of alherosclerosis. Trans fats in particular seem to reduce the amount of HDL, thus increasing the risk of coronary artery disease. Thus consumption of trans fats is recommended to be as low as possible.

Pathophysiology of Dislipidemias

Hyperlipidemia is defined as increased concentrations of triglycerides or cholesterol. In humans hyperlipidemia results from a combination of dietary, genetic, and metabolic factors.²⁷⁵ In veterinary medicine, primary idiopathic hyperlipidemia appears to be familiar in Miniature Schnauzers and Beagles but has been reported in other breeds and occasionally in cats. Secondary hyperlipiemia is associated with other disorders, such as diabetes mellitus, hyperadrenocorticism, pancreatitis, and hypothyroidism.

Treatment of Hyperlipidemia

In humans the choices for treatment of hypertriglyceridemia vary with the category, three of which are defined according to concentration (mg/dL) of triglycerides (borderline high [150-199], high [200-499], or very high [≥500]), with a focus on the risk of coronary heart disease. Pharmacotherapy targets synthesis of cholesterol and includes the statins, niacin, bile acid sequestrants, and fibric acid derivatives.

Statins

Statins competitively inhibit (hepatic) HMG-CoA reductase and thus block the rate-limiting step in cholesterol synthesis. At higher doses the more potent drugs (e.g., atorvastatin, simvastatin) also reduce triglycerides associated with increased VLDL. In humans statins have proved effective in reducing morbidity and mortality associated with hyperlipidemia and coronary heart disease.²⁷⁵ Six products are approved for use in the United States, with lovastatin, simvastatin, and pravastatin the most commonly prescribed. Each statin is structurally similar to HMG-CoA. LDL receptor expression increases, causing LDL-C concentrations to decrease. Humans taking the highest doses of the most potent statins realize up to a 45% reduction in triglycerides. A similar reduction can be achieved with niacin and fibric acid derivatives, but fibric acid may not decrease LDL-C. The statins have a number of nonlipid-lowering cardioprotective effects, although mechanisms are not known. These include inhibition of enhanced vascular endothelial nitric oxide production, inhibition of vascular smooth muscle proliferation, facilitation of apoptosis, and stabilization of vascular atherosclerotic plaques. Platelet aggregation is decreased. Oral bioavailability is variable among drugs (30% to 85%); simvastatin and lovastatin are administered as prodrugs.²⁷⁵ All undergo extensive first-pass metabolism, resulting in systemic bioavailability of 5% to 30%. Atorvastatin, lovastatin, simvastatin, and others (but not pravastatin, fluvastatin, and rosuvastatin) are metabolized by CYP 3A4, increasing the risk of drug interactions. Entry into the liver for several statins is mediated by transport proteins, which may compete with other drugs. Most metabolites have some degree of activity. Those products that make it to systemic circulation are highly bound to proteins. Elimination half-lives are generally less than 4 hours (exceptions are 20-hour atorvastatin and rosuvastatin), and effect appears to be time dependent in that lovastatin is slightly more effective when given as 40 mg twice daily, as opposed to 80 mg once daily. Elimination of parent and metabolites is largely biliary. Two potentially serious side effects of statins have been reported: hepatotoxicity and myopathy. Statins cause increased liver enzymes in 3% of human patients. However, the incidence of serious hepatotoxicity is rare (1 case per million users annually). Hepatic enzymes should be measured at baseline and repeated at 3 to 6 months, then yearly thereafter if normal. Myopathy (rhabdomyolysis; approximately 0.01% and monitored by serum creatine kinase) appears to be dose dependent and is most commonly associated with gemfibrozil. Myopathy can be associated with myoglobinuria and, rarely, death. Niacin will increase the risk (discussed later), as will macrolide antimicrobials, cyclosporine, imidazole antifungals, and inhibitors of CYP3A4. Creatine kinase might be monitored in at-risk patients (e.g., drug interactions).²⁷⁵ Combined use of statins with other drugs can reduce either LDLC-C or triglycerides greater than statin use alone; current treatment of dyslipidemias (such as that which characterizes prediabetes) increasingly is based on combination therapy. Combination with bile acid sequestrants can reduce LDL-C by another 20% to 30%; the addition of niacin will reduce concentrations even further (up to 70% in humans), although the risk of myopathy increases with high statin and niacin doses. Combination with fibrates is particularly effective when treating hypertriglyceridemia.²⁷⁵

Niacin

Niacin (nicotinic acid) is a water-soluble compound that in its amide form (nicotinamide) acts as a B vitamin complex. However, only niacin lowers lipids (although nicotinamide can act as a source of niacin) and only at doses higher than that associated with B vitamin activity.²⁷⁵ Triglycerides may reduce up to 45%; LDL-Cholesterol (LDL-C) decreases up to 30%, and HDL-C increases up to 40% (humans). The mechanism reflects inhibition of hormone-sensitive lipase-induced lipolysis in adipose tissue. The transport and esterification of free fatty acids to the liver is inhibited, and hepatic triglyceride synthesis is decreased. Adipocyte adenylyl cyclase may be the ultimate enzyme inhibited. Niacin may also inhibit diacylglycerol acyltransferase 2, the rate-limiting enzyme of triglyceride synthesis. Niacin also enhances LPL activity, thus promoting the clearance of chylomicrons and VLDL triglycerides. The identification of a niacin receptor may ultimately lead to development of drugs that target the receptor.²⁷⁵ In humans administration of regular or crystalline niacin (2 to 6 g divided into 2 to 3 daily doses) causes maximal effects within 4 to 7 days. The high dose is necessary to ensure sufficient niacin; at lower doses most is converted to nicotinamide. The half-life of niacin is only 30 to 60 minutes in humans, necessitating at least twice-daily dosing; an extended-release preparation allows once-daily dosing. Use in humans is limited by cutaneous flushing, skin rashes, and dyspepsia. Flushing, interestingly, resolves after 1 to 2 weeks of stable dosing but will return if several doses are missed and is minimized by starting at a low dose (e.g., 100 mg twice daily in humans) that is gradually increased (weekly) to a maximum total daily dose of 2 g. Co-administration of aspirin also will reduce flushing.²⁷⁵ Dyspepsia is reduced if administered with a meal. Niacin is contraindicated in patients with gastrointestinal ulceration. Hepatotoxicity is a serious but rare adverse reaction to niacin. All sustained-release niacin (over-the-counter) preparations have been associated with hepatotoxicity (including fulminating hepatic necrosis), particularly at high doses; the risk may be less with Niaspin an FDA-approved extended release coated tablet. Toxicity may take several years to develop and has occurred in human patients who tolerated crystalline niacin. Niacin increases the risk of statin-induced myopathy; the statin dose should be reduced to approximately 25% when used in combination.²⁷⁵ Niacin should either be avoided or used cautiously in diabetics (types I or II); any change in insulin need should be anticipated for insulin-dependent diabetics. The risk of niacin-induced hyperglycemia might be reduced (but probably not avoided) in the diabetic patient with use of sustained-release niacin.²⁷⁵

Bile acid (resin) sequestrants

Cholestyramine and colestipol are anion-exchange resins prepared as hygroscopic powders and administered as chloride salts.²⁷⁵ The highly positively charged particles bind to the negatively charged bile acids, precluding their absorption. Hepatic synthesis consequently increases, resulting in lowered cholesterol. As with statins, LDL receptors increase and LDL-C decreases. However, because statins are more effective, generally resins are used as second-line treatment. Unfortunately, resin-induced increase in bile-acid production causes an increase in hepatic triglyceride synthesis, leading to potentially marked increases in serum triglyceride concentrations, and severe hypertriglyceridemia is a contraindication for use; an exception is colesevelam, which does not appear to significantly increase triglycerides. Resins are not orally absorbed. Rarely, hyperchloremic acidosis may occur. Cholestyramine and colestipol are administered as a slurry, which is associated with gastrointestinal upset (including dyspepsia and bloating); again, the exception is colesevelam, which is administered as a soft-gel capsule. Cholesteramine and colestipol will impair the absorption of many drugs. Resins generally are administered before or with a meal. Although colesevelam is less likely to affect absorption of other drugs, it nonetheless should be administered 1 hour after or 3 to 4 hours before any other orally administered drug. Additional flavoring may facilitate administration of cholesteryamine and colestipol.²⁷⁵

Fibric acid

The ester form of ethyl chlorophenoxyisobutyric (clofibrate) was the first to be approved in the United States, but its use was not associated with a reduction in mortality associated with coronary heart disease. Gemfibrozil is a nonhalogenated phenoxypentanoic acid and as such is not halogenated fibrates. Its use has been demonstrated to reduce mortality rates in men. The mechanism by which fibric acid derivatives decrease cholesterol is not certain, but they appear to interact with and stimulate peroxisome proliferator-activated receptors. Fatty acid oxidation is stimulated, LPL synthesis and apoA-I and II expression increase, and apoC-III (an inhibitor of lipolytic processing) expression is reduced. Most fibric acids also are antithrombotic, inhibiting coagulation and enhancing fibrinolysis. Those (human) patients most likely to respond are those with dysβlipoproteinemia (type III). In human patients with mild hypertriglyceridemia, gemfibrozil may cause triglyceride to decrease up to 50% without a change in LDL-C. In contrast, with second-generation drugs (fenofibrate, bezafibrate, ciprofibrate) LDL may decrease up to 20% and up to 30% in patients with marked hypertriglyceridemia (400-1000 mg/dL). Fibric acids have been the drugs of choice for treatment of severe triglyceridemia and chylomicronemia. Fibric acid compounds usually are well tolerated. Side effects are not uncommon, occurring in 5% to 10% of human patients; however, discontinuation of the drug is generally unnecessary. Side effects reflect the gastrointestinal tract, cutaneous lesions (rash, urticaria, alopecia), increased liver enzymes, and myalgias. Myopathies may occur in patients receiving clofibrate, gemfibrozil, or fenofibrate, including up to 5% of patients receiving a combination of statins with gemfibrozil. Minor increases in liver transaminases and alkaline phosphatase have been reported. Gemfibrozil will inhibit transport-mediated hepatic uptake of statins and compete with statins for glucuronidation (an exception being fenofibrate), potentially increasing concentrations of both drugs. Effects of oral anticoagulants are potentiated, and the risk of choleliths may increase. Both renal and hepatic diseases are contraindications to fibric acid administration.

Inhibition of dietary cholesterol absorption

Ezetimibe appears to inhibit a transport protein specific to cholesterol (and plant sterol) absorption. Whereas cholesterol absorption may be markedly decreased, triglyceride absorption will not be affected; serum cholesterol concentrations may decrease up to 50%, whereas triglyceride may decrease only up to 5%. Cholesterol synthesis generally increases; hence ezetimibe is often coupled with a statin. Increased LDL receptor expression is accompanied by decreased LDL-C. Because ezetimibe is insoluble in water, it has not been studied intravenously, and bioavailability is not known. However, after intestinal epithelial glucuronidation, it is absorbed to undergo enterohepatic recirculation, with 70% excreted in the feces and about 10% in the urine. Ezetimibe has been associated with rare allergic reactions.

Dirlotapide is a selective inhibitor of MTP. MTP is required for the assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins, the primary structural protein of plasma VLDLs. Consequently, MTP inhibitors block the assembly and release of lipoproteins into the blood stream. In field trials, serum lipids were decreased in obese dogs treated with dirlotapide, but changes were not clinically significant. However, depending on the pathophysiology of hypertriglyceridemia, consideration might be given to the potential for dirlotapide, particularly in combination with other therapies (e.g., gemfibrozil), for treatment.

Heartworm Disease (Dirofilariasis)

Physiology and Pathophysiology

Both the adult worms and the microfilariae of Dirofilaria immitis are responsible for the clinical signs associated with heartworm disease. Heartworms live 5 to 7 years in dogs (2 to 3 years in cats) but are most susceptible to adulticide therapy while young. Maximal microfilaria production occurs after 8 to 18 months of adult worm development, and microfilariae live about 18 to 24 months. The adults are covered with a canine antigen that provides an immunologic sanctuary, protecting the worm against immunologic rejection. However, its subsequent absence contributes to a marked inflammatory host response on worm death. The severity of heartworm disease and the onset of clinical signs reflect, in part, the number of infecting worms. Large numbers of worms are more likely to cause greater pulmonary hypertension, thromboembolism, and risk of vena cava syndrome. Experimentally, the endothelium of the pulmonary artery responds to the presence of heartworms within 3 days. Endothelial damage leads to edema associated with vascular permeability. Trophic factors released by platelets and leukocytes stimulate the multiplication of smooth muscle cells, which subsequently migrate from the interna to media, where they continue to rapidly multiply. Cells continue to divide and produce collagen.

Arteries dilate, become tortuous, and develop aneurysms. Obstructed blood flow is rerouted to regions of normal lungs. Interstitial pulmonary edema worsens. Pulmonary disease further worsens as fragments of dead worms are carried distally into the smaller pulmonary arteries. Villous proliferation is coupled with thrombi formation and a granulomatous response to the dead heartworms. Pulmonary blood flow may be totally obstructed, and the caudal pulmonary lung lobes may become consolidated. Decreased endothelium-dependent relaxation can be correlated with pulmonary arterial blood pressure in dogs with heartworms, suggesting that this may be an important factor in the development of dirofilariasis-induced pulmonary hypertension.^276,^277,^277a Increased pulmonary vascular resistance can cause acute right-sided heart failure.

The clinical signs associated with heartworm disease and its treatment again depend on the number of worms present but also on the duration of infection and the host response, which can be quite variable. Coughing and dyspnea, the most common clinical signs, reflect disease of the caudal lung lobe arteries. Pulmonary edema and inflammatory response to dead heartworms are the most likely inciting causes. Dyspnea also might reflect ventilation perfusion mismatching as blood flow is diverted to patent arteries. Exercise intolerance is most likely to be associated with right ventricular hypertrophy and dilation resulting from severe arterial disease and impaired pulmonary blood flow. Mild to moderate hypoxemia worsens pulmonary hypertension. Right-sided CHF increases the magnitude of exercise intolerance and may lead to overt signs of right-sided heart failure such as ascites and an enlarged liver. Thromboembolism worsened by the inflammatory response to dead heartworms often is accompanied by hemoptysis; this was particularly true after treatment with thiacetarsamide. Blood loss resulting from vascular and airway rupture is most likely to occur after coughing in areas of severe vascular and parenchymal disease.

Occult Heartworm Disease

The incidence of occult disease can vary (from 5% to 67% of infected dogs) depending on geographic region. Occult infections may be caused by infection of one sex only (57% to 85% of occult infections), prepatent infections (particularly in colder months), drug-induced adult worm sterility, or immune-mediated elimination of microfilariae. Immune-mediated destruction of microfilariae occurs in the presence of excessive IgG production directed toward the microfilariae. A granulomatous reaction may follow phagocytosis of antibody–microfilaria–leukocyte complexes. Up to 15% of dogs with occult heartworm disease can be expected to develop immune-mediated pneumonitis characterized by coughing and dyspnea. Radiographically, the reaction causes diffuse interstitial and alveolar infiltrates. Tracheal lavage may reveal an eosinophilic exudate, and clinical laboratory tests reveal eosinophilia, basophilia, and hypergammaglobulinemia. Other potential sequelae of immune-mediated destruction of microfilariae include CHF, vena cava syndrome, and severely enlarged pulmonary arteries.

Therapy

Current recommendations for treatment and prevention of heartworm disease as recommended by the American Heartworm Society can be reviewed at http://www.heartwormsociety.org.^277a

Pretreatment Assessment

Pretreatment evaluation should focus on assessment of the risk of complications after adulticide therapy. In general, the risk of treatment was greater for thiacetarsemide compared to melarsomine, the currently approved canine adulticide. Diagnostic measures weigh the likelihood of success against the risk of side effects or complications. The extent and type of supportive therapy should be determined on the basis of the severity of infection before treatment. The development of thromboembolism is the complication most amenable to pretreatment assessment.

Up to 70% of dogs with severe heartworm disease may have an occult infection; as the number of adult heartworms increases, the number of microfilariae produced by each female decreases.²⁷⁷ The presence of occult disease also may indicate a greater likelihood of immune-mediated microfilarial disease. Infection indicated by positive tests should be confirmed before adulticide therapy is implemented. Antigen tests that quantitate antigen indirectly provide information regarding the adult heartworm load and can be of benefit in the assessment of the severity of infection. Radiographs are an important baseline test for assessing the severity of disease, with a focus on the caudal pulmonary lung field. Right ventricular enlargement should be assessed carefully by radiographic means. Cardiac ultrasonography is the preferred method of assessing right ventricular function and the extent and impact of pulmonary hypertension. Ultrasonography also might be helpful in identifying those animals with a high worm burden.

Ideally, a minimum database consisting of a complete blood count, routine serum chemistries, and urinalysis should be collected as part of the pretreatment evaluation. Findings of hypoalbuminemia, increased liver enzyme activity, azotemia, and proteinuria should lead to more intensive assessment of renal and hepatic function. Although renal dysfunction should be interpreted as a cause for concern, evidence of hepatic dysfunction should be expected in some animals, particularly those with evidence of right-sided CHF, and is not necessarily indicative of a decision not to treat. Up to a tenfold increase in liver enzyme activity can be tolerated before treatment. Leukocytosis is indicative of an inflammatory response in the lung parenchyma. Evidence of thrombocytopenia should lead to more aggressive evaluation of thromboembolic disease, including the presence of low-grade disseminated intravascular coagulopathy. Overt signs of bleeding and abnormal coagulation parameters may be absent in patients with low-grade disseminated intravascular coagulopathy; however, thrombocytopenia should persist.

Severe Pulmonary Arterial Disease and Pretreatment Therapy

Severe pulmonary arterial disease is indicated by the tortuosity and enlargement of the pulmonary lobar arteries, which in normal animals should not exceed in diameter the width of the ninth rib. Approximately 10% of infected dogs can be expected to have severe disease. Evidence of pulmonary thromboembolism before treatment should lead to a pretreatment course of glucocorticoids (1 to 2 mg/kg per day) until clinical and radiographic indicators of thromboembolism begin to resolve (generally 3 to 7 days). Glucocorticoids should not, however, be used routinely because of their ability to increase survival of adult heartworms. Because of the role that platelets have in causing the thromboembolic (including inflammatory) response, drugs such as aspirin, which impair platelet activity, may be beneficial. However, care should be taken to avoid COX-2 preferential drugs that may increase the risk of thromboembolism.

Anticoagulants such as heparin can increase pulmonary blood flow and reduce the severity and incidence of thromboembolic disease, including associated signs such as coughing and hemoptysis. Antithrombotic therapy generally consists of aspirin (4 to 6 mg/kg per day) for 2 to 3 weeks before treatment. Aspirin therapy is continued during and 3 to 4 weeks after adulticide therapy. Attention should be paid to the development of gastrointestinal side effects with protracted aspirin use, although they are less likely to occur with the low dose used for thromboembolic disease. Aspirin should not be used in the presence of hemoptysis. Evidence of gastrointestinal side effects should lead to therapy with sucralfate and H₂-receptor blockers; misoprostol might be avoided because of the unknown impact of this prostaglandin on pulmonary blood flow in the face of pulmonary arterial disease. Low-dose heparin (50 to 70 U/kg subcutaneously every 8 hours) may further increase survivability after therapy²⁷⁸ and is particularly crucial if there is evidence of disseminated intravascular coagulopathy (decreasing platelet count). For such patients heparin therapy should be continued for at least 7 days, and until the platelet count exceeds 150,000/μL, therapy can be continued for several weeks if needed.

If the severity of pulmonary arterial disease reflects a large burden of adult worms, the likelihood of fatal complications after adulticide therapy can be decreased by reducing the adult heartworm burden surgically (by way of the jugular vein), partial adulticide therapy (with melarsomine dihydrochloride), or cage confinement and antithrombotic therapy. Partial adulticide therapy (see package insert) involves injecting only the first of the two adulticide injections of drug, followed by a 30-day hiatus in patient activity. At the end of 1 month, the full treatment protocol is implemented. Because up to 50% of animals with severe pulmonary arterial disease can be expected to have signs associated with right-sided CHF, therapy with diuretics and a low-sodium diet may be indicated.

KEY POINT 14-64

To prevent fatal complications in patients with dirofilariasis, large worm burdens should be decreased before full adulticide therapy.

Pneumonitis

Glucocorticoids (prednisone 1 to 2 mg/kg per day or dexamethasone 0.2 to 0.4 mg/kg per day) are indicated to control the inflammatory response of pneumonitis. A parenteral route can be used for severely affected animals. Clinical improvement should occur within the first 24 hours, with radiographic resolution of pulmonary infiltrates associated with the pneumonitis in 3 to 5 days. Glucocorticoids should be discontinued when radiographic lesions are maximally resolved. Adulticide therapy should begin as soon as possible.

Prophylactic Therapy

Prophylaxis may be seasonal or throughout the year, depending on geographic location. Prophylaxis between May and October may be sufficient in the northern half of the country. Prophylaxis may contribute to collateral protection of unprotected dogs by decreasing the reservoir population, particularly in areas where mosquito and dog populations are low. Therapy should begin at 6 to 8 weeks of age if the season is appropriate. Once-daily administration of diethylcarbamazine (DEC) has been replaced with a macrolide antibiotic. Diethylcarbamazine (2.5 to 3 mg/kg orally once daily) affected L3 to L5 molting stage; however, efficacy may be lost with as little as three missed doses. DEC was safe when given to heartworm-negative dogs. But when administered to a dog infected with as few as 50 microfilariae/mL blood, DEC causes a severe anaphylactic-like reaction in up to 85% of animals. The reaction is characterized by depression, lethargy, vomiting, diarrhea, bradycardia, and shock, followed by death. Hepatomegaly and thrombocytopenia occur. Treatment is supportive (e.g., fluids, shock doses of glucocorticoids).

The macrolide antimicrobials are effective for the prevention of heartworm disease when given monthly, a distinct advantage to DEC therapy, particularly for owners whose compliance with daily therapy is poor. Macrolides are effective against microfiariae, third- and fourth-stage larvae, and potentially adult worms, with younger worms most susceptible to their effects. Efficacy is greatest for 1 month, but an additional month generally can be expected. Moxidectin is unique in its longer half-life of 20 days, its chemical side chains (compared with other avermectins), and its availability in slow-release microspheres. Oral choices of macrolide antibiotics include ivermectin (2-day half-life) (Heartgard; Merck; 6 to 12 μg/kg by mouth monthly at 6 weeks or older; 24 μg/kg by mouth monthly in cats), milbemycin oxime (Interceptor; Novartis; 0.5 to 1 mg/kg or 500 to 1000 μg/kg monthly by mouth) in dogs at 8 weeks or older; and moxidectin (ProHeart, Fort Dodge; 3 to 6 μg/kg by mouth monthly). Topical options include selamectin (Revolution, Pfizer; 6 to 12 mg/kg, topical in dogs 6 weeks or older), and moxidectin topical (with imidacloprid; Advantage Multi for dogs).²⁷⁹ Moxidectin also is available as an injectable slow-release product (ProHeart, Fort Dodge, 170 μg/kg as microspheres subcutaneously every 6 months in dogs 6 months or older) in several countries.²⁸⁰ It was voluntarily withdrawn in the United States (but not other countries) in 2004 for potential and controversial safety issues but was reintroduced in 2008. An advantage of this product is retro-protection of 4 months and full protection that extends beyond its 6-month labeled claim. Ivermectin is highly effective in preventing heartworm infections in dogs when given monthly (5.98 μg/kg). It does not control other helminthes but is available in a combination product with pyrantel, which controls hookworms and roundworms. Milbemycin controls roundworms, hookworms, and whipworms. Selamectin is effective against hookworms and roundworms, as well as fleas (adults), ear and sarcoptic mange mites, and selected ticks.

The duration of retroactive protection varies with the macrolide. Ivermectin, but not milbemycin, appears to retroactively protect against infection if given as long as 4 months after infection. Both drugs are effective at 3 months after infection. Retroactive efficacy (and partial adulticide effects of ivermectin) may warrant prophylactic therapy during the off season, particularly in light of a recent survey finding that 80% of respondents failed to give their dogs monthly heartworm preventive on the due date. Unlike DEC, the avermectins do not appear to cause adversity when given as preventives to heartworm-positive dogs. In a review, McCall²⁸¹ summarizes the “safety-net” (reachback) and adulticide effects of macrocyclic lactones. Up to 95% efficacy against adults may be realized, but treatment requires 9 to 30 months, with continuous monthly therapy resulting in better efficacy. Increased dose and shorter intervals do not appear to affect efficacy. The effect is greater on younger worms than on older worms, supporting better efficacy with earlier as opposed to later treatment. Among the drugs, efficacy in killing mature worms is ranked ivermectin > selamectin and moxidectin injectable > milbemycin.

The microfilaricidal effect of macrolides at prophylactic doses has several implications. First, adulticide therapy need not be followed by microfilaricide therapy; prophylactic therapy will lead to resolution of microfilaria. Second, microfilaria testing should precede initiation of prophylaxis therapy to prevent mistaking pretreatment infection for therapeutic failure and to minimize the risk of the sequelae of rapid microfilaria kill. Third, administration of a macrolide antibiotic (except moxidectin) at prophylactic doses is the most frequent cause of iatrogenic occult infections resulting from either microfilaricidal effects or sterilization of the female adult worm. Most adult infections become occult within 6 (2 to 9) months after beginning therapy. It is important that antigen testing rather than concentration tests be used as screening procedures in animals to be treated prophylactically.

The American Heartworm Society suggests that efficacy of prophylactic products should be tested at 3 months (4 for injectable 6-month product), after the start of the new product, or at the restart of lapsed prophylaxis. A negative status should be confirmed by testing before the change (i.e., change in drugs or re-initiation of lapsed prophylaxis). A positive test before the change or at 3 months indicates failure of the original drug or infection during the lapse in therapy. A negative test at 3 months should be followed by retesting at 8 to 9 months; a positive result at that time indicates that infection may have occurred before or during transition to the new drug, or failure of the new drug. A positive test after 9 months indicates failure of the new product or noncompliance.

Adverse reactions associated with macrocyclic lactones were addressed in Chapter 4. Adversities generally involve the central nervous system. Mealey²⁸² reviewed the impact of the MDR1 (currently ABCB1) gene product P-glycoprotein on the safe use of macrocyclic lactones in dogs. Mealey²⁸² underscores the fact that all macrocyclic lactones are safe in all dogs, regardless of the presence of the deletion, when used at the approved preventive dose (Table 14-5). Adversities occur when used off label (e.g., treatment of mange at daily doses of 300 to 600 μg/kg). Accidental overdose is more likely with large animal preparations because of unintentional exposure²⁸³ or intentional exposure with a miscalculated compounded product.²⁸² Internet-based recipes offered by lay users will contribute to increased risk of toxicity with off-label use of large animal products.²⁸² Known safe and toxic doses (in μg/kg) in gene-deficient dogs are provided in Table 14-5. Because the proposed mechanism of central nervous system adversities (disorientation to seizures) reflects enhanced chloride ion flow through gaba- channels, anticonvulsant drugs that do not target the GABA receptor (e.g., levetiracetam, zonisamide to a lesser degree) might be preferred over those that do (e.g., benzodiazepines, phenobarbital).

Table 14-5 Safe and Toxic Doses of Macrocyclic Lactones in ABCB1 Deficient Dogs²⁸²

KEY POINT 14-65

The duration of retroprotection of macrolides varies with the drug but generally ranges from 3 to 4 months.

KEY POINT 14-66

P-glyocoprotein deficiency leading to macrocyclic lactone toxicity in Collies and working breeds of dogs can be detected on the basis of a molecular test.

In 2004 Proheart (injectable moxidectin) was voluntarily withdrawn from the U.S. market; no other country withdrew the product. In support of its reintroduction in 2008, Fort Dodge provided to the Center for Veterinary Medicine a review of adverse events associated with its injectable product and two other unnamed oral monthly products. The data, which were collected from medical records of animals receiving the drugs or vaccines (alone or in combination), have been published.²⁸⁴ In addition to the adverse events, the report offers a reasonable perspective on the difficulties associated with assessing adverse events as they currently are reported in veterinary medicine. Among the adverse events examined was association of treatment with cancers. Differences were limited to the incidence per 10,000 days at risk for mast cell tumors (0.024 for animals treated with one of the heartworm preparations, 0.043 for animals receiving vaccinations only, and 0.072 for Proheart 6 only), with no relationship demonstrated regarding the number of doses received (from 1 to 5). Allergic rates and all other safety profiles were similar among the three preventives studied. Interestingly, all heartworm preventives studied were associated with an increased incidence of allergic reactions. The apparent lack of substantial differences in adverse events for Proheart 6 compared with monthly preventives should be weighed against the risk of the sequelae of therapeutic failure as a result of poor compliance.

Adulticide Therapy

Melarsomine

Melarsomine is a trivalent arsenical that offers several advantages to the older arsenical, thiacetarsamide.²⁸⁵ Because it is unstable in an aqueous solution, it is manufactured as a lyophilized powder that must be reconstituted immediately before use. Although its mechanism of action is not clear, it is equal to or better in efficacy for treatment of dirofilariasis based on controlled clinical trial in dogs with class 2 (moderate) heartworm disease. Melarsomine also is characterized by a wider therapeutic index than thiacetarsamide, although the margin is still considered low. Death associated with pulmonary inflammation can occur with as little as three times the recommended dose. However, melarsomine may be less likely than thiacetarsamide to cause pulmonary arterial vasoconstriction.²⁸⁶ Melarsomine is administered deeply through an intramuscular route (2.5 mg/kg twice at 24-hour intervals) in dogs with mild to moderate disease. One half of worms, primarily males, die after the first injection; the remaining die with second treatments. According to the package insert, a 10% death rate is expected in dogs with class III disease when two doses are given initially. As such, in dogs with severe heartworm disease (see package insert for characteristics), an alternative dosing regimen consisting of one 2.5 mg/kg injection, followed 1 month later by the full regimen, is recommended. However, the alternative regimen increasingly is being implemented as the rule rather than the exception, regardless of the state of disease. The American Heartworm Society cites the alternative regimen as being not only safer but also more effective, resulting in fewer treatment failures. Reaction to the intramuscular injection can be expected in at least 30% of animals being treated and is minimized by making sure that the injection is deep. Care should be taken to ensure that the needle is appropriate for the depth of muscle, that injection is complete before needle withdrawal, and that sites of injection are alternated. Local reaction should be limited to edema and slight pain. Other side effects to mesarlomine reflect reaction to the dead heartworms or the drug (hepatotoxicity).

Clinically ill patients should be stabilized before treatment. Instead of melarsomine, macrocyclic lactones delivered at prophylactic doses may be administered with the intent to kill adult worms. The American Heartworm Society recommends treatment with a macrocyclic lactone for 6 months if immediate therapeutic intervention is not necessary. Treatment also will decrease circulating microfilariae and kill migrating larvae. Reduction in antigenic mass may reduce the risk of thromboembolism. In worms less than 4 months in development, ivermectin will also stunt immature worms and reduce female worms. Finally, administration for at least 3 months (or injection of slow-release moxidectin) will allow development of immature worms to a stage susceptible to melarsomine killing.

Efficacy varies with the drug and duration. Efficacy generally requires at least 1 year of therapy, with older worms requiring up to 2 years of therapy. When administered as prophylactic doses, ivermectin and selamectin reduce adult numbers by 56% after 16 months of therapy; abnormalities in surviving worms may decrease their life span. Precardiac larvae and young (less than 7 months) worms are most susceptible to ivermectin, with susceptibility inversely correlated with worm age. Treatment of older worms may require melarsomine to prevent continued development of disease as worms slowly die. Moxidectin (parenteral) and milbemycin are associated with rapid microfilaria killing and therefore should be used cautiously. Further, milbemycin does not appear to reduce worm counts, although it may sterilize female worms. The slow death of adults associated with macrocycline lactones may decrease the risk of thromboembolic disease; however, animals should be monitored at least every 4 to 6 months until worms are dead.

Complete killing of adult worms may not be necessary for clinical improvement. Further, clinical signs may not improve if residual worms are killed (i.e., through retreatment). Because surviving worms may not produce microfilariae, antigen testing is the most accurate method of evaluating successful therapy. Worms continue to die for up to 1 month after therapy; therefore antigen testing generally should occur at 5 to 6 months after therapy. Worms that survive adulticide therapy tend to be antigen-producing females; accordingly, the absence of antigen at 6 months indicates successful therapy. The presence of antigens at a later date (after a negative test) is indicative of reinfection rather than therapeutic failure.

Alternative Adulticides

The impact of preventives on maturing or adult heartworms was addressed under prophylaxis. Alternative adulticides do not appear to be effective. Levamisole efficacy is variable and unpredictable and generates iatrogenic occult infections. Side effects, including emesis, nervousness, ataxia, hallucinations, and seizures, are not unusual. Interestingly, tetracycline antimicrobials decrease microfilaria production and some adulticide effects in Onchocerca spp. owing to death of a symbiotic gut microbe (Wolbachia spp. of the order Rickettsiales). A surface protein on the organisms may contribute to pulmonary and renal inflammation. Tetracyclines also may cause infertility in female worms. McCall²⁸⁷ reported that the combination of doxycycline (10 μg/kg) with ivermectin (6 μg/kg) for several months will eliminate heartworms. The study involved six groups of five dogs experimentally infected with adult heartworms. Groups received either placebo, ivermectin (6 μg/kg for 36 weeks), doxycycline (10 μg/kg/day for 18/36 weeks), or both drugs with or without melarsomine. All dogs treated with the combination were amicrofilaremic after week 9, and antigen test scores gradually decreased in these animals. In dogs treated with either ivermectin or doxycycline, counts decreased but some microfilariae were still present at 36 weeks. With regard to the adult worms, the percentage of reduction was 20% for ivermectin, 9% for doxycycline, and 78% for the combination. In dogs also treated with melarsomine, the percentage of reduction was 100% for melarsomine alone compared with 93% for melarsomine, ivermectin, and doxycycline. On the basis of these findings, further clinical studies are warranted to assess the use of tetracyclines (specifically doxycycline) in the treatment of heartworms.

The risk of pulmonary embolism is greater with a larger worm load and rapid kill and in dogs with moderate to severe radiographic changes. Small dogs (<15 kg) may be at greater risk. Clinical signs of embolism (fever, cough, hempotysis, right-sided heart failure) generally occur within 7 to 10 days but may occur at any time up to 4 to 6 weeks after treatment; exercise often is not restricted in afflicted animals. The most critical therapy for preventing thromboembolism is exercise restrictions for at least 1 month after therapy. Glucocorticoids have been recommended (0.5 mg/kg alternate days) for clinically affected animals; impact on efficacy of melarsomine has not been determined. Routine use of aspirin for prevention of pulmonary thromboembolism is not recommended and, according to the American Heartworm Society, may be contraindicated. Other potential reactions to dead or dying worms include exsanguination because of disseminated intravascular coagulopathy. Treatment of pulmonary thromboembolism is controversial and includes careful fluid therapy; use of heparin (75 IU/kg subcutaneously thrice daily until platelet count has normalized [5-7 days]) and aspirin (5 to 7 mg/kg/day) has been advocated by some but remains controversial. Cough suppressants should be used as indicated; antimicrobial use should be implemented only in the face of nonresponsive fever. The role of vasodilator therapy in management of pulmonary thromboembolism is controversial. Hydralazine has shown some efficacy in improved cardiac output in dogs with heart failure associated with heartworm disease. Alternative therapies recommended by Atkins and coworkers⁵³ include amlodipine or diltiazem.

Right-sided heart failure may accompany pulmonary thromboembolism or postcaval syndrome. Treatment may include diuretics (furosemide, spironolactone), ACE inhibitors (targeting fluid retention and myocardial remodeling), and aspirin (targeting thromboembolic disease). Digoxin has not proved effective and is not generally recommended unless treatment focuses on supraventricular arrhythmias or refractory heart failure.

Microfilaricide Therapy

Because of the microfilaricide effect of macrocyclic lactones, the need for microfilaricide therapy is increasingly considered unnecessary as a follow-up to adulticide therapy. Regardless of the drug used, microfilariae generally resolve after several months of prophylactic therapy in the treated or untreated heartworm-infested dog. No drug is approved for use as a microfilaricide in the United States. However, if rapid removal of microfilariae is warranted, the macrocyclic lactones can be used, although duration of efficacy varies. A single dose may be insufficient to clear microfilariae; subsequent doses can be administered as needed. Ivermectin (unapproved as a microfilaricide) is 90% effective after a single dose (0.05 mg/kg or 50 μg/kg orally; approximately 8 times the preventive dose) 4 weeks after adulticide therapy is complete. Large animal preparations have been diluted 1 to 9 mL with propylene glycol (Ivomec) or water (Eqvalan) and administered at a rate of 1 mL/20 kg; however, this may increase the risk of adverse reactions. Administration in the morning is recommended to allow observation for the day. Care should be taken to avoid overdosing, particularly in Collie or related breeds that might be predisposed to toxicity (discussed later). Because milbemycin is the most potent and potentially more consistently effective microfilaricide, it can be used for rapid kill (0.5 mg/kg). Alternatively, prophylactic doses of any macrolide could be reduced to a 2-week interval. Animals should be hospitalized for the first 8 hours after therapy, particularly if rapid-kill doses are administered. Rapid kill of large numbers of microfilariae 4 to 8 hours after the first dose rarely is accompanied by acute circulatory collapse. Predisposed animals include dogs weighing less than 16 kg or harboring more than 10,000 microfilariae per mL of blood, although reactions have occurred in animals with as few as 5000 microfilariae per mL of blood. Pretreatment with antihistamines and glucocortocoids should be considered in predisposed animals. Therapy includes fluid support and shock doses of short-acting glucocorticoids. Pretreatment with prednisolone may decrease adverse effects in dogs with a high microfilarial load. Clinical signs are not likely with subsequent microfilaricide treatment. Predisposed animals might also be treated with prophylactic doses of ivermectin. Moxidectin and selamectin also are microfilaricidal, although an appropriate dose has not been recommended.

Avermectin Toxicities

Adverse reactions to ivermectin and milbemycin microfilaricide therapy are more likely in Collies and Collielike dogs, including Border Collies and Old English Sheepdogs, than in the general population. Toxicity reflects a gene mutation in the p-glycoprotein efflux pump (homozygous or affected present in 35% of studied collies). Toxicity is characterized by acute ataxia, mydriasis, weakness, and seizures. Coma and death may follow. Toxicity predictably occurs at 10 times the recommended dose (50 μg/kg) for ivermectin and 5 times for milbemycin. Moxidectin and selamectin appear to be safe in collies at 10 times and 5 times, respectively, the prophylactic dose. Less common (<5%) toxicities occur in other dogs and are limited to lethargy and vomiting, which generally occur within 2 hours after drug administration. Occasionally, tachycardia, tachypnea, weakness, and pale mucous membranes accompany therapy. Treatment of toxicity includes fluid administration, glucocorticoids, and other supportive therapy. Animals with a very high microfilarial load may be more likely to have an adverse reaction to microfilaricide doses; adversity might be reduced in such animals by reduction of the dose of ivermectin by one third.

A concentration microfilarial test should be performed 3 to 4 weeks after microfilaricide treatment with ivermectin. Persistence of microfilariae after adulticide treatment (within the past year) may reflect failure of microfilaricide therapy (approximately 10% of animals) or a surviving gravid female. Microfilaricide therapy should be repeated, and, should microfilaria still persist, an adult antigen test should be repeated 60 to 90 days after adulticide. If the test is positive, the adult worms most likely are young females, and repeated adulticide therapy may not be effective. Therapy should be withheld for 1 year, but microfilaricide therapy should begin. When given at doses that are microfilaricidal, ivermectin also will prevent infection. Ivermectin can be used as a preventive in older or severely affected animals that are heartworm positive but for which adulticide therapy is not immediately or ever anticipated. Ivermectin not only will prevent further infection in these animals but also will reduce the microfilarial load, thus decreasing the risk of future adulticide complications. When a microfilaricide is administered, any animal will be protected against reinfection that may have occurred during the 1 to 2 months that elapsed between adulticide and microfilaricide therapy. Because the prophylactic doses of ivermectin can reduce microfilariae, causing an occult disease (generally within 6 months of prophylactic therapy), antigen testing rather than microfilarial concentration is the recommended method of screening for heartworm disease in animals on a monthly preventive program.

A number of other drugs are microfilaricidal, including fenthion, diethylcarbamazine, levamisole (11 mg/kg orally once daily for 7 to 10 days), and dithiazanine iodide (4.4 to 8.8 mg/kg orally once daily for 7 to 10 days); the latter drug is approved by the Food and Drug Administration for this use in dogs. The safety and efficacy of these products are not, however, predictable.²⁸⁸ Treatment usually requires multiple days of therapy.

Feline Heartworm Disease

Differences exist in the pathyophysiology of heartworm infection as it occurs in the cat compared with the dog. Cats are more resistant to infection; accordingly, the rate of infection is lower²⁷⁷ both in incidence and worm count (generally less than 6 and often only 2 or 3); further, the life expectancy of adult worms is shorter (2 to 3 years). Diagnostic limitations caused by low antigen load may underestimate the true prevalence of infection in cats. Despite the low worm load, the pathophysiology of the disease is similar in cats but more exaggerated, and sudden death is more frequent. Proliferation and inflammation are marked in the cat, and trophic factors from leukocytes may largely be responsible for the differences in the magnitude of response.²⁷⁷ However, worm-mediated immune suppression may preclude emergence of clinical signs. The magnitude of thromboembolism apparently does not correlate with the number of infecting worms. Pulmonary infiltrates with eosinophils may develop. Paroxysmal coughing and dyspnea are the most common presenting signs, yet vomiting may be the only sign in some cats. Acute pulmonary thromboembolism is not unusual. Other clinical signs that may require pharmacologic management include tachycardia or bradycardia and neurologic disturbances (e.g., ataxia, blindness, seizures). Right-sided heart failure may occur with chronic disease, as might pleural effusions. Diagnosis of heartworm disease in the cat is more difficult than in the dog. Microfilariae usually are absent, and antigen testing tends to be less sensitive than in the dog because of the low worm burden. Even very sensitive tests, capable of detecting one female worm, may fail as a result of the frequency of unisex (male) infections in cats. Although antibody tests can detect either sex of larva or adult, they cannot discriminate active from past infection. Further, tests vary with the age of larvae. Nonselective angiography and echocardiography can be helpful in diagnosing feline heartworm diseases, although serologic testing based on adult antigens should be used to confirm the diagnosis.

Several preventives are currently approved in the United States for use in cats, including ivermectin (Heartgard for Cats: 55 μg/cat up to 2.3 kg or 5 lb; 165 μg/cat up to 7 kg or 15 lb, oral;), selamectin (Revolution for cats; 15 mg/cat if 2.3 kg or less, 45 mg for cats > 2.3 kg, topical) and moxidectin topical (with imidacloprid; Advantage Multiplex for Cats, 2.3, 4, and 8 mg topical for <2.3 kg (5 lb), 2.3 to 4.1 kg and > 4.1 kg (9 lb) cats, respectively).^289,²⁹⁰ The need for adulticide therapy in cats is controversial. Infection may be self-limiting in asymptomatic cats or in cats with mild pulmonary infiltrates with eosinophils. Cats may respond to low doses of glucocorticoids. Adulticide should be reserved for cats that maintain clinical signs despite glucocorticoid therapy. Cats with low worm burden are more amenable to treatment. The worm burden might be surgically reduced in cats with a larger worm number. Thiacetarsemide has been studied in uninfected cats (n=14), and all but one cat reacted adversely; 66% developed lethargy, depression, and anorexia, and at least one third vomited.²⁹¹ Three of 14 cats undergoing the treatment protocol developed clinical signs consistent with fulminating pulmonary edema typical of anaphylaxis or an anaphylactoid reaction. All three of the cats died. Nine other cats developed acute respiratory signs. A follow-up study²⁹² with 23 cats (17 with heartworms) found no adversity to thiacetarsamide therapy. Yet Rawlings and Calvert²⁷⁷ report findings similar to those of Turner et al.²⁹¹ when treating cats with spontaneous infections. Melarsomine appears to be more toxic to cats than dogs; the American Heartworm Society notes that doses as low as 3.5 mg/kg may be toxic. Of the macrolide antimicrobials, ivermectin (24 μg/kg every 30 days for 2 years) has been demonstrated to reduce worm burden by 65% compared to untreated cats.

Cats also are at risk of developing acute pulmonary thromboembolism within the first 3 weeks of adulticide therapy. Glucocorticoids and heparin (50 to 70 U/kg subcutaneously every 8 hours) with or without aspirin therapy should be administered in the face of thromboembolism. Platelet counts should be monitored and antithrombotic therapy implemented if counts decrease below 100,000/mL. The presence of allergic pneumonitis may delay adulticide therapy. Treatment with prednisolone (1 to 2 mg/kg per day) for several days should resolve clinical signs, but clinical signs may return during adulticide therapy.

Microfilaricide therapy is largely unnecessary for cats because of the low incidence of microfilariae-positive disease. If microfilariae are present, ivermectin is an effective microfilaricide. Prophylaxis can be implemented with ivermectin (24 μg/kg), milbemycin oxime (2 mg/kg), or selamectin (6 to 12 mg/kg).

Geographic differences in infection incidence is marked, with differences reflecting weather, economic foundation, and so forth. Clinicians should be aware that disease can occur at 3 months. Heartworms secrete substances that prevent vascular responses, and stimulate (possibly protective) inflammation. Note that the disease includes several processes. These include fibrosis, scarring, and similar lesions at the microcapillary level; alveolar capillary fibrosis; lesions up to the fourth or fifth obstruction of cross-sectional area of right or left caudal lobar arteries, and reduced blood flow. Occult disease with adult worms producing microfilariae worsens the disease (eosinophilic infiltrates or pneumonitis).

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