ETIOLOGY

The circulatory system consists of a pump (the heart) and a circuit (the vasculature). Circulatory shock can result from abnormal functioning of the pump or circuit, or both. It is clinically very important to differentiate pump failure (cardiogenic shock due to acute or chronic heart failure) from circuit failure, because the diagnosis and treatment of cardiogenic shock is vastly different to that of circuit shock. Cardiogenic shock is covered in detail in Chapter 8, whereas circuit failure is addressed in the following section.

Circuit failure occurs whenever the cardiac output is reduced below a critical point because of inadequate venous return to the heart. There are four main ways that circuit failure occurs:

Regardless of the initiating cause for circuit failure and inadequate venous return, tissue hypoperfusion results, leading to impaired oxygen uptake and anaerobic metabolism. The end result of inadequate tissue perfusion is the development of multiple organ failure, l-lactate acidemia, and strong ion (metabolic) acidosis, manifest as the hypodynamic stage of shock. Hypovolemia and poor tissue perfusion results in cold extremities, elevated heart rate, a weak thready pulse, decreased capillary refill times and altered mental status. Cardiac arrhythmias may occur because of myocardial ischemia and electrolyte and acid–base disturbance. There is anorexia and gastrointestinal stasis. Signs of renal failure include anuria or oliguria and azotemia.

Common causes of circuit failure in large animals are as follows.

PATHOGENESIS

CLINICAL FINDINGS

Depression, weakness and listlessness are accompanied by a fall in temperature to below normal. The skin is cold and skin turgor is decreased. The mucosae are pale gray to white and dry, and capillary refill time is extended beyond 3–4 s.

There is an increase in heart rate to 120–140 beats/min in horses and cattle, with abnormalities of the pulse including small and weak pressure amplitudes (a ‘thready’ pulse). Cardiac arrhythmias are present terminally. Venous blood pressure is greatly reduced in hypovolemic and hemorrhagic shock and the veins are difficult to raise. Arterial blood pressure, measured either directly by arterial puncture or by indirect oscillometric methods, is decreased terminally and fails to provide an early indicator of the severity of the circulatory failure.

Anorexia is usual but thirst may be evident and there is anuria or oliguria. Nervous signs include depression, listlessness and obtusion, and coma in the terminal stages.

During the early hyperdynamic stage of maldistributive shock the temperature is normal or elevated, mucous membranes are injected and brick-red in color, there is tachycardia but normal capillary refill time, and the extremities (particularly ears) are cool to the touch. Whereas these signs are not specific for shock, the recognition of this stage in animals that are at risk for maldistributive shock, such as the neonate or animals with early signs of acute intestinal accident, can allow the early institution of therapy, which will frequently result in a better outcome than therapy instituted when the later stages of shock are manifest.

Therapeutic reversal of maldistributive shock in its later stages is difficult. In contrast, circulatory failure that is a result of hypovolemic or hemorrhagic shock is relatively easily treated and can be successfully reversed even at stages of profound depression.

CLINICAL PATHOLOGY

The use of clinical pathology is directed at determining the cause and severity of shock and at monitoring the effectiveness of therapy. Volume expansion and restoration of tissue perfusion will usually correct acid–base and strong ion (metabolic) acidosis in the majority of animals with shock and abnormalities are addressed once fluid balance is established.¹⁸

Examination of the blood for hematocrit and plasma protein concentration are valuable in indicating the magnitude of the blood loss in hemorrhagic shock and provide a clinically useful index to the progress of the disease. However, there can be a delay in the fall of the hematocrit following hemorrhage for up to 4–6 hours because splenic contraction temporarily augments circulating red cell numbers. The hematocrit and plasma protein concentrations usually fall to their lowest levels 12–24 hours following hemorrhage, and determination at this time provides a clinically useful index of the amount of blood lost. Signs of a regenerative response (increased hematocrit, presence of reticulocytes, increased red blood cell volume) should be seen within 4 days of an acute hemorrhage in ruminants and pigs but cannot be used as a guide in the horse. In general, the hematocrit increases by 1% per day following acute hemorrhage in ruminants.

Abdominocentesis, thoracocentesis and ultrasound are used to identify sites of internal bleeding. Thrombocyte and clotting factor examinations are indicated in cases in which unexplained spontaneous hemorrhages occur.

NECROPSY FINDINGS

In hemorrhagic shock there is extreme pallor of all tissues and a thin watery appearance of the blood may be accompanied by large extravasations of blood if the hemorrhage has been internal. Where the hemorrhage has been chronic, anemia and edema are characteristic findings. In obstructive shock there is a large increase in pericardial fluid (usually blood), or the presence of a large thrombus in the cranial or caudal vena cava or pulmonary circulation, or evidence of severe abdominal distension (such as in ruminal tympany). There are no specific findings in hypovolemic or maldistributive shock, although in maldistributive shock the capillaries and small vessels of the splanchnic area may be congested and there may be evidence of pulmonary edema. With death from septic shock the major findings relate to the changes associated with the infectious disease. Dehydration is evident in animals dying from hypovolemic shock.

TREATMENT

TYPE I

In immediate hypersensitivity reactions the antigen, or allergen, reacts with antibody, which may be either circulating or cell-bound, to set in train a series of complex biochemical and pharmacological reactions that culminate in the release of pharmacologically active mediators. There are a number of recognized mediators and the importance of any one varies with the host species and possibly the nature of the hypersensitivity reaction. In general they act to contract smooth muscle and increase capillary permeability. These agents may act immediately at the site of antigen–antibody reaction or they may be carried in the blood to produce effects in susceptible tissues at sites remote from the primary focus. The difference in manifestation of acute, immediate-type hypersensitivity reactions between species appears to depend largely on differences in the tissue site of antibody binding and the distribution of susceptible smooth muscle, as well as differences in the major pharmacological mediators of the reaction. The high incidence of atopic hypersensitivity with familial predisposition seen in humans and dogs does not occur in large animals.

The literature on immunoglobulin-E-mediated hypersensitivity in food-producing animals has been reviewed and the details are available.¹

Immunological injury in the absence of significant release of pharmacological mediators also occurs but it is rarely approached from the clinical standpoint as a primary allergy and is generally considered in the disease complex in which it is occurring. The anemia and glomerulitis that accompany equine infectious anemia is an example. Serum sickness is rare in large animals.

TYPE II

Autoimmune reactions are uncommon in farm animals. They contribute to the formation of spermatic granulomas. Isoimmune hemolytic anemia and thrombocytopenic purpura could be considered as examples and are dealt with elsewhere under those headings.

TYPE III

Arthus-type reaction or the Arthus phenomenon is the development of an inflammatory lesion, with induration, erythema, edema, hemorrhage and necrosis, a few hours after intradermal injection of antigen into a previously sensitized animal producing precipitating antibody; it is classed as a type III hypersensitivity reaction in the Gell and Coombs classification of immune responses. The lesion results from the precipitation of antigen–antibody complexes, which causes complement activation and the release of complement fragments that are chemotactic for neutrophils; large numbers of neutrophils infiltrate the site and cause tissue destruction by release of lysosomal enzymes.

TYPE IV

Cell-mediated or delayed hypersensitivity is of importance in the tuberculin and other long-term skin sensitivity tests, but similar delayed reactions to topically applied antigens are not common in farm animals. Queensland and sweet itch are probably examples. Delayed hypersensitivity reactions may contribute to the pathology of many diseases such as mycoplasmal pneumonia in swine, but those are considered clinically under their initiating etiology.

TREATMENT

The treatment of allergic states is by the use of functional antagonists which have opposing effects to those of the allergic mediators, and the specific pharmacological antagonists, especially antihistamines and corticosteroids. The functional antagonists include the sympathomimetic drugs, those related to epinephrine and, to a less extent, the anticholinergic drugs. Of the sympathomimetic drugs there is a choice between those with an alpha-response (vasoconstriction and maintaining vascular permeability) and those with a beta-response (bronchodilatory and cardiac-stimulatory). Of the pharmacological antagonists, antihistamines have very limited usefulness, being effective only when the allergic mediator is histamine, the corticosteroids have very wide applicability, and the NSAIDs, including acetylsalicylic acid, phenylbutazone and meclofenamic acid, all inhibit prostaglandin synthesis and thus reduce inflammation.

ETIOLOGY

Most commonly, severe anaphylactic reactions are seen in farm animals following the parenteral administration of a drug or biological product.¹ Other routes of entry of the allergen, such as via the respiratory or gastrointestinal tract, may also result in anaphylactic reactions. The reaction may occur at the site of exposure or in other areas.

In general the reaction is due to sensitization to a protein substance entering the bloodstream and a second exposure to the same substance. In veterinary practice such incidents are not uncommon, although the sensitizing substance cannot always be isolated.

Although severe anaphylactic reactions occur usually after a second exposure to a sensitizing agent, reactions of similar severity can occur with no known prior exposure. In large-animal practice this is most likely to occur after the injection of sera and bacterins, particularly heterologous sera and bacterins in which heterologous serum has been used in the culture medium.

Hypersensitivity reactions are sometimes observed at a higher incidence than normal in certain families and herds of cattle.

Anaphylactic reactions can occur in the following circumstances:

PATHOGENESIS

Anaphylactic reactions occur as the result of antigen reacting with circulating or cell-bound antibody. In humans and dogs a specific class of reaginic antibody, IgE, has been identified and has particular affinity for fixed tissue mast cells.¹ The tissue distribution of mast cells in part accounts for the involvement of certain target organs in anaphylactic reactions in these species. Homocytotropic antibody has been detected in farm animals but the classes of antibody involved in anaphylactic reactions have not been fully identified and are likely to be diverse. Anaphylactic antibodies may be transferred via colostrum.

Antigen–antibody reactions occurring in contact with, or in close proximity to fixed tissue mast cells, basophils and neutrophil leukocytes result in the activation of these cells to release pharmacologically active substances that mediate the subsequent anaphylactic reaction. These substances include biogenic amines such as histamine, serotonin and catecholamines; vasoactive polypeptides such as kinins, cationic proteins and anaphylatoxins; vasoactive lipids such as prostaglandins and slow reacting substance of anaphylaxis (SRS-A); and others. Knowledge of the type and relative importance of pharmacological mediators of anaphylaxis in farm animals rests with studies of severe anaphylactic reactions that have been induced experimentally, but it is likely that these mediators are also of significance in less severe reactions. From these studies it appears that histamine is of less importance as a mediator in farm animals than in other species and that prostaglandins and SRS-A are of greater importance. Bradykinin and 5-hydroxytryptamine (5-HT) are also known to act as mediators in cattle but the reactions in all species are complex and involve a sequence of mediator effects.

In the horse, there are four phases in the development of the anaphylactic response. The first is acute hypotension combined with pulmonary arterial hypertension 2–3 minutes after the injection of the triggering agent; it coincides with histamine release. In the second phase, blood plasma 5-HT levels rise, and central venous blood pressure rises sharply at about 3 minutes and onward. The third phase commences at about 8–12 minutes, and is largely reflex and manifested by a sharp rise in blood pressure, and alternating apnea and dyspnea. Finally, there is a second and more protracted systemic hypotension due to prostaglandin and SRS-A influence which persists until the return to normality.

In cattle, there is a similar diphasic systemic hypotension with marked pulmonary venous constriction and pulmonary artery hypertension. An increase in mesenteric venous pressure and mesenteric vascular resistance causes considerable pooling of blood on the venous side of the mesenteric vessels. In both cattle and horses these reactions are accompanied by severe hemoconcentration, leukopenia, thrombocytopenia and hyperkalemia.

Sheep and pigs also show a largely pulmonary reaction.

In horses and cattle the marked changes in vascular tone coupled with increased capillary permeability, increased secretion of mucous glands and bronchospasm are the primary reactions leading to the development of severe pulmonary congestion, edema and emphysema and edema of the gut wall. Death is due to anoxia.

Less severe reactions are also dependent upon the effect of mediators on capillary permeability, vascular tone and mucous gland secretion. The major manifestation depends on the distribution of antibody-sensitized cells and of susceptible smooth muscle in the various organs. In cattle, reactions are generally referable to the respiratory tract but the alimentary tract and skin are also target organs. Sheep and pigs show largely a pulmonary reaction and horses manifest changes in the lungs, skin and feet.

Sensitization of a patient requires about 10 days after first exposure to the antigen, and persists for a very long time: months or years.

CLINICAL FINDINGS

CLINICAL PATHOLOGY

Blood histamine levels may or may not be increased and few data are available on blood eosinophil counts. Tests for sensitivity to determine the specific sensitizing substance are rarely carried out for diagnostic purposes but their use as an investigation tool is warranted. Serological tests to determine the presence of antibodies to plant proteins in the diet have been used in this way.

Some significant changes occur during immediate anaphylaxis in cattle and horses but whether they have diagnostic importance is uncertain. There is a marked increase in packed cell volume, a high plasma potassium concentration and a neutropenia.

NECROPSY FINDINGS

In acute anaphylaxis in young cattle and sheep the necropsy findings are confined to the lungs and are in the form of severe pulmonary edema and vascular engorgement. In adult cattle there is edema and emphysema without engorgement. In protracted anaphylaxis produced experimentally in young calves, the most prominent lesions are hyperemia and edema of the abomasum and small intestines. In pigs and sheep pulmonary emphysema is evident and vascular engorgement of the lungs is pronounced in the latter. Pulmonary emphysema and widespread petechiation in the horse may be accompanied by massive edema and extravasations of blood in the wall of the large bowel. There may also be subcutaneous edema and lesions of laminitis.

TREATMENT

Treatment should be administered immediately; a few minutes’ delay may result in the death of the animal. Epinephrine is the most effective treatment for anaphylaxis and anaphylactic shock. Epinephrine administered intramuscularly (or one-fifth of the dose given intravenously) is often immediately effective, the signs abating while the injection is being made. Corticosteroids potentiate the effect of epinephrine and may be given immediately following the epinephrine. Antihistamines are in common use but provide variable results due to the presence of mediators other than histamine. Atropine is of little value.

The identification of mediators other than histamine in anaphylactic reactions in farm animals has led to studies of the effectiveness of drugs more active against these mediators than antihistamines. Acetylsalicylic acid, sodium meclofenamate and diethylcarbamazine have all shown ability to protect against experimentally induced anaphylaxis in cattle and horses and warrant trial in anaphylactic reactions in these species. One of the important clinical decisions, especially in horse practice, is to decide whether an animal is sufficiently hypersensitive to be at risk when being treated. An acute anaphylactic reaction, and even death, can occur soon after intravenous injection of penicillin into a horse. In suspect cases it is customary to conduct an intradermal or a conjunctival test for hypersensitivity with a response time of about 20 minutes, but these tests have their limitations. The types of sensitivity are not necessarily related and there is no sure relationship between anaphylactic sensitivity and either skin (or conjunctival) sensitivity or circulating antibody, and the test often gives false negatives. The reason why some animals develop systemic hypersensitivity and some develop cutaneous hypersensitivity does not appear to be related to the nature of the reagin but may be related to the size of the sensitizing dose.

ETIOLOGY

Exposure to any of the etiological agents described under anaphylaxis may result in this milder form of hypersensitivity. Exposure may occur by injection, by ingestion, by inhalation or by contact with the skin.

PATHOGENESIS

In anaphylactic reactions the clinical signs may depend on the portal of entry. Thus ingestion may lead to gastrointestinal signs of diarrhea, inhalation to conjunctivitis, rhinitis, and laryngeal and bronchial edema. Cutaneous lesions can result from introduction of the reagin via any portal. They are usually manifested by angioedema, urticaria or a maculopapular reaction. All the lesions result from the liberation of histamine, serotonin (5-HT) and plasma kinins as in anaphylactic shock.

CLINICAL FINDINGS

In ruminants inhalation of a sensitizing antigen may cause the development of allergic rhinitis. On ingestion of the sensitizing agent there may be a sharp attack of diarrhea and the appearance of urticaria or angioneurotic edema; in ruminants mild bloat may occur. Contact allergy is usually manifested by eczema. In farm animals the eczematous lesion is commonly restricted to the skin of the lower limbs, particularly behind the pastern, and at the bulbs of the heels, or to the midline of the back if the allergy is due to insect bites. In many cases of allergic disease the signs are very transient and often disappear spontaneously within a few hours. Cases vary in severity from mild signs in a single system to a systemic illness resembling anaphylactic shock. On the other hand, cases of anaphylaxis may be accompanied by local allergic lesions.

DIFFERENTIAL DIAGNOSIS

The transitory nature of allergic manifestations is often a good guide, as are the types of lesion and sign encountered. The response to antihistamine drugs is also a useful indicator. Skin test programs as applied to humans should be utilized when recurrent herd problems exist. The differential diagnosis of allergy is discussed under the specific diseases listed above.

TREATMENT

A combination of epinephrine, antihistamines and corticosteroids is usually highly effective. Skin lesions other than edema may require frequent local applications of lotions containing antihistamine substances. Continued exposure to the allergen may result in recurrence or persistence of the signs. Keeping the animals indoors for a week often avoids this, probably because the allergen occurs only transiently in the environment. Hyposensitization therapy, as it is practiced in human allergy sufferers, may have a place in small animal practice but is unlikely to be practicable with farm animals.

ETIOLOGY

Edema results from four causes: increased hydrostatic pressure in capillaries and veins due to chronic (congestive) heart failure or obstruction to venous return; decreased plasma oncotic pressure; increased capillary permeability in endotoxemia, part of the allergic response, vasculitis and damage to the vascular endothelium; or obstruction to lymphatic flow.

PATHOGENESIS

Edema is the excessive accumulation of fluid in the interstitial space of tissue caused by a disturbance in the mechanism of fluid interchange between capillaries, the interstitial space and the lymphatic vessels. At the arteriolar end of the capillaries the hydrostatic pressure of the blood is sufficient to overcome its oncotic pressure and fluid tends to pass into the interstitial space. At the venous end of the capillaries the position is reversed and fluid tends to return to the vascular system. The pressure differences are not great, but there is a large area for exchange, and a small increase in hydrostatic pressure or a small decrease in oncotic pressure leads to failure of the fluid to return to the capillaries.

Increased fluid passage into the interstitial space can also occur where there is increased vascular permeability due to vascular damage. Under these circumstances, fluid accumulates in the interstitial space when the fluid flux across the endothelium is greater than the ability of the lymphatic system to drain it. Alternatively, capillary hydrostatic pressure, oncotic pressure and vascular permeability might be normal, but fluid and vascular permeability can accumulate in the interstitial space when lymphatic drainage is occluded.

Edema of the lower limbs of immobilized horses (‘filling’) is usually ascribed to poor lymphatic or venous return due to inactivity of the ‘foot pump’. Lower limb edema in horses may also be related to changes in the hematocrit and plasma protein concentration in the distal limb vasculature as a result of inactivity.

CLINICAL FINDINGS

Accumulation of edematous transudate in subcutaneous tissues is referred to as anasarca, in the peritoneal cavity as ascites, in the pleural cavities as hydrothorax and in the pericardial sac as hydropericardium. Anasarca in large animals is usually confined to the ventral wall of the abdomen and thorax, the brisket and, if the animal is grazing, the intermandibular space because of the large hydrostatic pressure gradient between the submandibular space and heart. Intermandibular edema may be less evident in animals housed such that they do not have to lower their heads to feed. Edema of the limbs is uncommon in cattle, sheep and pigs but occurs in horses quite commonly when the venous return is obstructed or there is a lack of muscular movement. Hydrothorax is not common with generalized edema and is usually an indication of an obstructive intrathoracic lesion. Local edema of the head in the horse is a common lesion in African horse sickness and purpura hemorrhagica.

Edematous swellings are soft, painless and cool to the touch, and pit on pressure. In ascites there is distension of the abdomen and the fluid can be detected by a fluid thrill on tactile percussion, fluid sounds on succussion and by paracentesis. A level top line of fluid may be detectable by any of these means. In the pleural cavities and pericardial sac the clinical signs produced by the fluid accumulation include restriction of cardiac movements, embarrassment of respiration and collapse of the ventral parts of the lungs. The heart sounds and respiratory sounds are muffled, and the presence of fluid may be ascertained by percussion and thoracocentesis or pericardiocentesis.

More localized edemas cause more localized signs: pulmonary edema is accompanied by respiratory distress and in some cases by an outpouring of froth from the nose; cerebral edema is manifested by severe nervous signs of altered mentation. A not uncommon entity is a large edematous plaque around the umbilicus in yearling horses. The plaque develops rapidly, causes no apparent illness and subsides spontaneously after about 7 days. Thrombophlebitis is a common cause of localized edema, particularly of the head in horses and cattle with thrombophlebitis of both jugular veins. Head edema usually occurs in affected animals only when there is rapid and complete occlusion of both jugular veins by thrombophlebitis; a slower rate of jugular vein occlusion permits development of collateral veins for venous drainage of the head.

CLINICAL PATHOLOGY

Cytological examination of a sample of fluid reveals an absence of inflammatory cells where edema is the result of increased hydrostatic pressure, decreased plasma oncotic pressure (hypoalbuminemia), increased vascular permeability or obstruction to lymphatic flow. Thoracocentesis or abdominocentesis is useful to differentiate the causes of fluid accumulation, in conjunction with measurement of serum albumin concentration and central venous pressures.

Examinations should always be directed towards determining the mechanism for hypoalbuminemia; in particular, the renal and gastrointestinal systems and liver are examined for evidence of disease and altered function. In general, the serum albumin concentration is usually less than 15 g/L in animals with generalized edema due to decreased plasma oncotic pressure. Generalized edema should always be expected whenever serum albumin concentration is less than 10 g/L.

NECROPSY FINDINGS

The nature of the accumulation of fluid in most cases is obvious on gross postmortem examination but the determination of the cause of the disease that has resulted in hypoalbuminemia may require further histological and cultural examination. Necropsy findings for the specific diseases where edema is a feature are given in the individual disease sections.

TREATMENT

The treatment of edema should be aimed at correcting the cause, whether it is increased hydrostatic pressure, decreased plasma oncotic pressure, increased endothelial permeability, or obstruction to lymphatic drainage. Chronic (congestive) heart failure may need to be treated with digoxin and thrombophlebitis of the jugular veins may need specific treatment (see Ch. 8). Hypoalbuminemia may require the administration of plasma or plasma substitutes, although this is only a short-term measure and is expensive. Parasitic gastroenteritis requires administration of the appropriate anthelmintic, obstructive edema requires removal of the physical cause, and increased permeability edema requires resolution of the cause of endothelial damage.

Ancillary nonspecific measures include restriction of the amount of salt in the diet and the use of diuretics. Diuretics may relieve the effects of pressure temporarily but the primary cause needs to be addressed for a satisfactory outcome. Aspiration of edema fluid is rarely successful and is not routinely recommended. Aspiration usually provides temporary relief because the fluid rapidly accumulates.

ETIOLOGY

There are two major causes of dehydration:

Deprivation of water, a lack of thirst due to toxemia, and the inability to drink water as in esophageal obstruction, are examples of dehydration due to inadequate water intake. The most common cause of dehydration is when excessive fluid is lost. Diarrhea is the most common reason for excessive fluid loss, although vomiting, polyuria and loss of fluid from extensive skin wounds or by copious sweating may be important in sporadic cases. Severe dehydration also occurs in acute carbohydrate engorgement in ruminants, acute intestinal obstruction and diffuse peritonitis in all species, and in dilatation and volvulus of the abomasum. In most forms of dehydration, deprivation of drinking water being an exception, the serious loss, and the one that needs correction, is not the fluid but the electrolytes (Fig. 2.1).

Fig. 2.1 Etiology and pathogenesis of dehydration.

The ability to survive for long periods without water in hot climates represents a form of animal adaptation that is of some importance. This adaptation has been examined in camels and in Merino sheep. In the latter, the ability to survive in dry, arid conditions depends on a number of factors, including insulation, the ability to carry water reserves in the rumen and extracellular fluid space, the ability to adjust electrolyte concentrations in several fluid locations, the ability of the kidney to conserve water and the ability to maintain the circulation with a lower plasma volume. Dehydrated mammals in hot environments can save water by reducing the rate of panting and sweating and regulating body temperature above hydrated levels. Sweating is a significant avenue of evaporative heat loss in goats when they are hydrated and exposed to high ambient temperatures above 40°C.

Observations of drinking behavior of cattle transported to the abattoir indicate that those animals that had been sold in livestock markets prior to arrival at the abattoir are more thirsty and more tired than cattle sent directly from farms.¹ This indicates inadequate water intake and dehydration.

PATHOGENESIS

Two factors are involved in the pathogenesis of dehydration:

The initial response to negative water balance is the withdrawal of fluid from the tissues and the maintenance of normal blood volume. The fluid is drained primarily from the intracellular and interstitial fluid spaces. Essential organs including the central nervous system, heart and skeleton contribute little and the major loss occurs from connective tissue, muscle and skin. The loss of fluid from the interstitial and intracellular spaces results in loss of skin elasticity, dryness of the skin and mucosa, and a reduction and retraction of the eyeball (enophthalmia) due to reduction in the volume of the postorbital fat deposits. In the goat, total body water may be reduced as much as 44% before death occurs.

The secondary response to continued negative water balance is a reduction in the fluid content of the blood causing a reduction in circulating blood volume (volume depletion) and an increase in the concentration of the blood (hemoconcentration). Because of the hemoconcentration, there is an increase in the viscosity of the blood, which impedes blood flow and may exacerbate peripheral circulatory failure. The loss in circulating blood volume also contributes to the mental depression of dehydrated animals, which is also due to varying degrees of acidemia and toxemia depending on the cause of the dehydration. In deprivation of water and electrolytes or in deprivation of water alone or inability to consume water in an otherwise normal animal (e.g. esophageal obstruction), the dehydration is minimal because the kidney compensates effectively by decreasing urine output and increasing urine osmolality. In addition, water is preserved by reduced fecal output and increased absorption, which results in dehydration of the contents of the rumen and large intestine, which in turn results in dry, scant feces.

In calves with acute diarrhea there is increased fecal output of water compared to normal calves but the total water losses are not much greater than in normal calves. In the diarrheic calf the kidney compensates very effectively for fecal water loss, and the plasma volume can be maintained if there is an adequate oral fluid intake. Urine excretion decreases, the urine becomes progressively more concentrated and the renal insufficiency may accentuate pre-existing acidemia and electrolyte imbalance, hence the importance of restoring renal function. The newborn calf is able to concentrate urine at almost the same level as the adult. This illustrates the importance of oral fluid and electrolyte intake during diarrhea to compensate for continuous losses. However, it is possible for metabolic acidosis to occur in diarrheic calves and goat kids that are not dehydrated.^2,3

Goats are more sensitive to water deprivation during pregnancy and lactation than during anestrus. Water deprivation for 30 hours causes a marked increase in the plasma osmolality and plasma sodium concentration in pregnant and lactating goats. Pregnant and lactating goats drink more than goats in anestrus.

The dehydration in horses used for endurance rides is hypotonic, in which both sodium and water are lost through sweating. This may account for the lack of thirst in some dehydrated horses with the exhaustion syndrome. Weight losses of 10–15 kg/h may occur in horses exercising in high environmental temperatures exceeding 32°C (89°F) and a horse weighing 450 kg can lose 45 L of fluid in a 3-hour ride.

Dehydration exerts important effects on tissue metabolism. There is an increase in breakdown of fat, then carbohydrate and finally protein, to produce water of metabolism. The increased endogenous metabolism under relatively anaerobic conditions results in the formation of acid metabolites and the development of metabolic acidosis. Urine formation decreases because of the restriction of renal blood flow and this, together with the increased endogenous metabolism, causes a moderate increase in blood levels of nonprotein nitrogen.⁴ The body temperature may increase slightly initially – dehydration hyperthermia – because of insufficient fluid to maintain the loss of heat by evaporation. The onset of sweating in steers after exposure to high environmental temperatures has been shown to be delayed by dehydration.

Dehydration may cause death, especially in acute intestinal obstruction, vomiting and diarrhea, but it is chiefly a contributory cause of death when combined with other systemic states, such as acidosis, electrolyte imbalances, toxemia and septicemia.

CLINICAL FINDINGS

The first and most important clinical finding in dehydration is dryness and wrinkling of the skin, giving the body and face a shrunken appearance. The eyes recede into the sockets and the skin subsides slowly after being picked up into a fold. The dehydration is usually much more marked if water and electrolyte losses have been occurring over a period of several days. Peracute and acute losses may not be obvious clinically because major loss will have occurred from the intravascular compartment and only minor shifts have occurred from the interstitial spaces. Sunken eyes and inelastic skin are not remarkable clinical findings of dehydration in the horse.

The best indicator of hydration status in calves has been demonstrated to be the degree of recession of the eye into the orbit. Hydration status is assessed by gently rolling the lower eyelid out to its normal position and estimating the distance of eye recession in millimeters. This distance is multiplied by 1.7 to provide an estimate of the degree of dehydration as a percentage of euhydrated body weight.⁵ The second best indicator of hydration status in calves is the elasticity of the skin of the neck and lateral thorax, which are assessed by pinching the skin between the fingers, rotating the skin fold 90° and noting the time required after release of the skin fold for the skin fold to disappear (normally <2 s). The elasticity of the skin fold on the upper or lower eyelid is a poor indicator of hydration status in calves and is not recommended. The best methods for assessing hydration status in adult cattle and other large animals has not been determined but it is likely that eye recession and skin tent duration in the neck region provide the most accurate and sensitive methods for estimating hydration status.

In diarrheic calves, the severity of dehydration, hypothermia and metabolic acidosis are associated with the degree of mental depression.⁶ The combined effects of acidemia and dehydration also contribute to hypothermia.

Loss of body weight occurs rapidly in dehydration and muscular weakness and inappetence or anorexia are common. In horses deprived of water for 72 hours there is a mean body weight loss of about 15%, and 95% of the animals have a urine specific gravity of 1.042, a urine osmolality of 1310 mosmol/kg and a urine osmolality/serum osmolality ratio of 4:14. Prerenal azotemia also develops.

The degree of thirst present will depend on the presence or absence of other diseases causing an inflammatory response or endotoxemia. In primary water deprivation, dehydrated animals are very thirsty when offered water. In dehydration secondary to enteritis associated with severe inflammation, acidemia and electrolyte imbalance, there may be no desire to drink. Horses that become dehydrated in endurance rides may refuse to drink and the administration of water by oral intubation and enemas may be necessary. In cattle on pasture and deprived of water for up to 9 days and then given access to water, there will be staggering, falling, convulsions and some death – signs similar to salt poisoning in pigs. Experimental restriction of the water intake in lactating dairy cattle for up to 4 days may reduce milk yield by 75% and decrease body weight by 14%. A 10% reduction in water intake causes a drop in milk production that may be difficult to detect. Behavioral changes are obvious: cows spend considerable time licking the water bowls. In cold climates, cattle are often forced to eat snow as a source of water. The snow must be soft enough so that it can be scooped up by the cattle and 3–5 days are necessary for the animals to adjust to the absence of water and become dependent on snow. During this time there is some loss of body weight. Lactating ewes relying on snow as a source of free water reduce their total water turnover by approximately 35%.

CLINICAL PATHOLOGY

Dehydration is characterized by an increase in the packed cell volume and total serum protein concentration, although the latter response may be modified by the presence of severe enteritis, peritonitis, or proteinuria.

ETIOLOGY

The ingestion of excessive quantities of water when animals are very thirsty may result in overhydration, which is also called water intoxication. The primary cause of acute overhydration is a rapid decrease in the osmolality of the small intestinal contents, which are normally isotonic to plasma. Such a rapid decrease in luminal osmolality occurs within 5 minutes of water ingestion² because thirsty calves close their esophageal groove when drinking. This results in a large volume of water in the abomasum, which is subsequently emptied into the duodenum. Free water rapidly moves from the small intestinal lumen into the intravascular compartment because of the large surface area for absorption in the small intestine and development of an osmotic gradient between the small intestinal lumen and intestinal capillary bed. The end result is a rapid decrease in plasma osmolality and expansion and rupture of erythrocytes, leading to intravascular hemolysis, hemoglobinemia, hemoglobinuria, hyponatremia, hypochloremia and a decrease in plasma protein concentration from preingestion values.

EPIDEMIOLOGY

The syndrome has been reported from several countries but is uncommon. Calves 2–4 months of age are most commonly affected but the disease is also recorded in adult cattle,¹ sheep³ and pygmy goats.⁴ Water intoxication occurs in calves in normal husbandry systems when animals that have had limited access to water are suddenly given free access. Commonly water intoxication occurs when calves previously fed a milk replacer diet but no other fluid, or weaned calves that have been on a starter diet but limited water, are turned out to pasture or to yards where water is freely available. Calves that are not fed supplementary salt or that have lost salt as a result of severe exercise or high environmental temperatures may be at higher risk⁵ but the syndrome also occurs where salt has not been restricted. The majority of calves show clinical signs within minutes to hours of access to water.

The condition has been reproduced in calves by gavage with water at 12% of body weight.⁶

CLINICAL FINDINGS

Hemoglobinuria as a result of intravascular hemolysis is prominent and there may be a moderate to severe hemolytic anemia. Dark red urine is passed shortly following access to water. Additional signs include tachycardia and hypothermia if the temperature of the water ingested is below body temperature. Affected animals are usually depressed and weak.

CLINICAL PATHOLOGY

Hemoglobinuria and hemoglobinemia are evident and there is hypo-osmolality, hyponatremia and hypochloremia.⁵ Serum total protein and albumin concentration may be decreased but are usually within the normal range because animals are usually mildly dehydrated and thirsty before ingesting large volumes of water.

TREATMENT

Treatment of affected animals is usually not attempted as the hypo-osmotic lysis has already occurred when clinical signs are manifest and serum osmolality is usually gradually increasing as the distal convoluted tubules eliminate excessive free water. Hypertonic saline (7.2% NaCl, 5 mL/kg BW over 5 min intravenously) is usually administered to correct the hyponatremia and hypochloremia but treatment is not necessary in mild cases. Case fatality is low and hemoglobinuria persists for only a few hours.

CONTROL

Water intoxication does not occur commonly and can be avoided by preventing thirsty animals from having unlimited access to water. Calves should have free access to water by the end of the first week of life.

HYPONATREMIA

Sodium is the most abundant ion in the extracellular fluid and is chiefly responsible for the maintenance of osmotic pressure of the extracellular fluid. The most common cause of hyponatremia is increased loss of sodium through the intestinal tract in enteropathies (Fig. 2.2). This is particularly marked in the horse with acute diarrhea and to a moderate extent in calves with acute diarrhea. The sodium is lost at the expense of the extracellular fluid. In calves with acute diarrhea due to enterotoxigenic E. coli the sodium concentration of the intestinal fluid secreted in response to the enterotoxin is similar to that of plasma, and hyponatremia usually occurs (hypotonic dehydration). Animals affected with diarrhea of several days’ duration continue to lose large quantities of sodium and the hyponatremia may become severe. Hyponatremia can become severe when sodium-free water or 5% dextrose are used as the only fluid therapy in animals already hyponatremic. Hyponatremia can also occur in animals with proximal tubular dysfunction.

Fig. 2.2 Etiology and pathogenesis of hyponatremia.

Hyponatremia causes an increase in the renal excretion of water in an attempt to maintain normal osmotic pressure, which results in a decrease in the extracellular fluid space, leading to a decreased circulating blood volume, hypotension, peripheral circulatory failure and ultimately renal failure. Muscular weakness, hypothermia and marked dehydration are common findings.

Isotonic dehydration occurs when there is a parallel loss of sodium and water. Hypertonic dehydration, which is uncommon, occurs when there is a loss or deprivation of water with minor losses or deprivation of sodium. Hypertonic dehydration can occur in animals that are unable to consume water because of an esophageal obstruction. The dehydration in isotonic and hypertonic dehydration is mild compared to the marked clinical dehydration that can occur in hypotonic dehydration accompanied by marked loss of water and concentration of the extracellular space (Fig. 2.3).

Fig. 2.3 Types of dehydration.

There are no clinical signs that are characteristic of hyponatremia. There is usually dehydration, muscular weakness and mental depression, which occur with other disturbances of both water and electrolytes and with acid–base imbalance. Similarly, there are no clinical signs characteristic of hypochloremia. However, hyponatremia affects the osmotic pressure of the extracellular fluid, and hypochloremia promotes the reabsorption of bicarbonate and further development of alkalosis. Polyuria and polydipsia occur in cattle with dietary sodium chloride deficiency.

HYPOCHLOREMIA

Hypochloremia occurs as a result of an increase in the net loss of the electrolyte in the intestinal tract in acute intestinal obstruction, dilatation and impaction and volvulus of the abomasum and in enteritis (Fig. 2.4). Normally a large amount of chloride is secreted in the abomasum by the mucosal cells in exchange for bicarbonate, which moves into the plasma. The hydrogen, chloride and potassium ions secreted in gastric juice are normally absorbed by the small intestine. Failure of abomasal emptying and obstruction of the proximal part of the small intestine will result in the sequestration of large quantities of chloride, hydrogen and potassium ions which leads to a hypochloremic, hypokalemic metabolic alkalosis. A severe hypochloremia can be experimentally produced in calves by feeding them a low chloride diet and daily removal of abomasal contents. Clinical findings include anorexia, weight loss, lethargy, mild polydipsia and polyuria. A marked metabolic alkalosis occurs, with hypokalemia, hyponatremia, azotemia and death.

Fig. 2.4 Etiology and pathogenesis of hypochloremia.

HYPOKALEMIA

Hypokalemia may occur as a result of decreased dietary intake, increased renal excretion, abomasal stasis, intestinal obstruction and enteritis, and repeated administration of corticosteroids with mineralocorticoid activity (Fig. 2.5). The prolonged use of potassium-free solutions in fluid therapy for diarrheic animals may result in excessive renal excretion of potassium and hypokalemia. Alkalosis may result in an exchange of potassium ions for hydrogen ions in the renal tubular fluid, resulting in hypokalemia. Hypokalemia can cause muscle weakness, prolonged unexplained recumbency, inability to hold up the head, anorexia, muscular tremors and, if severe enough, coma. The treatment of ketosis in lactating dairy cows with multiple dosages of isoflupredone, a glucocorticoid with some mineralocorticoid activity, can cause hypokalemia and recumbency, with a high case fatality rate.¹

Fig. 2.5 Etiology and pathogenesis of hypokalemia.

The most common occurrence of hypokalemia in ruminants is in diseases of the abomasum that cause stasis and the accumulation of fluid in the abomasum. Potassium becomes sequestered in the abomasum along with hydrogen and chloride, resulting in hypokalemia, hypochloremia and metabolic alkalosis.

Metabolic alkalosis and hypokalemia in cattle are often accompanied by muscular weakness and paradoxic aciduria. Hypokalemia causes muscle weakness by lowering the resting potential of membranes, resulting in decreased excitability of neuromuscular tissue. Thus, the differential diagnosis of the animal with muscle weakness should always include hypokalemia.

Hypokalemia and alkalosis also are often directly related because of the renal response to either. Hypokalemia from true body deficits of potassium will cause decreased intracellular concentration of this ion. The intracellular deficit of potassium and excess of hydrogen will cause hydrogen secretion into the urine when distal sodium reabsorption is required. This situation exists in metabolic alkalosis, where sodium bicarbonate reabsorption in the proximal nephron is decreased because of the excess of plasma bicarbonate. Distal nephron avidity for sodium is increased to protect extracellular fluid volume, and the increased distal sodium reabsorption is at the expense of hydrogen secretion, although it is contrary to the need of acid retention in the presence of alkalosis. In other words, the kidney prioritizes maintenance of plasma volume above that of acid–base balance, presumably because respiratory compensation can usually keep blood pH within the normal physiological range. Because electroneutrality of extracellular fluid must be maintained by reabsorbing an equivalent charge of cations and anions, the reabsorption of chloride and of bicarbonate in the kidneys are inversely proportional to each other. Thus, with excess trapping of chloride in the abomasum, the kidneys will compensate for the resulting hypochloremia by increasing bicarbonate reabsorption, which may proceed until metabolic alkalosis develops.

The treatment of hypochloremic, hypokalemic alkalosis requires correction of extracellular fluid volume and sodium and chloride deficits with 0.9% NaCl infusions and oral KCl. Providing adequate chloride ion allows sodium to be reabsorbed without bicarbonate. Increased proximal reabsorption of sodium will decrease distal acid secretion because less sodium is presented to the distal nephron. As less bicarbonate is reabsorbed and less acid secreted, the metabolic alkalosis is resolved. Specially formulated solutions containing potassium are necessary in cases of severe hypokalemia and small-intestinal obstruction.

Hypokalemia also occurs following treatment of the horse affected with metabolic acidosis and hyponatremia, and probably reflects whole-body potassium depletion. Horses used for endurance rides may be affected by hypokalemia, hypocalcemia and alkalosis due to loss of electrolytes during the competition. Synchronous diaphragmatic flutter also occurs, which may be the result of the electrolyte imbalance (particularly hypocalcemia) causing hyperirritability of the phrenic nerve.

Since potassium is the major intracellular cation, the measurement of plasma or serum potassium is not a reliable indication of whole-body potassium status. Extremely low levels or high levels are usually indicative of a potassium imbalance, often associated with other electrolyte and acid–base imbalances. In severe alkalosis, for example, potassium leaves the extracellular space and becomes concentrated in the cells. This may result in low serum potassium levels when, in fact, there might not be potassium depletion of the body. Conversely, in severe metabolic acidosis of calves with acute diarrhea, the potassium leaves the cells and moves into the extracellular fluid. This results in hyperkalemia in some cases where the body potassium is normal or even decreased. When changes occur in the concentration of intracellular and extracellular potassium, the ratio of intracellular to extracellular potassium may decrease by as much as 30–50%, which results in a decrease in the resting membrane potential. This is thought to be the explanation for the effects of hypokalemia and hyperkalemia on muscle function.

The potassium concentration of red blood cells may be a more accurate indicator of whole-body potassium deficit in diarrheic horses and provides a basis for a calculated oral dose of potassium chloride in horses with diarrhea, which is a safe therapeutic procedure.

Potassium should be administered intravenously or orally. The intravenous route is used only for the initial treatment of recumbent ruminants with severe hypokalemia and rumen atony, as it is much more dangerous and expensive than oral treatment. The most aggressive intravenous treatment protocol is an isotonic solution of KCl (1.15% KCl), which should be administered at less than 3.2 mL/kg per hour, equivalent to a maximal delivery rate of 0.5 mEq of K⁺/kg BW per hour. Higher rates of potassium administration run the risk of inducing hemodynamically important arrhythmias, including ventricular premature complexes that can lead to ventricular fibrillation and death. A less aggressive intravenous treatment is an isotonic equimolar mixture of NaCl (0.45% NaCl) and KCl (0.58%KCl), and the least aggressive intravenous treatment is the addition of 10 mmol of KCl/L of Ringer’s solution, which will increase the solution osmolarity to 329 mosmol/L. Clinical experience with oral administration of KCl has markedly decreased the number of adult ruminants treated with intravenous KCl.

Oral administration of potassium is the method of choice for treating hypokalemia. Inappetent adult cattle should be treated with 30–60 g of feed grade KCl twice with a 12-hour interval, with the KCl placed in gelatin boluses. Adult cattle with severe hypokalemia (<2.5 mEq/L) should initially be treated with 120 g of KCl, followed by two 60 g KCl treatment at 8-hour intervals, for a total 24-hour treatment of 240 g KCl. Higher doses have been administered to dairy cows but these are accompanied by diarrhea, and oral administration of 0.58 g KCl/kg BW was toxic in 6-month-old Holstein calves, manifest by excessive salivation, muscular tremors of the legs and excitability, and a peak plasma [K⁺] of 9.0 mEq/L. Extrapolating this toxic dose in normokalemic calves to hypokalemic 600 kg cows suggests that a daily dose of 240 g KCl approaches the upper limit of safety. The recommended doses are empirical but are effective in rapidly increasing serum [K⁺] and [Cl⁻]. Inappetent horses often have whole-body potassium depletion and would benefit from supplementary dietary potassium (25–50 g/d KCl).

HYPERKALEMIA

Hyperkalemia is not as common in farm animals as hypokalemia, occurring most commonly in severe metabolic acidosis. The classic description for the development of hyperkalemia in metabolic acidosis involves a purported redistribution of potassium from the intracellular space to the extracellular space because a large proportion of the excess hydrogen ions are buffered intracellularly. Thus potassium is supposedly exchanged with hydrogen ions across the cell membrane in order to maintain electroneutrality. A more likely mechanism is that metabolic acidosis is accompanied by acidemia and a decreased intracellular pH; during intracellular acidosis the function of all enzyme systems is decreased. As a direct result of the intracellular acidosis, the Na–K-ATPase activity is decreased, with potassium leaving the cell down its concentration gradient.

Hyperkalemia is potentially more life-threatening than hypokalemia. Hyperkalemia (when over 7–8 mmol/L) has a profound effect on cardiac function. There is usually marked bradycardia and arrhythmia and sudden cardiac arrest may occur. The electrocardiogram (ECG) changes in experimentally induced hyperkalemia in the horse have been described. The changes include four successive stages as hyperkalemia increased. There was a widening and lowering of amplitude followed by inversion and disappearance of the P wave, an increase in the amplitude of the T wave, an increase in the QRS interval, with some irregularity in the ventricular rate, and periods of cardiac arrest that became terminal or were followed by ventricular fibrillation. The minimum plasma potassium concentration required to induce ECG changes was 6–7 mmol/L and severe cardiotoxic effects occurred at levels between 8–11 mmol/L. The effects of hyperkalemia on the ECG are exacerbated by the presence of hyponatremia.

Hyperkalemia has traditionally been treated by intravenous administration of sodium bicarbonate, glucose, insulin and sometimes calcium. Hypertonic saline is just as effective as is hypertonic sodium bicarbonate in decreasing hyperkalemia and hyperkalemia-associated bradyarrhythmias, as a result of sodium-induced intracellular movement of potassium, extracellular volume expansion and the strong ion effect of increasing the serum concentration of a strong cation. The long-held myth regarding the need to administer glucose and insulin to ‘drive’ potassium into the cells during hyperkalemia needs to be re-evaluated. Calcium counteracts the effect of hyperkalemia on the resting membrane potential by increasing the threshold potential to a higher value, thereby returning an appropriate difference between resting and threshold potentials. Calcium can be administered intravenously at 0.2–0.4 mL of a 23% calcium gluconate solution/kg BW. The focus of treatment in hyperkalemia should be correction of acidemia, plasma volume expansion and increasing the serum sodium concentration. Glucose and insulin are not routinely needed to correct hyperkalemia.

Hyperkalemic periodic paralysis occurs in heavily muscled Quarterhorse. Affected horses become weak, may stand base-wide and are reluctant to move. Sweating commonly occurs and generalized muscle fasciculations are apparent. Affected horses remain bright and alert but may yawn and do not eat or drink. Some horses become recumbent and may appear to be in a state of flaccidity. Attacks may occur in a rest period following exercise or at random. During the episode the serum potassium concentration is elevated by up to twofold and returns to normal values when the animal recovers. Treatment consists of sodium bicarbonate, hypertonic saline or 5% dextrose given intravenously, possibly with insulin.

HYPOCALCEMIA

Hypocalcemia or milk fever may occur in recently calved mature dairy cows that have been inappetent or anorexic for a few days. Hypocalcemia can be due to a reduction in dry matter intake because of illness or it may be the earliest stages of hypocalcemic parturient paresis. The clinical findings include anorexia, mild tachycardia with a reduction in the intensity of the heart sounds and occasionally an arrhythmia, a decrease in the frequency and amplitude of rumen contractions or complete ruminal stasis, and a decrease or complete absence of feces, which may last from 6–36 hours if untreated.

Hypocalcemia cases often mimic intestinal obstruction and create problems in the differential diagnosis. Affected cattle may not exhibit any evidence of muscular weakness and the detection of the hypocalcemic state can be elusive. The total serum calcium concentrations range from 1.5–2.0 mmol/L and the response to intravenous therapy is usually good, although recovery may require several hours before the appetite returns to normal and feces are passed.

Calcium should be administered by the intravenous, subcutaneous, or oral route. Calcium gluconate and calcium borogluconate are the preferred forms for intravenous and subcutaneous administration because CaCl₂ causes extensive necrosis and sloughs of tissue when administered perivascularly. Compared to calcium gluconate, calcium borogluconate has improved solubility and shelf life. Plasma ionized calcium concentrations are increased to a greater extent following CaCl₂ treatment when high equimolar solutions of CaCl₂ and calcium gluconate are administered, leading to more cardiac arrhythmias during CaCl₂ administration. A typical treatment to an adult lactating dairy cow with periparturient hypocalcemia is 500 mL of 23% calcium borogluconate by slow intravenous injection with cardiac auscultation, this provides 10.7 g of calcium. Although the calculated calcium deficit in a recumbent periparturient dairy cow is 4 g calcium, additional calcium should be provided to overcome the continued loss of calcium in milk. A field study comparing the effectiveness of different doses of calcium for treating periparturient milk fever determined that 9 g of calcium was superior to 6 g. A good rule of thumb for administering 23% calcium borogluconate solutions (2.14 g calcium/100 mL) to cows with periparturent hypocalcemia is therefore to administer 1 mL/kg BW. There do not appear to be any clinically important advantages to slow administration of the solution over 6 h, when compared to 15 min.²

The normal cardiac response to intravenous calcium administration is an increase in the strength of cardiac contraction and a slowing of the heart rate. Intravenous administration is continued until the first arrhythmia is detected (a bradyarrhythmia such as a prolonged pause); the rate of intravenous administration is then slowed until a second arrhythmia is detected, at which time intravenous administration is discontinued and the remainder of the solution is placed subcutaneously over the lateral thorax. This treatment method titrates the calcium dose required for each animal. Auscultation of the heart is an absolute requirement during treatment: visual monitoring of the jugular pulse at the base of the neck does not allow the early detection of bradyarrhythmias, making it more likely that the cow will receive a toxic and possibly lethal dose of calcium. The maximum safe rate of calcium administration in cattle is 0.07 mEq of Ca²⁺/kg BW/min, which is equivalent to 0.065 mL 23% calcium borogluconate/kg BW/min. For a 500 kg normocalcemic dairy cow, this corresponds to a maximum safe rate of administration of 33 mL/min. Typical rates of administration through a 14-gauge needle are 50 mL/min; this rate of administration is safe for cows with hypocalcemia, provided that cardiac auscultation is performed during administration.

Subcutaneous administration of calcium solutions has been practiced for many years. To facilitate absorption, it is preferable to administer no more than 125 mL at a site. A 14-gauge needle is placed subcutaneously over the lateral thorax, 125 mL is administered, the needle is redirected and another 125 mL is administered. The process is then repeated on the other side of the cow. Although the effectiveness of subcutaneous administration of calcium has been documented in healthy normal cows, there do not appear to be any reports documenting the rapidity by which subcutaneous calcium is absorbed by cows with periparturient hypocalcemia. Subcutaneous administration of calcium gluconate is not recommended in recumbent cows because poor peripheral blood flow is suspected to lead to slow absorption from the subcutaneous site. Calcium chloride is not recommended for subcutaneous administration because of extensive tissue damage; the addition of dextrose to the administered calcium is also not recommended because it increases the tonicity of the solution and propensity for bacterial infection and abscessation. Rectal calcium administration is not recommended because it causes severe mucosal injury and tenesmus but does not increase plasma concentrations of calcium.

Oral administration of calcium has also been practiced for many years, usually by ororuminal intubation of calcium borogluconate solutions designed for parenteral administration. Over the past decade there has been increased interest in improving the efficacy of oral calcium formulations. The results of a number of studies indicate that oral calcium salts are effective at increasing plasma calcium concentration; orally administered calcium is absorbed by a dose-dependent passive diffusion process across ruminal epithelium and a dose-independent calcium-binding protein mechanism in the small intestine that is modulated by vitamin D. Rapid correction of hypocalcemia by oral calcium administration is predominantly by passive ruminal diffusion, as small intestinal absorption is too slow to be of clinical value.

Two calcium formulations are currently recommended for oral administration to ruminants; CaCl₂ and calcium propionate, but most commercially available products contain 50 g of CaCl₂. Calcium chloride has the advantage of low cost and low volume (because of its high solubility), but CaCl₂ can severely damage the pharynx and esophagus in ruminants with reduced swallowing ability, can lead to necrosis of the forestomach and abomasum when administered in high doses, and can lead to aspiration pneumonia when administered as a drench. Calcium propionate has the advantage that it is less irritating while providing a gluconeogenic substrate (propionate), but the disadvantages of higher volumes and cost. Oral calcium solutions should only be administered to cattle that have normal swallowing ability, precluding their administration to animals with advanced clinical signs of hypocalcemia. Higher plasma calcium concentrations are obtained more quickly when calcium solutions are drenched after administration of vasopressin to induce esophageal groove closure, or when the calcium solution is administered as a drench instead of ororuminal intubation. Calcium solutions are suspected to have a higher likelihood of aspiration pneumonia than calcium gels (with a consistency similar to toothpaste), although this supposition does not appear to have been verified. Commercially available formulations of calcium gels contain 50 g of CaCl₂ and increase plasma calcium concentrations within 30–60 minutes and for at least 6 hours. Retreatment at 12-hour intervals (if needed) therefore appears indicated and provide 100 g of CaCl₂ and 37 g of calcium over 24 hours, but more aggressive treatment protocols are not recommended.

HYPOPHOSPHATEMIA

Hypophosphatemia also occurs in cattle under conditions similar to those of hypocalcemia. A decrease in feed intake or alimentary tract stasis will result in a decrease in serum inorganic phosphate. Acute recumbency in lactating dairy cattle may be associated with marginal phosphorus deficiency,³ although a cause and effect relationship between hypophosphatemia and recumbency has not been established.⁴ However, many inappetent and weak cows have marginal hypophosphatemia and clinically appear to benefit from normalization of their plasma concentration of phosphate. As such, it is currently recommended that ruminants with marked hypophosphatemia and signs of illness should be treated with phosphorus-containing solutions.

Almost all commercially available intravenous solutions for treating hypophosphatemia use phosphite (PO₂²⁻) or hypophosphite (PO₃³⁻) salts as the source of phosphorus because these salts are very soluble, even in the presence of calcium and magnesium. However, the phosphorus in phosphite and hypophosphite is unavailable to mammals, meaning that the vast majority of ‘phosphate’-containing solutions have no efficacy in treating hypophosphatemia. Instead, the monobasic monophosphate form of sodium phosphate (NaH₂PO₄) should be administered. The pH of the solution should be mildly acidic (pH 5.8) to maintain phosphate solubility in cold weather but is not needed in warm ambient temperatures. A recommended treatment to an adult lactating dairy cow with severe hypophosphatemia is 300 mL of 10% NaH₂PO₄ (monohydrate) solution by slow intravenous injection; this provides 7 g of phosphate and increases plasma phosphate concentrations for at least 6 hours. Human enema formulations that contain a mixture of monobasic sodium phosphate monohydrate and dibasic sodium phosphate heptahydrate in a buffered solution have also been administered to cattle with hypophosphatemia but are not recommended. This human enema solution is extremely hypertonic and must therefore be diluted before administration. A major drawback with intravenous administration of phosphate solutions is that they should not be administered within 2 hours of intravenous calcium administration, because of concerns that calcium-phosphate precipitates may be formed in the plasma of cattle with treatment-induced hypercalcemia and hyperphosphatemia. This has traditionally been evaluated by calculating the calcium– phosphorus product, whereby metastatic calcification may occur if the product of serum calcium concentration and serum phosphate concentration (both in mg/dL) exceeds 70.

Hypophosphatemia is more safely treated by administration of oral monosodium phosphate, and this is the preferred method of administration in ruminants with rumen motility. Oral administration also results in a more prolonged increase in plasma phosphorus concentration. Recommended dose is 200 g of feed grade monosodium phosphate (contains 50 g of phosphate) administered in gelatin boluses, drench, or by ororuminal intubation. Phosphorus in other feed grade minerals (such as bone meal or dicalcium phosphate) is poorly available and is not recommended for the treatment of hypophosphatemia.

HYPOMAGNESEMIA

Magnesium is usually administered parenterally only when a ruminant exhibits clinical signs of hypomagnesemia. Treatment of hypomagnesemia is more dangerous (to the animal and clinician) and less satisfying than treatment of periparturient hypocalcemia; the response to treatment is much slower in hypomagnesemia presumably because magnesium concentrations must be normalized in cerebrospinal fluid, which turns over at approximately 1% per minute.

Treatment of hypomagnesemia has historically used 25% Epsom salts solution (magnesium sulfate heptahydrate; MgSO₄.6H₂O); this solution concentration was selected because it provided approximately 1 mmol of magnesium per liter. It should be noted that 25% Epsom salts solution is markedly hypertonic (2028 mosmol/L). A typical treatment for an adult cow has been slow intravenous administration (over at least 5 min) of 100 mL of the 25% Epsom salts solution, this provides 2.5 g of magnesium (25 mg of magnesium/mL of solution). More recently, hypomagnesemia has been treated using commercially available combined calcium and magnesium solutions; 500 mL of these solutions typically contain 1.6–2.7 g of magnesium in the form of a borogluconate, chloride or hypophosphite salt. Although the calculated extracellular deficit in a cow with hypomagnesemia is 2 g of magnesium, we should provide additional magnesium to correct presumed intracellular deficiencies and to overcome the anticipated urinary loss of magnesium. Combined calcium and magnesium solutions are preferred for intravenous administration to 25% Epsom salts solution because ruminants with hypomagnesemia frequently have hypocalcemia, and hypercalcemia provides some protection against the toxic effects of hypermagnesemia. Moreover, administration of solutions containing magnesium as the only cation increases the risk of developing cardiac and respiratory failure during treatment. The maximum safe rate of administration of magnesium in cattle is 0.08 mEq Mg²⁺/kg BW per minute, which is equivalent to 0.04 mL 25% Epsom salts/kg BW per minute. For a 500 kg beef cow with hypomagnesemia, this corresponds to a maximum safe rate of administration of 20 mL/min.

Magnesium-containing solutions (such as 25% Epsom salts solution) can also be administered subcutaneously, although this frequently leads to necrosis of the skin, particularly when 50% Epsom salts solution is administered. Only combined calcium and magnesium solutions should therefore be administered subcutaneously.

The oral bioavailability of magnesium is low and much lower than that of calcium. Accordingly, oral administration of magnesium is not recommended for the treatment of hypomagnesemia, but is essential for the prevention of hypomagnesemia. Magnesium absorption from the rumen is facilitated by volatile fatty acids but decreased by potassium and the ammonium ion.

Rectal administration may be the only practical and safe method for treating a convulsing hypomagnesemic beef cow. After evacuating the rectal contents, an enema containing 60 g of Epsom salts (magnesium sulfate heptahydrate) or magnesium chloride in 200 mL of water can be placed in the descending colon (and not the rectum) and the tail held down for 5 minutes; this increases plasma magnesium concentrations within 10 minutes. However, enema solutions can be prematurely evacuated, eliminating the chance for therapeutic success, and some degree of colonic mucosal injury is expected because of the high osmolarity of 30% solutions (approximately 2400 mosmol/L). The safety of this treatment protocol does not appear to have been evaluated, although a 50 mL enema of a 30% MgCl₂.6H₂O solution rapidly and effectively increased serum magnesium concentration in 7–10-week-old calves and relieved clinical signs of hypomagnesemia.

Oral administration of magnesium hydroxide and magnesium oxide excessively alkalinizes the rumen and can create a severe metabolic alkalosis (strong ion alkalosis), as absorption of magnesium leads to hypermagnesemia and increased plasma strong ion difference. Because oral administration of sodium bicarbonate causes expansion of the plasma volume and creates a metabolic alkalosis (strong ion alkalosis) without hypermagnesemia, it is likely that oral sodium bicarbonate is a more effective treatment for grain overload in ruminants.

ETIOLOGY

The traditional Henderson–Hasselbalch approach to acid–base balance indicates that general causes of nonrespiratory (metabolic) acidosis can be divided into three categories on the basis of pathogenesis (Fig. 2.6):

Fig. 2.6 Etiology and pathogenesis of acidema.

For comparison, the strong ion approach indicates that general causes of nonrespiratory (metabolic) acidosis can be divided into two categories: strong ion acidosis due to a decrease in strong cation concentration (hyponatremia) or increase in strong anion concentration (hyperchloremia, hyper l-lactatemia, hyper d-lactatemia, ketoacidosis), and nonvolatile buffer ion acidosis due to an increase in albumin, globulin and phosphate concentration.

Some common specific causes include acute diarrhea in newborn animals, acute enteritis in adult cattle and horses and carbohydrate engorgement in ruminants and horses. Metabolic acidosis without dehydration, which is probably due to hyper d-lactatemia, has been described in neonatal goat kids¹ and neonatal calves.² Respiratory acidosis also occurs where there is retention of carbon dioxide in the blood as a result of interference with normal respiratory exchange. Thus pneumonia, severe pulmonary emphysema, depression of the respiratory center and left-sided heart failure may all be accompanied by respiratory acidosis. Metabolic acidosis occurs in the newborn at the time of parturition if this is prolonged and difficult. It is also common in shock with peripheral circulatory failure and anaerobic oxidation. A decrease in renal excretion of acid in renal insufficiency or renal failure also contributes to a metabolic acidosis. The administration of excessive quantities of acidifying solutions for the treatment of metabolic alkalosis also may cause acidosis. Acute intestinal obstruction in the horse is commonly accompanied by metabolic acidosis, whereas in other species alkalosis occurs, at least initially.

PATHOGENESIS

The traditional Henderson–Hasselbalch approach indicates that metabolic acidosis is characterized by a low arterial blood pH and a reduced plasma bicarbonate concentration, following the loss of bicarbonate or the addition of hydrogen ions. Extra- and intracellular buffering and respiratory compensation minimize the change in pH until the kidney can excrete sufficient hydrogen ions to correct the acid–base imbalance.³ In general, the body will tolerate a pH range of 7.0–7.6, although survival has been reported at pH values beyond these limits for short periods, particularly in neonatal animals with diarrhea.

Acidemia generally depresses cardiac contractility and cardiac output in the denervated heart. In the intact animal, however, activation of the sympathetic nervous system in response to acidemia causes increased cardiac contractility, increased heart rate and increased cardiac output. In acidemia, the myocardial response to catecholamines is not depressed until the blood pH is decreased to below 7.0–7.1.⁴ The increased carbon dioxide tension of the blood and depletion of bicarbonate causes an increase in the depth and then the rate of respiration by stimulation of the respiratory center (Kussmaul breathing). However, when hypovolemic shock is severe enough, there is often depressed respiratory function, resulting in the additional accumulation of hydrogen ions, and so the acidemia is accentuated.

Acidemia causes varying degrees of depression of the central nervous system and muscular weakness.^1,5 Central nervous abnormalities may develop in neonatal foals that develop severe respiratory compromise, resulting in hypoxemia and hypercapnia, because of the reduced ability of the cerebrospinal fluid to buffer acid–base changes.⁶ Carbon dioxide concentration within the central nervous system (CNS) may have an effect on respiratory rate, neurotransmitter activity, CNS activity, cerebral blood flow and cerebral extracellular fluid volume. If the blood–CSF and brain–CSF interfaces in the neonate are immature and unable to adequately compensate for vascular changes in CO₂, the hypercapnia may contribute to the CNS abnormalities that are often seen in sick newborn foals. The increased cerebral blood flow may be associated with cerebral edema, resulting in the depression of cerebral activity observed in these sick foals.

The increased urinary excretion of acids in acidosis also causes polyuria, which may be sufficiently severe to cause dehydration or accentuate concomitant dehydration.

CLINICAL FINDINGS

The major clinical manifestation of metabolic acidosis is mental depression and varying degrees of muscular weakness. Newborn calves and goat kids with metabolic acidosis are depressed, weak and reluctant to suck.⁵ In severe acidemia, affected animals may be in lateral recumbency and appear to be in a state of coma. The depth and rate of respirations may be increased because of the increased Pco₂. Respiratory compensation is normally evident when the bicarbonate level is diminished to 50% of normal. Calves affected with severe acidemia and dehydration due to acute diarrhea may be unable to compensate because of depressed respiratory function. Their respiratory rate will be much slower and the depth of respiration much more shallow than normal. There is usually tachycardia, which becomes worse as the acidosis becomes more severe, and the amplitude of the pulse and blood pressure both decrease. A concomitant hyperkalemia will cause bradycardia, heart block, sudden collapse and rapid death. This is particularly evident when animals with acidosis and hyperkalemia are transported and handled for treatment. The increased muscular activity appears to accentuate the abnormalities and sudden death is not uncommon. Weakness, lassitude and terminal coma are frequent observations.

A syndrome of metabolic acidosis with minimal signs of dehydration or diarrhea has been described in calves from 1–4 weeks of age.^2,7 Affected calves are depressed, weak and ataxic, and the suck and menace reflexes may be weak or absent. Some calves appear comatose. On succussion of the abdomen fluid-splashing may be audible, which suggests that the syndrome may be related to diarrhea, which most of the calves may have had but from which they appeared to recover. The same abnormality has also occurred in goat kids with no apparent history of previous diarrhea.¹ The abnormal laboratory findings include a reduced venous blood pH, Pco₂ and bicarbonate ion concentration, marked hyper d-lactatemia, elevated blood urea nitrogen, increased anion gap and a neutrophilic leukocytosis with a left shift. Many of the clinical signs appear to be primarily the consequence of hyper d-lactatemia.² The intravenous administration of 2.5–4.5 L of isotonic (1.3%) sodium bicarbonate solution, the amount depending on the severity of the condition,⁷ is necessary.

ETIOLOGY AND PATHOGENESIS

Alkalemia is caused by an increased absorption of alkali, excessive loss of acid or a deficit of carbon dioxide (Fig. 2.7). Abomasal atony due to dilatation, impaction or torsion of the abomasum is one of the commonest causes of alkalemia in cattle. There is continuous secretion of hydrochloric acid and potassium into the abomasum, with failure of evacuation of the abomasal contents into the duodenum for absorption. Sequestration of hydrochloric acid and potassium occurs in the abomasum, along with reflux into the rumen, all of which results in a hypochloremic, hypokalemic alkalosis. In metabolic alkalosis, potassium will shift from the extracellular to the intracellular space, resulting in a hypokalemia when in fact there may not be depletion of total body potassium. In cattle with metabolic alkalosis there is a paradoxical aciduria, which is not well understood but may be due to severe electrolyte depletion placing limits on the kidney to regulate acid–base balance. Paradoxic aciduria must be differentiated from postparturient aciduria, which has been reported to occur in dairy cows.

Fig. 2.7 Etiology and pathogenesis of alkalemia.

Metabolic alkalosis has been recorded in cows with severe coliform mastitis but the pathogenesis is unknown.⁸

CLINICAL FINDINGS

The clinical findings of alkalosis are not characteristic enough to be recognized reliably. Alkalosis results in slow, shallow respirations in an attempt to preserve carbon dioxide. Muscular tremors and tetany with tonic and clonic convulsions may occur because of depression of the ionized fraction of serum calcium. Hyperpnea and dyspnea may also occur in the terminal stages.