Hypothermia, hyperthermia, fever

Excessive loss of heat

Exposure to excessively cold air temperatures causes heat loss if increased metabolic activity, shivering and sustained muscular contraction and peripheral vasoconstriction are unable to compensate.

Insufficient heat production

Insufficient body reserves of energy and insufficient feed intake result in insufficient heat production.

Hypothermia also occurs secondary to many diseases in which there may be a decrease in the ability to shiver and skeletal muscle contraction associated with decreased cardiac output, decreased peripheral perfusion and shock. Examples include parturient paresis, acute ruminal acidosis (grain overload), and during anesthesia and sedation, and the reduction of metabolic activity that occurs in the terminal stages of many diseases. A sudden fall in body temperature in a previously febrile animal, the so-called premortal fall, is an unfavorable prognostic sign.

Combination of excessive heat loss and insufficient heat production

A combination of excessive heat loss and insufficient heat production is often the cause of hypothermia. Insufficient energy intake or starvation of newborn farm animals in a cold environment can be a major cause of hypothermia. This may not occur under the same environmental conditions if the animals receive an adequate energy intake. Fatal hypothermia may also occur in other circumstances, such as in certain breeds of pig (pot-bellied) following general anesthesia or sedation with higher doses of azaperone.¹ Mature pot-bellied pigs deprived of feed and kept outdoors during cooler months of the year may develop hypothermia, which would not normally occur in these conditions if the pigs were receiving adequate food.²

Neonatal hypothermia

Newborn farm animals are prone to hypothermia in cool environments and hypothermia is a major cause of neonatal mortality. The neonates cannot maintain their rectal temperatures at normal values during the first few hours after birth under cold environmental conditions. Hypothermia and environmental thermoregulatory interactions are of particular importance in piglets and lambs because of their surface to volume ratio but are also relevant in calves and sick foals.

At birth, the neonatal ruminant moves from a very stable thermal environment, of similar temperature to its core body temperature, to a variable and unstable thermal environment that is 10–50°C colder than its core temperature. The coat is wet with placental fluids and energy loss is increased by evaporation and the low insulative value of a wet coat. The newborn calf becomes hypothermic in the first 6 hours after birth and only limited tissue substrates are available as energy sources. Neonates also are exposed to a variety of environmental pathogens against which they have little specific immunity. Thus the neonatal period is one of the most critical to the survival of an animal and during this period the morbidity and mortality can be high under adverse environmental conditions.

The continued emphasis in modern agriculture on the production of neonates throughout the year, including times of inclement weather and limited feed (late winter and early spring calving in beef herds in northern climates), the emphasis on short calving seasons, the use of high stocking densities, the production of animals with high muscle growth potential, which may be associated with an increased incidence of dystocia resulting in decreased vitality of newborn animals at birth, all appear to combine to increase the incidence of mortality due to hypothermia and related diseases of the neonate.

In lambs, more than 30% of deaths occur in the first few days of life and mortalities may be greater than 10%, with more than half of the losses due to hypothermia from either exposure or starvation. In calves, approximately 50% of deaths occur within 48 hours of birth and most losses are either directly due to, or follow, dystocial parturitions where stillbirths and early postnatal mortality rates are about 20% compared with less than 5% in calves born without dystocia (eutocial).³

Thermoregulation in neonatal farm animals

Risk factors for neonatal hypothermia

Post-shearing hypothermia in sheep

Sudden unpredicted summer rainfall can cause high mortality due to hypothermia in newly shorn sheep.¹³ A fall in body weight in the period immediately preceding shearing is another major risk factor. It is estimated that in Australia 0.8 million sheep die annually during the first 14 days after shearing and many of the deaths are associated with cold, wet, windy weather. Overall, crude mortality rates can range from 12–34% for sheep up to 28 days after shearing. In outbreaks in Australia in January the mean temperature can be 10°C, with a high rainfall and high wind velocity, accounting for a wind chill factor (a function of temperatures, rain and wind velocity). Other factors that increase heat loss include sunshine versus cloud, and the depth of the wool cover. The speed of the wind at the location of the animals varies greatly depending on the presence of protective windbreaks such as trees.

Cold environments and animal production

Farm animals maintain a relatively constant body core temperature during exposure to the extreme range of thermal environments experienced in countries such as Canada.¹⁴ The severity of the winter is particularly challenging. Homeothermy is achieved by physiological and behavioral mechanisms that modify either rates of heat loss from the body or the rate at which heat is produced by metabolism of feed or body energy reserves. Despite the extremely cold temperatures that occur in most of the agricultural regions of Canada, the effective severity of extremely cold temperatures is reduced because of the dryness of the frozen environment and the effective external insulation of the animal’s hair coat. The influence of wind can add to cold stress and the provision of shelter from wind by natural tree shelter belts or manmade structures such as porosity fences is required.

Prolonged exposure to cold results in subtle adaptation of hormonal and metabolic responses. Acclimatization to cold and winter conditions generally has little long-term effect on energy metabolism but increases thermal insulation and appetite. During prolonged exposure of cattle and sheep to cold environments down to −10 to −20°C there is a reduction in the apparent digestibility of the diet.¹⁴ To offset the lowered digestibility, the animals would accordingly need to consume more feed to achieve a similar digestible energy intake when kept outdoors during winter than if they were kept in a heated barn.

Neonatal hypothermia

Body temperatures may be as low as 35°C in neonatal calves, piglets, lambs and foals exposed to a cold environment within hours after birth or following 12–24 hours of profuse diarrhea accompanied by marked dehydration and acidosis. However, acute dehydration in a thermoneutral environment is accompanied by a mild increase in rectal temperature. In the early stage of hypothermia, affected animals may be shivering and trembling and the skin of their extremities and ears feels cool to touch. Hypothermic piglets will attempt to huddle together, are lethargic, do not suck and eventually become recumbent and die. Hypothermic calves exposed to a cold environment will assume sternal recumbency, lie quietly, will have a weak suck reflex and will die in a few hours. In later stages, further weakness leading to coma is common. The mucous membranes of the oral cavity are cool and may be dry. The heart rate is commonly slower than normal and the intensity of the heart sounds decreased. Death is common when the body temperature falls below 35°C but field observations indicate that the temperature may fall below 30°C and animals still survive if treated intensively.

Shorn sheep hypothermia

Sheep with hypothermia associated with recent shearing and inclement weather have a range of body temperatures from 35–38°C. They huddle in tight groups and the animals that cannot maintain sufficient heat will become weak, recumbent and die within a few hours. They may be found in lateral or sternal recumbency, with their heads back over their shoulders. Palpebral reflexes are decreased, skin and extremities are cold, mucous membranes are pale to white and generalized weakness similar to circulatory collapse is common.

Hypothermia secondary to other diseases

The hypothermia secondary to other diseases is usually not marked and there are clinical findings related to the underlying illness. Hypothermia is common in diseases such as milk fever in cattle but returns to normal within a few hours after successful treatment with calcium salts. Successful treatment of the primary disease will usually return the temperature to within the normal range.

Necropsy findings

Lesions associated with hypothermia depend on the duration and severity of the hypothermia. Fatal hypothermia in lambs and calves is characterized by an absence of lesions. A relative absence of milk in the abomasum is common. Experimental cold stress may result in subcutaneous edema of the ventral body wall and subcutaneous edema and hemorrhages of the extremities. Marked reductions in the amount of perirenal adipose tissue may be obvious. However, intense cold exposure of short duration may cause death of calves with no significant changes in the visual appearance of perirenal, pericardial or cardial adipose tissue depots.

Hypothermic newborn lambs

A system for the detection and treatment of hypothermia in newborn lambs can improve the survival rate.¹⁷ Most lambs become hypothermic within 5 hours or at more than 12 hours after birth. Hypothermia in the first 5 hours of life is most commonly caused by a high rate of heat loss from the wet newborn lamb, whereas a depressed rate of heat production consequent to starvation is the most common cause in the older lamb. Twin and triplet lambs are more susceptible to hypothermia than singles because of lower body energy reserves; the ewe takes longer to lick dry two or three lambs, and the milk requirement of two or three lambs is higher than that of a single lamb and starvation is more likely.

Using an electronic thermometer, the body temperature of any weak or suspect lamb is taken.¹⁸ Lambs of any age with mild hypothermia (37–39°C) are dried off if necessary to reduce heat loss, given ewe or cow colostrum by stomach tube and placed in a sheltered pen with the ewe. Lambs less than 5 hours of age with severe hypothermia (<37°C) are dried off and given an intraperitoneal injection of 20% glucose at a temperature of 39°C. A large lamb (>4.5 kg) is given 50 mL, a medium lamb (3.0–4.5 kg) 35 mL and a small lamb (<3.0 kg) 25 mL. Hypothermic lambs are then placed in warming pens, measuring 2 × 2 m and made of horizontally laid straw bales, two bales high. The pen is divided horizontally into two chambers by a sheet of weld mesh upon which the lambs lie. Warm air, at 38–40°C, is blown into the lower chamber from a domestic heater, and a sheet of polythene fitted over the entire pen retains the heat. When the lamb’s temperature reaches 37°C, it is removed from the warmer and immediately fed ewe or cow colostrum by stomach tube at a rate of 50 mL/kg BW. Any lamb that is vigorous and able to suck is returned to its ewe in a sheltered pen and monitored over the next several hours. Colostrum can be hand milked from the ewe after administration of oxytocin.

The immersion of hypothermic lambs in water at 38°C can result in the recovery to an euthermic state in about 28 minutes at a reduced expense in metabolic effort by lambs. However, this requires extra labor and lambs must be quickly dried, otherwise the heat loss is exaggerated after removal from water because of the wet fleece.

Hypothermic newborn calves

Clinical management of hypothermic newborn calves is similar to that of lambs. Supplemental heat must be provided immediately. Rewarming can be done in small, enclosed boxes bedded with blankets and heat provided by infrared heat lamps. Colostrum or milk should be warmed to 40°C and intubated using an esophageal feeder. Fluids given intravenously must be warmed; one practical method requires submersion of the intravenous line in a sustained source of warm water. Intravenous dextrose (1 mL of 50% dextrose/kg BW) should be routinely administered to all hypothermic calves because most have moderate to severe hypoglycemia. This dosage rate of 50% dextrose will increase the serum glucose concentration of the calf by approximately 100 mg/dL, assuming that the extracellular fluid space is 50% of the calf’s body weight. The rectal temperature should be taken every 30 minutes during treatment to assess progress.

A more aggressive rewarming technique involves the repeated administration of warm (40°C) 0.9% NaCl enemas via a flexible soft tube; a 20–30F Foley catheter works well in this regard when it is advanced through the anus and the bulb inflated to maintain the catheter in the rectum. Rectal fluid should be aspirated before infusing additional fluid volumes via the Foley catheter in order to maximize the warming ability of enema fluids. Use of enema fluids as part of the rewarming protocol makes it more difficult to monitor the increase in body temperature. Whether immersion of hypothermic calves in water at 38–40°C is beneficial has not been determined, but immersion presents practical difficulties.

Hypothermic newborn foals

The clinical management of sick foals that are prone to hypothermia is presented below under Control.

Hypothermic newborn piglets

Hypothermic piglets must be placed in a warming box with a heat lamp and treated with intraperitoneal administration of glucose for the hypoglycemia. The subject is presented in additional detail in Chapter 3.

Lambs and calves

Prevention of hypothermia in calves depends on the planning and implementation of effective management strategies that will limit the risk factors known to predispose newborn calves to hypothermia and starvation. Management strategies to prevent hypothermia from excessive heat loss are most important in the first 24 hours after birth. They include changing the calving season to a warmer time of the year to minimize exposure to severe weather. Measures to minimize excessive heat loss include providing a dry, draft-free environment for calving and lambing. Providing a protective shelter for beef cow/calf pairs for calving and during the first week after birth can reduce mortality from hypothermia. In extensive beef cow/calf herds, calf huts large enough for 8–10 calves provide excellent shelter from wind, rain and snow.

The provision of adequate surveillance and assistance at the time of lambing or calving is necessary to minimize the incidence of dystocia and its consequences for the neonate. The ingestion of adequate quantities of colostrum, beginning as soon after birth as possible, is important in order to provide immunoglobulins and energy sources for the neonate.

Piglets

The newborn piglet requires an adequate intake of colostrum within a few hours after birth, continued intake of milk after the colostral period, a warm external environment of 30–34°C for at least the first 3 days of life (with heat lamps) and protection from traumatic injuries such as crushing by the sow. Sows do not instinctively remove the amniotic fluid from the surface of piglets; it is removed by contact with other surfaces or by evaporation. Smaller than normal or weak piglets should be dried manually to minimize excessive heat loss. Cross-fostering is used when gilts or sows have large litters that they cannot nurse adequately.

Sick foals

Sick foals are prone to hypothermia but cold stress can be reduced by good management procedures, including the following:¹²

High environmental temperature

The upper border of the thermoneutral zone – the upper critical temperature – is the effective ambient temperature above which an animal must increase heat loss to maintain thermal balance. The upper critical temperature in sheep with a light wool coat on board ship appears to be 35°C (95°F) at a humidity of 33–39 mmHg (4.4–5.2 kPa) vapor pressure. Differences between breeds of animal in their tolerance to environmental high temperatures, exposure to sunlight and exercise are important in animal management and production. Water buffalo have been shown to be less heat-tolerant than Shorthorn steers, which were less tolerant than Javanese Banteng and Brahman crossbreds – the last two appear to be equally tolerant. The differences appear to be at least partly due to capacity to increase cutaneous evaporation under heat stress.

There are similar differences in heat tolerance between lactating and nonlactating cows; lactating animals show significantly greater increases in rectal temperature and heart and respiratory rates when the environmental temperature is raised. This is primarily a result of the greater dry matter intake and heat of fermentation in dairy cattle that must be dissipated. Heat stress is therefore an important production-limiting disease when dairy cattle are kept in conditions of high heat and humidity.

Rested, hydrated horses are well able to maintain homeothermy in the hottest environmental conditions. Their most efficient mechanism in ensuring that body temperature is kept low is their capacity for heavy sweating.

Other causes of hyperthermia

Necropsy findings

At necropsy there are only poorly defined gross changes. Peripheral vasodilatation may be evident, clotting of the blood is slow and incomplete, and rigor mortis and putrefaction occur early. There are no constant or specific histopathological changes.

Septic fevers

These include infection with bacteria, viruses, protozoa or fungi as:

Aseptic fevers

Endogenous pyrogens

Endogenous pyrogens are proteins released from monocytes and, to a lesser extent, lymphocytes. These proteins were originally designated as monokines and lymphokines respectively, but are now more commonly referred to under the more general term of cytokines. One of the pyrogenic cytokines is interleukin-1, formerly known as lymphocyte activating factor. Interleukin-1 stimulates T-lymphocyte proliferation in the presence of antigen and thereby enhances the immune response. The mediators between endogenous pyrogen and the hypothalamus appear to be prostaglandins and the level of calcium in the hypothalamus appears to regulate its activity.

Interleukin-1 initiates fever by inducing an abrupt increase in the synthesis of prostaglandins, particularly prostaglandin E₂, in the anterior hypothalamus. The elevated prostaglandin levels in the hypothalamus raise the thermostatic set point and induce the mechanisms of heat conservation (vasoconstriction) and heat production (shivering thermogenesis) until the blood and core temperature are elevated to match the hypothalamic set point.

Prostaglandin precursors are believed to be the chemical mediators of fever according to the following sequence:

A cytokine known as tumor necrosis factor (TNF)-α reproduces many of the physiological derangements observed in septic shock and mediates many of the deleterious effects of Gram-negative bacterial infection, including fever.

In addition to their pyrogenic activity, cytokines mediate the acute phase response, which is a term now being used to describe the reaction of animals to pathogen invasion, tissue injury, immunological reactions and inflammatory processes. During the acute phase response, the liver increases the synthesis of certain proteins, whereas albumin synthesis is reduced. Haptoglobins, fibrinogen, ceruloplasmin and proteinase inhibitors have been examined in cattle with the acute phase response.¹ In this response, the serum iron concentration decreases during fever, which inhibits the growth of certain bacteria that require iron. Blood concentrations of zinc also decrease, with a simultaneous increase in serum copper concentrations.² Measurement of acute phase proteins may provide a basis for monitoring the severity of some infections and act as an aid in making a diagnosis. The concentration of fibrinogen can be a useful addition to routine hematological determination in animals.³

The physiological mechanisms involved in the production of fever after stimulation by pyrogens must be matured or sensitized by previous exposure to pyrogen. Injection of pyrogens into newborn lambs does not cause fever but subsequent injections do.

Effect of pyrogens on the hypothalamus

The effect of bacterial and tissue pyrogens is exerted on the thermoregulatory center of the hypothalamus so that the thermostatic level of the body is raised. The immediate response on the part of organs involved in heat regulation is the prevention of heat loss and the increased production of heat. This is the period of increment, or chill, which is manifested by cutaneous vasoconstriction, resulting coldness and dryness of the skin and an absence of sweating. Respiration is reduced and muscular shivering occurs, while urine formation is minimal. The extremities are cold to the touch and the rectal temperature is elevated and the pulse rate increased. When the period of heat increment has raised the body temperature to a new thermostatic level the second period of fever, the fastigium, or period of constant temperature, follows. In this stage the mechanisms of heat dissipation and production return to normal. Cutaneous vasodilatation causes flushing of the skin and mucosae, sweating occurs and may be severe, and diuresis develops. During this period there is decreased forestomach motility in ruminants, metabolism is increased considerably to maintain the body temperature, and tissue wasting may occur. There is also an inability to maintain a constant temperature when environmental temperatures vary.

When the effect of the pyrogenic substances is removed, the stage of decrement, or fever defervescence, appears and the excess stored heat is dissipated. Vasodilatation, sweating and muscle flaccidity are marked and the body temperature falls. The fall in body temperature after the initial rise is accompanied by a decline in plasma zinc and plasma total iron concentrations. If the toxemia accompanying the hyperthermia is sufficiently severe, the ability of tissues to respond to heat production or conservation needs may be lost and as death approaches there is a precipitate fall in body temperature.

Febrile response

The febrile response, and the altered behavior that accompanies it, are thought to be part of a total mechanism generated to conserve the resources of energy and tissue being wasted by the causative infection. The febrile response has major effects on immune mechanisms. Endogenous pyrogens stimulate T-cell proliferation. The increased body temperature causes increases in leukocyte mobility, leukocyte bactericidal and phagocytic activities, lymphocyte transformation, and also enhances the effects of interferon and interleukin-1.

Some possible adverse effects of fever include anorexia, which can lead to excessive catabolism if prolonged. Rarely, extremely high fevers can result in disseminated intravascular coagulation and effects on the central nervous system that may lead to convulsions.

Necropsy findings

The necropsy findings will be characteristic of the individual disease process and are commonly characterized by varying degrees of peracute, acute and chronic inflammation depending on the severity of the disease, the length of illness and whether or not treatment had been given. In the case of longstanding fevers the above findings are still characteristic but they may fluctuate in severity daily or over longer periods.

Fever must be differentiated from hyperthermia due to a physical cause such as heat stroke or exhaustion or malignant hyperthermia. In fever of unknown origin, the history, physical examination, laboratory findings and epidemiological setting should be reviewed. Localizing clinical findings may provide a clue to the body system or organ involved. Common inflammatory processes include:

Many animals are placed in the category of fever of unknown origin because the veterinarian overlooks, disregards or rejects an obvious clue. No algorithms or computer-assisted diagnostic programs are likely to solve the diagnostic challenge. In order to improve the diagnostic accuracy, veterinarians will have to work harder. This requires obtaining a detailed history, repeated physical examinations, reconsideration of the epidemiological characteristics of the affected animal, requesting consultations from colleagues, and the investment of time to consider the diagnosis and the circumstances.

Antimicrobial agents

The most important aspects of the clinical management of fever should be directed at its cause. The main objective is to identify and treat the primary disease. Antimicrobial agents are indicated for the treatment of bacterial infections. The selection of antimicrobial, the route of administration and the duration of treatment depend on the cause of the infection, its severity and the accessibility of the lesion to the drug. The use of antimicrobial agents to prevent secondary bacterial infections in animals with viral diseases (e.g. viral interstitial pneumonia) is controversial and of doubtful benefit.

In animals with a fever of unknown origin, broad-spectrum antimicrobial agents seem rational. However, blind therapy is not recommended because it may lead to drug toxicity, superinfection due to resistant bacteria, and interference with subsequent accurate diagnosis by cultural methods. In addition, the fall of the temperature following treatment may be interpreted as a response to therapy, with the conclusion that an infectious disease is present. If such a trial is begun the response should be monitored daily to determine effectiveness and continued efforts should be made to determine the cause of the fever. In some cases it may be necessary to surgically remove by drainage techniques the source of the infection located in abscesses or body cavities such as the pleural cavity.

Antipyretics

Since fever ordinarily does little harm and usually benefits the animal’s defense mechanism, antipyretic agents are rarely essential and may actually obscure the effect of a specific therapeutic agent or of the natural course of the disease. If the fever is high enough to cause discomfort or inappetence, or is so high that death due to hyperthermia is possible, then nonsteroidal anti-inflammatory drugs (NSAIDs) should be administered. Most NSAIDs, such as flunixin meglumine, are inhibitors of prostaglandin synthesis and act centrally to lower the thermoregulatory set point. Rectal temperatures start to decline within 30 min of parenteral NSAID administration but usually do not completely return to within the normal physiological range.

All species

Anthrax, pasteurellosis and salmonellosis are found in all species of food animal.

Neonatal septicemias

Neonatal septicemias are caused most commonly by Gram-negative bacteria.

Cattle

Histophilus somni, Pasteurella multocida, Mannheimia haemolytica, Pasteurella (Yersinia) pseudotuberculosis, acute and chronic infections with bovine virus diarrhea virus and bovine malignant catarrh are encountered.

Sheep (young lambs)

Histophilus somni is the main pathogen.

Pigs

Hog cholera and African swine fever viruses and Erysipelothrix insidiosa are encountered.

Horses, donkeys, mules

African horse sickness and M. haemolytica infection are implicated.

Secondary septicemias

The principal cause of death in subacute radiation injury is septicemia resulting from loss of leukocyte production because of injury to bone marrow. Septicemia may also result when there is a congenital defect in the immune system or when immunosuppression occurs in older animals as a result of corticosteroid therapy or toxin such as bracken.

Disseminated intravascular coagulation

Disseminated intravascular coagulation (DIC) is common in severe septicemic disease, especially that which terminates fatally. It is initiated by vascular injury with partial disruption of the intima, caused by the circulation of foreign materials such as bacterial cell walls, antigen–antibody complexes and endotoxin, with subsequent platelet adherence and the formation of platelet thrombi. Once coagulation proceeds, the initial hypercoagulable state changes to hypocoagulation, as clotting factors and platelets are consumed. The activation of the fibrinolysis system can be a major cause of the hemorrhagic diathesis present in this syndrome.

Neonatal septicemia

Neonatal septicemia is common in all farm animal species from a few hours up to several days of age. The following features are common:

Colostrum-deprived foals are commonly very ill and become comatose and die within several hours. Localized infections in the joints and lungs are frequent in foals that survive for several days. Septic polyarthritis is common and is characterized by heat, pain, synovial distension and lameness. Pneumonia is often observed and is characterized by dyspnea and abnormal lung sounds. The survival rate of foals with confirmed septicemia in one series was 70%.⁹

In calves under 30 days of age with septicemia clinical findings can include evidence of shock with cold extremities, dehydration, weak pulse, prolonged capillary refill time, weakness and recumbency.² Findings indicative of localization include ophthalmitis, neurological abnormalities, omphalophlebitis and polyarthritis.

Clinical sepsis score

A clinical sepsis score for the early diagnosis of septicemia in newborn foals has been evaluated and validated.¹⁰ It should be recognized that application of such scoring systems is statistically flawed, as it assigns equal weights to predictors and equal weights to change in severity within a given predictor. Nevertheless, such sepsis scores have been adopted by some and do have the value of facilitating the identification of neonates at risk for being septicemic. A score for predicting bacteremia in neonatal dairy calves from 1–14 days of age has also been suggested to predict clinically whether a sick calf has bacteremia.¹¹ The calves are scored according to degrees of hydration status, fecal appearance, general attitude, appearance of scleral vessels and umbilical abnormality. However, the sensitivity, specificity and positive predictive value are too low to be of diagnostic value.⁵

Blood culture

Isolation of the causative bacteria from the bloodstream should be attempted by culture. Ideally, blood cultures should be obtained just before the onset of fever and from a major vein or any artery. The standard is three blood cultures or animal inoculation at the height of the fever. A minimum of 10 mL of blood (preferably 30 mL) should be collected anaerobically after aseptic preparation of the venipuncture site by clipping and scrubbing with povidone iodine scrub. Blood samples should be inoculated into a broth medium with the ratio of blood to broth being 1:10 to 1:20,¹² and the culture bottles should be examined for growth daily for up to a week.¹³ Growth is manifest as turbidity and possibly by the presence of hemolysis.

Hemogram

The presence of leukopenia or leukocytosis is an aid in diagnosis and the type and degree of leukocytic response may be of prognostic significance.

Plasma fibrinogen concentrations may be increased.² Consumption coagulopathy is detected by falling platelet counts, prothrombin and fibrinogen values, and also by the presence of fibrin degradation products.

Immunoglobulin status

Low levels of serum protein and immunoglobulins are associated with failure of transfer of colostral immunoglobulins in newborn farm animals with consequent septicemia due, most commonly, to Gram-negative bacteria.

Serology

Serological tests are available for most infectious diseases described in this book.

Necropsy findings

The lesions will reflect the specific disease causing the septicemia. Subserous and submucosal hemorrhages may be present, together with embolic foci of infection in various organs accompanied by the lesions typical of the specific pathogen.

Antigenic toxins

These are produced by bacteria and to a lesser extent by helminths. Both groups of pathogens act as antigens and stimulate the development of antibodies. Antigenic toxins are divided into exotoxins and endotoxins.

Metabolic toxins

These may accumulate as a result of incomplete elimination of toxic materials normally produced by body metabolism, or by abnormal metabolism. Normally, toxic products produced in the alimentary tract or tissues are excreted in the urine and feces or detoxified in the plasma and liver. When these normal mechanisms are disrupted, particularly in hepatic dysfunction, the toxins may accumulate beyond a critical point and the syndrome of toxemia appears. In obstruction of the lower alimentary tract there may be increased absorption of toxic phenols, cresols and amines that are normally excreted with the feces, resulting in the development of the syndrome of autointoxication. In ordinary circumstances in monogastric animals these products of protein putrefaction are not absorbed by the mucosa of the large intestine but when regurgitation into the small intestine occurs there may be rapid absorption, apparently because of the absence of a protective barrier in the wall of the small intestine.

In liver diseases, many of the normal detoxification mechanisms, including oxidation, reduction, acetylation and conjugation with such substances as glycine, glucuronic acid, sulfuric acid and cysteine, are lost and substances which are normally present in insufficient quantity to cause injury accumulate to the point where illness occurs. The production of toxins by abnormal metabolism is taken to include the production of histamine and histamine-like substances in damaged tissues. Ketonemia due to a disproportionate fat metabolism, and lactic acidemia caused by acute ruminal acidosis (grain overload), are two common examples of toxemia caused by abnormal metabolism.

Biochemical mediators

Endotoxins do not cause their effects via direct toxic effect on host cells but rather induce the production of soluble and cell-bound mediators from a broad range of host cells, including endothelial and smooth muscle cells, polymorphonuclear granulocytes, platelets, thrombocytes and cells of the monocyte/macrophage lineage. These cells release a series of phlogistic biochemical mediators, which include cytokines, platelet-activating factor, thromboxane A₂, prostaglandins, leukotrienes, proteinases, toxic oxygen metabolites and vasoactive amines. Macrophages become highly activated for enhanced secretory, phagocytic and cidal functions by the lipopolysaccharide. The cytokines derived from the macrophages are responsible for many of the pathophysiological consequences of endotoxemia. Pulmonary intravascular macrophages are the most important producers of cytokines in large animals.

Animals have evolved to recognize and respond to the lipopolysaccharide of Gram-negative bacteria. Although lipopolysaccharide may directly injure the host tissue, many of its effects are indirectly mediated through inappropriate activation of host defense mechanisms, culminating in multiple-organ dysfunction and failure. Importantly, the response to endotoxin can be attenuated with certain substances. Experimentally, the use of detergents, such as a nonionic surfactant, can attenuate the response of the horse given endotoxin.⁴ The literature on the pathophysiological effects of endotoxemia and Gram-negative bacteremia in swine has been reviewed.⁵

There is a large individual variability in the response to endotoxin administration, with much of the variability still being unexplained. Circulating lipopolysaccharide forms complexes in plasma with high density lipoproteins or a unique plasma protein termed lipopolysaccharide-binding protein (LBP) and bound lipopolysaccharide is cleared from plasma within a few minutes by fixed and circulating macrophages in the bovine lung and liver that recognize the lipopolysaccharide–LBP complex. The lipopolysaccharide–LBP complex binds to a membrane-bound receptor (mCD14) on mononuclear cells via a secreted linking protein called MD-2 and then attaches to a toll-like receptor 4 (TLR4) on the mononuclear cell membrane; the lipopolysaccharide–LBP–mCD14–MD-2 complex is then internalized and lipopolysaccharide is thought to be destroyed in the process. Internalization of lipopolysaccharide activates the intracellular signaling pathway via nuclear factor kappa B (NF-κB), which translocates to the nucleus and causes the transcription of many cytokine genes and release of proinflammatory cytokines, of which TNF-α, interleukin-1 and interleukin-6 are the most important. Some of the genes activated include those that code for cyclooxygenase 2 (COX-2, the inducible form of cyclooxygenase), inducible nitric oxide (iNOS), endothelial adhesion molecules, which promote the adhesion of neutrophils to endothelial surfaces, and chemokines.

The plasma concentrations of the arachidonic acid metabolites, thromboxane A₂ and prostacyclin, increase in several species during endotoxemia, and these eicosanoids are probably responsible for the hemodynamic abnormalities caused by endotoxin. Endotoxin initiates cellular events that activate a cell-membrane enzyme known as phospholipase A₂. Activation of this enzyme leads to the hydrolysis of membrane-bound phospholipids; arachidonic acid is released from the phospholipid portion of damaged mammalian cell membranes.⁶ The enzyme cyclooxygenase converts arachidonic acid into intermediate endoperoxides, which are substrates for the formation of prostaglandins, thromboxane and prostacyclin, by specific synthetases. Platelets are the principal source of thromboxane, which acts as a potent vasoconstrictor and induces platelet aggregation. Most prostacyclins are synthesized in vascular endothelial cells and cause vasodilation and inhibit platelet aggregation. The generalized endotoxin-induced production of cyclooxygenase products may contribute to the multisystemic organ dysfunction, shock and disseminated coagulopathy that culminates in death.

TNF-α is released by macrophages early in the course of endotoxemia and circulating TNF-α activity correlates with the severity and outcome of disease. Infusion of TNF induces an endotoxemic-shock-like syndrome and TNF-α blockade confers marked protection against the effects of Gram-negative sepsis and lipopolysaccharide administration. Experimentally, pretreatment of horses with monoclonal antibody to TNF-α can reduce the hematological and clinical effects of endotoxin-induced TNF activity⁷ and interleukin-6 activity can be reduced by neutralization of TNF-α.⁸ Interleukin-1 release is proinflammatory and leads to pyrexia and the hepatic acute phase response. Interleukin-6 contributes to the hepatic acute phase response and promotes B-lymphocyte proliferation. Interleukin-6 may have value as a prognostic indicator, as its plasma concentration appears to be a better predictor of mortality in humans than TNF-α or interleukin-1.

The systemic effects of endotoxemia can be demonstrated experimentally by parenteral injection of purified endotoxin, TNF-α or interleukin-1. In naturally occurring disease, however, the total effect includes those of bacterial toxins plus those of mediators produced by tissues in response to the toxins, and the counterbalancing effects of anti-inflammatory molecules that are also secreted during sepsis, such as interleukin-4, interleukin-10, interleukin-11, interleukin-13, and soluble CD14 receptors. The pathophysiological effects of endotoxemia associated with Gram-negative bacteria are summarized here according to their effects on various body systems or functions.

Cardiopulmonary function

The hemodynamic effects of endotoxemia are manifested in two phases.⁹ In the early stages, heart rate and cardiac output commonly increase, although systemic blood pressure remains near or slightly less than normal. This is known as the hyperdynamic phase of endotoxemia. Oxygen demands of peripheral tissues are increased during the hyperdynamic phase, resulting in compensatory mechanisms that increase blood flow in an attempt to meet the increased metabolic demands. However, despite the absolute increase in cardiac output and oxygen delivery during this hyperdynamic phase, blood flow still may be inadequate to meet the needs of tissues in a hypermetabolic state. During the hyperdynamic state, affected animals hyperventilate and have decreased capillary refill time and red, congested mucous membranes. Microcirculatory shunting of blood continues in organs such as the gastrointestinal tract and kidney. Ischemia of intestinal mucosa is manifested clinically by ileus and diarrhea may occur. Decreased renal perfusion will result in decreased urine output.

With uncontrolled endotoxemia, the hyperdynamic phase progresses to the hypodynamic phase of shock. Changes include decreased cardiac output, systemic hypotension, increased peripheral resistance and decreased central venous return. Hypothermia, rapid irregular pulses, prolonged capillary refill time, pale to cyanotic mucous membranes, acidemia and hypoxemia provide clinical evidence of this advanced stage of endotoxemia. The skin and extremities are cool. Severe pulmonary edema and increasing pulmonary hypertension occur. In horses, administration of endotoxin at high dosages can induce circulatory shock with increased heart rate, decreased cardiac output and stroke volume, and concomitant increases in peripheral vascular resistance. The slow intravenous infusion of low dosages of endotoxin into conscious horses results in pulmonary hypertension without causing hypotensive, hypovolemic shock.¹⁰ Intestinal vasoconstriction occurs as part of the compensatory response to endotoxemia following slow infusion of low dosages of endotoxin.

Infusion of endotoxin into swine induces widespread changes including intense pulmonary vasoconstriction and hypertension, bronchoconstriction, increased vascular permeability, hypovolemia, systemic hypotension, pulmonary edema, hypoxemia, granulocytopenia and thrombocytopenia.⁵ The vascular changes in endotoxemia include increased vascular permeability, changes in vascular tone and microvascular obstruction. Increased capillary permeability promotes transmural movement of albumin and other colloids, which carry water to the interstitial space. The result is hypoalbuminemia, hypoproteinemia, interstitial edema, pulmonary edema, relative hypovolemia, decreased return to the heart and further decreases in cardiac output. Arterial and arteriolar vasoconstriction develops in the systemic and pulmonary circulations. Prolonged infusion of endotoxin into sheep causes systemic hypotension, pulmonary hypertension and acute lung injury with progressive respiratory failure.¹¹

Endotoxemia causes an acute and severe neutropenia, which precedes neutrophilia and hemoconcentration. Neutropenia is due mainly to leukocyte margination and sequestration; persistence of severe neutropenia is a poor prognostic indicator. Hemoconcentration is due to movement of fluid from the vascular to extravascular spaces. Endotoxin administration causes an immediate accumulation, margination and activation of leukocytes in the microcirculation, particularly in the alveolar capillaries. This is followed by degranulation and leukocyte migration into the interstitium and endothelial cell damage. Pulmonary sequestration of neutrophils is preceded by endotoxin uptake by pulmonary intravascular macrophages, indicating that the pulmonary macrophage response is pivotal to the subsequent inflammatory response. Leukopenia appears to be an immediate response to endotoxin administration, and is observed as early as 5 min after infusion. The rebound leukocytosis is caused by humoral effects on the bone marrow; a neutrophil-releasing factor that promotes release of neutrophils from bone marrow, and macrophage-colony-stimulating factor, which stimulates granulopoiesis. Colostrum-fed calves have a greater neutrophilia in response to endotoxin than colostrum-deprived calves, possibly because of absorption of a granulopoietic factor from colostrum. Endotoxemia also induces a lymphopenia that is secondary to the release of endogenous corticosteroids and redistribution of lymphocytes from peripheral blood and the spleen to lymphatic tissue.

Thrombocytopenia is consistently observed after endotoxin administration, but occurs later than neutropenia, although it is sustained for a longer period of time. Endotoxin affects platelet function by a number of different mechanisms.

Hemostatic system

Endotoxins cause endothelial injury directly or indirectly, and thereby expose subendothelial collagen and tissue thromboplastin, initiating the intrinsic and extrinsic coagulation cascades, respectively.³ Endotoxin can initiate the coagulation cascade directly by activation of factor XII or by inducing platelet release of thromboxane and other procoagulant substances. Endotoxin may induce coagulopathy indirectly by endothelial damage with secondary factor XII activation, or through the effects of complement activation. Macrophages and leukocytes have been shown to release a procoagulant substance in response to endotoxin, which functions similarly to factor VII and may also have a role in perpetuating coagulopathy in endotoxemia via the extrinsic pathway.

Disseminated coagulopathy is the cause of diffuse microvascular thrombosis and eventual organ failure subsequent to endotoxemia. The experimental injection of endotoxin can cause diffuse microthrombosis in multiple or organ systems. The principal clinical finding of DIC in horses is petechial and/or ecchymotic hemorrhages on mucous membranes and sclerae with a tendency to bleed from venepuncture sites. Spontaneous epistaxis or prolonged hemorrhage after nasogastric intubation may also occur. The result of exaggerated thrombin formation during DIC is widespread fibrin deposition in the microcirculation causing circulatory obstruction and organ hypoperfusion that may lead to ischemic necrosis and failure. The ultimate consequences are multiple organ failure and death.

Thermoregulation

Bacterial endotoxins are potent stimulators of macrophage interleukins, which belong to a family of polypeptides functioning as key mediators of various infectious, inflammatory and immunological challenges to the host. Interleukin-1 induces fever, an increase in the number and immaturity of circulating neutrophils, muscle proteolysis through increased prostaglandin E₂ production, hepatic acute phase protein production, and reduced albumin synthesis. Interleukin-1 participates in the acute phase response, which is characterized by fever, hepatic production of acute phase proteins, neutrophilia and procoagulant activity.⁹

Endotoxins commonly cause a fever followed by hypothermia. Serum interleukin-6 concentrations are lower in endotoxin-induced colostrum-deprived foals and take longer to reach peak levels compared to colostrum-fed foals.¹² The higher and more rapid concentrations in colostrum-fed foals may be part of a resistance factor in equine neonates. Interleukin-6 plays a key role in host defense, regulating antigen-specific immune responses, hematopoiesis, cellular differentiation and the acute phase reaction subsequent to an inflammatory insult. Serum TNF-α responds in a similar pattern in colostrum-deprived and colostrum-fed foals given endotoxin and the mean rectal temperature in colostrum-deprived foals is significantly less than in colostrum-fed foals.¹²

Gastrointestinal function

Endotoxemia can cause a profound inhibition of gastrointestinal motility, including the stomach, small and large intestine. Postoperative ileus is a frequent and serious complication of equine colic surgery and there is a good correlation between the incidence of ileus and the presence of ischemic intestine. Low doses of endotoxin infused into ponies produced profound disruption of normal fasting intestinal motility patterns, with an inhibition of gastric contraction amplitude and rate, left dorsal colon contraction product and small-colon spike rate.¹³ In the small intestine, there is an increase in abnormally arranged regular activity and a decrease in irregular activity. Experimental endotoxemia in the horse causes cecal and proximal colonic hypomotility (ileus) by a mechanism involving α-adrenergic receptors, which is reversible by yohimbine.¹⁴ Numerous mediators may interact with the sympathetic nervous system to induce this effect.

The administration of endotoxin to adult dairy cows can reduce the frequency of reticulorumen contractions; this is caused by endotoxin-induced mediators¹⁵ and the effect can be abolished by flunixin meglumine. Endotoxemia also decreases the abomasal emptying rate in cattle and is suspected to play a role in the development of left displaced abomasum.

Carbohydrate metabolism

The effects on carbohydrate metabolism include a fall in plasma glucose concentration, the rate and degree varying with the severity of endotoxemia, a disappearance of liver glycogen and a decreased glucose tolerance of tissues so that administered glucose is not used rapidly. Endotoxic shock can result in lactic acidemia and both hyper- and hypoglycemic responses. Hyperglycemia occurs early and transiently in endotoxic shock, is accompanied by increased rates of glucose production and is dependent on mobilization of hepatic glycogen. Hypoglycemia is very common in prolonged or severe endotoxemia. Experimental infusion of endotoxin into sheep results in transient hyperglycemia associated with increased hepatic glucose production followed by hypoglycemia 3–8 hours later, when hepatic glucose production decreases. Sympathetic activation occurs early in endotoxemia and is probably responsible for the initial hyperglycemia and glycogenolysis. Blood pyruvate and lactate concentrations increase as a result of poor tissue perfusion and the anaerobic nature of tissue metabolism. By extrapolation from the known pathogenesis of endotoxic shock in horses, it is likely that the resulting accumulation of lactate has significant effects in causing mental depression and poor survival.

Protein metabolism

There is an increase in tissue breakdown (catabolism) and a concomitant increase in serum urea nitrogen concentration. The changes observed include alterations in individual plasma amino acid concentrations, increased urinary nitrogen excretion and increased whole-body protein turnover. The time-course changes in the concentrations of plasma amino acids and other metabolites during and after acute endotoxin-induced fever in mature sheep have been described. Rapid and extensive changes occur in the patterns of tissue protein metabolism in the ruminant in response to endotoxin administration, and these changes may contribute to economic losses incurred during infectious disease outbreaks. There is also an alteration in the aminogram (the relative proportions of the amino acids present in blood) and the electrophoretic pattern of plasma proteins. The globulins are increased and albumin decreased as part of the acute phase reaction.

Mineral metabolism

Negative mineral balances occur. These include hypoferremia and hypozincemia as part of the acute phase reaction as the animal attempts to sequester these microminerals from invading bacteria, but blood copper concentrations are commonly increased concurrently with an increase in blood ceruloplasmin levels.

Reproduction and lactogenesis

Endotoxemia can cause pregnancy failure in domestic animals, particularly when pregnancy is corpus-luteum-dependent. In horses and cattle, experimentally induced endotoxemia causes an immediate and pronounced release of prostaglandin F_2α. The intravenous administration of endotoxin may influence luteal function by the activation of the arachidonic acid cascade, by a direct effect of prostaglandin F_2α on the corpus luteum. The administration of endotoxin to mares pregnant 21–35 days results in a decrease in progesterone and fetal death, which can be prevented by daily treatment with a progesterone compound.¹⁶ Similar results have been produced in pregnant dairy cows during the first 150 days of lactation, and coliform mastitis in the first 5 months of lactation is becoming an increasingly important cause of early embryonic death and return to estrus. The uterus of the early postpartum cow is capable of absorbing endotoxin, which may provoke changes in the serum concentrations of prostanoids¹⁷ and is thought to contribute substantially to the systemic signs of toxic metritis in cows. Endotoxin has a negative effect on the genital functions of the ram; the changes in luteinizing hormone (LH) and testosterone are similar to those seen after heat-induced stress.

In recently farrowed swine with the mastitis–metritis–agalactia syndrome, it is suggested that the endotoxin from the mammary glands affected with mastitis may be important in the pathogenesis of the agalactia.

Combined effects on body systems

The combined effects of the hypoglycemia, hyper l-lactatemia and acidemia interfere with tissue enzyme activity and reduce the functional activity of most tissues. Of these factors, acidemia is probably the most important in adult animals; in neonates glucose levels are probably as important as acidemia because profound hypoglycemia is more commonly encountered in neonatal animals. Experimental endotoxemia in calves at 24–36 hours of age causes severe hypoglycemia, lactic acidemia and hypotension commonly associated with moderate to severe sepsis.¹⁸ The myocardium is weakened, the stroke volume decreases and the response to cardiac stimulants is diminished. There is dilatation and in some cases damage to capillary walls, so that the effective circulating blood volume is decreased; this decrease, in combination with diminished cardiac output, leads to a fall in blood pressure and the development of circulatory failure. The resulting decline in the perfusion of tissues and oxygen consumption contributes greatly to the animal’s decline and to the clinical signs, such as the dark red coloration of the oral mucosa. Respiration is little affected except in so far as it responds to the failing circulation.

There is decreased liver function, and the damage to renal tubules and glomeruli causes a rise in blood nonprotein nitrogen and the appearance of albuminuria. The functional tone and motility of the alimentary tract is reduced and the appetite fails; digestion is impaired, with constipation usually following. A similar loss of tone occurs in skeletal muscle and is manifested by weakness and terminally by prostration.

Apart from the effects of specific toxins on the nervous system, such as those of Clostridium tetani and Clostridium botulinum, there is a general depression of function attended by dullness, depression and finally coma. Because of the suspected role of E. coli in the etiology of edema disease of swine, it is noteworthy that some of the characteristic nervous system lesions of that disease are missing from experimentally induced porcine colitoxicosis. Changes in the hemopoietic system include depression of hemopoiesis and an increase in the number of leukocytes – the type of cell that increases often varying with the type and severity of the toxemia. Leukopenia may occur but is usually associated with aplasia of the leukopoietic tissue associated with viruses or specific exogenous substances such as radioactive materials. Most of these pathophysiological effects of endotoxicosis have been produced experimentally, and it is apparent that very small amounts of endotoxin can contribute greatly to the serious effects of intestinal disease, especially in the horse.

Endotoxin tolerance

The repeated administration of lipopolysaccharide results in attenuation of the host response, known as endotoxin tolerance. This refractoriness to endotoxin-mediated effects comprises two phases. Early phase tolerance is transient, occurs within hours or days and is not associated with anti-endotoxin antibody production. Late phase tolerance requires several days to develop and is long lasting, antigen specific and the result of antibody production. By this mechanism it is possible for individual animals to survive a dose of endotoxin lethal to the nontolerant individual. Experimentally, horses develop endotoxin tolerance following sequential sublethal infusions of endotoxin.¹⁹

Hypersensitivity

A secondary effect produced by some toxins is the creation of a state of hypersensitivity at the first infection so that a second infection, or administration of the same antigen, causes anaphylaxis or an allergic phenomenon such as purpura hemorrhagica. Also, a generalized Schwartzmann reaction can be induced in pigs by an injection of E. coli endotoxin, especially if there are two injections properly spaced (in time). Pigs on a vitamin-E-deficient diet are much more severely affected than pigs on a normal diet. Vitamin E is protective; selenium is not.

Other infectious toxins

In mycoplasmosis (Mycoplasma mycoides var. mycoides), at least part of the toxic effect is attributable to galactans contained in the toxins. These have a noticeably local effect in causing hemorrhages in alveolar ducts and pulmonary vessel walls so that pulmonary arterial blood pressure rises as systemic blood pressure falls. Later lesions are pulmonary edema and capillary thrombosis, which are characteristic of the natural disease of pleuropneumonia. Disseminated intravascular coagulation is also a characteristic of the lesions associated with the toxin of Pseudomonas spp.

Acute toxemia

The clinical findings of acute toxemia in most nonspecific toxemias are similar. The syndrome varies with the speed and severity of the toxic process but the variations are largely of degree. Depression, anorexia and muscular weakness are common in acute endotoxemia. Calves do not suck voluntarily and may not have a suck reflex. Scant feces are common but a low-volume diarrhea may also occur. The heart rate is increased and initially the intensity of the heart sounds is increased, but later as the toxemia worsens the intensity may decrease. The pulse is weak and rapid but regular. A fever is common in the early stages of endotoxemia but later the temperature may be normal or subnormal. In neonatal calves, foals and lambs a fever may not occur because of failure of thermoregulation or deprivation of colostrum. Terminally, there is muscular weakness to the point of collapse and death occurs in a coma or with convulsions.

Endotoxemia

When toxin formation or liberation into the circulation is rapid and the toxicity of the toxin high enough, the onset of cardiovascular collapse is rapid enough to cause a state of ‘toxic’ or ‘septic’ shock. The remarkable clinical findings are:

The syndrome is discussed also in the section on Shock. Endotoxemia is most commonly associated with bacteremia or septicemia due to infection with Gram-negative organisms, especially E. coli.

The clinical findings of severe endotoxemia include:

Renal failure is common and is characterized by anuria. If DIC develops, it is characterized by petechial and ecchymotic hemorrhages on mucous membranes and sclerae with a tendency to bleed from venepuncture sites.

Chronic toxemia

Lethargy, separation from the group, inappetence, failure to grow or produce and emaciation are characteristic signs of chronic toxemia.

Localized infection

With localized infections there are, in addition to the general signs of toxemia, the clinical effects of the space occupation by the lesion. These are presented under Localized infections.

Hematology

Changes in total and differential leukocyte numbers occur in endotoxemia. Leukocytosis and neutrophilia occur with mild endotoxemia and leukopenia, neutropenia and lymphopenia increase in severity and duration with increasing severity of endotoxemia. Endotoxin-induced rebound neutrophilia may occur and is attributed to an accelerated release of neutrophils from the bone marrow reserve into the circulation through generation of the neutrophil releasing factor.

In experimental sublethal endotoxemia in foals 3–5 days of age, there is leukopenia followed by leukocytosis, hypoglycemia, increased prothrombin time and partial thromboplastin time, and mild hypoxemia.²⁰

Serum biochemistry

A low plasma glucose concentration, high serum urea concentration (nonprotein nitrogen), and a low serum albumin and total protein concentration are usually present in acute endotoxemia. Decreased albumin and total protein concentrations are in response to increased capillary permeability, whereas the azotemia reflects a decreased glomerular filtration rate. Adult herbivores have a mild hypocalcemia, hypomagnesemia and hypokalemia, and hypophosphatemia,²¹ which most likely reflects inappetence and decreased gastrointestinal tract motility.

In more chronic toxemic states, a high serum total protein concentration, with globulins noticeably increased on electrophoretic examination, is more common.

Endotoxin

Endotoxin can be detected in the whole blood of horses using a whole blood hemagglutination inhibition assay.²² However, sensitivity, specificity and predictive values are not high enough to be of routine use.

Removal of foci of infection

Removal of endotoxin before it can be absorbed is an important cornerstone of treatment in foals and calves with omphalophlebitis, horses with ischemic or necrotic bowel and lactating dairy cattle with coliform mastitis.

Antimicrobial agents

Bactericidal Gram-negative antimicrobial agents are always indicated whenever there is evidence of septicemia or a localized infection causing endotoxemia. The choice and route of administration will depend on the pathogens suspected of causing the infection and endotoxemia and the site of infection. The speed of kill of Gram-negative bacteria may be an important clinical issue, as antimicrobial agents with a rapid kill (such as moxalactam) can produce a bolus release of endotoxin into the blood stream by punching multiple holes in the bacteria, causing a rapid explosion of the bacteria due to osmotic fluid shifts and bolus release of endotoxin. Antimicrobial agents that alter the cell wall of Gram-negative bacteria can theoretically produce a bolus release of endotoxin when administered to animals with Gram-negative septicemia. On this basis, β-lactam antibiotics effective against Gram-negative bacteria should theoretically be avoided, however, clinical experience has not indicated deleterious effects following administration of β-lactam antibiotics. Moreover, coadministration of aminoglycosides blocks the potential bolus release of endotoxin by β-lactam antibiotics.²³ However, it is clinically prudent to ensure that whenever antimicrobial treatment is initiated in endotoxemic animals, that NSAIDs are administered concurrently.

Aggressive fluid therapy

The intravenous infusion of large quantities of fluids and electrolytes is a high priority in the management of endotoxemia.²⁴ Maintenance of peripheral perfusion is essential to any therapeutic regimen for treatment of endotoxic shock. Large volumes of isotonic fluids have been standard practice. Lactated Ringer’s solution or other balanced electrolyte solution must be given by intravenous infusion over several hours. A beneficial response is noted by the following:

It may be necessary to deliver fluids in amounts equivalent to 0.5–1.0 times the estimated blood volume of the animal over a period of several hours. Glucose should always be included in the infusion fluids because hypoglycemia, increased glucose utilization and inappetence are usually present.

Hypertonic solutions

The use of hypertonic saline, 7.5% NaCl, may enhance tissue perfusion and decrease the volume of subsequent fluids required for a beneficial response.²⁵ Experimentally, the use of hypertonic saline in sublethal E. coli endotoxemia in mature horses was associated with a more effective cardiovascular response than was an equal volume of isotonic saline solution. Cardiac output is increased and peripheral vascular resistance is decreased compared to results for isotonic saline controls. Hypertonic saline rapidly expands the plasma volume and increases preload by acting as an effective osmotic agent in the extravascular compartment, causing a translocation of fluid from the intracellular space and gastrointestinal tract.

Hypertonic sodium bicarbonate is widely used for the initial treatment of metabolic acidosis in endotoxemic adult horses. However, in horses with experimental endotoxemia, hypertonic sodium bicarbonate did not normalize blood pH, and it increased blood l-lactate concentrations and caused hypokalemia, hypernatremia and hyperosmolality.²⁶

Nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been in general use for the treatment of endotoxemia because of their analgesic, anti-inflammatory and antipyretic properties. NSAIDs suppress production of thromboxane and prostaglandins and reduce the acute hemodynamic response to endotoxemia. Although NSAIDs are routinely administered to endotoxemic animals, a large-scale study in humans with severe sepsis failed to demonstrate an effect of ibuprofen on mortality, despite improvement in a number of clinical indices and decreased production of arachidonic acid metabolites.²⁷

Flunixin meglumine is the NSAID most commonly used in the treatment of endotoxemia in horses and cattle²⁸ and remains the NSAID of choice for treating this condition. Flunixin meglumine is a potent inhibitor of cyclooxygenase and its action on this enzyme to inhibit the synthesis of eicosanoids such as prostaglandin E₂ may explain the anti-inflammatory action of the drug. Flunixin meglumine also modulates the acute hemodynamic changes and hyper l-lactatemia commonly seen during endotoxemia, which may increase survival rate. Endotoxin-stimulated production of thromboxane B₂ (a metabolite of thromboxane) and prostaglandin F_1α are blocked by flunixin meglumine at 0.25 and 0.10 mg/kg respectively,²⁹ which resulted in a widespread clinical use of an ‘anti-endotoxemic’ dose of 0.25 mg/kg. However, the term ‘anti-endotoxemic effect’ should be discouraged as it is misleading, and a dose rate of 1.1 mg/kg BW every 12 hours is recommended in horses. Care should be taken to ensure adequate hydration in endotoxemic animals receiving multiple doses of flunixin meglumine. Flunixin meglumine is usually given intravenously or intramuscularly in cattle at 1.1–2.2 mg/kg BW every 24 hours.³⁰ The oral administration of flunixin meglumine at 2.2 mg/kg BW prior to experimentally induced endotoxemia in cattle exerted an effect equal to that after intravenous administration by minimizing the fever and prostaglandin F_2α metabolite concentration induced by the endotoxin administration. However, flunixin meglumine did not prevent the decrease in peripheral mononuclear cells and polymorphonuclear leukocytes seen after endotoxin administration. The bioavailability of flunixin meglumine in cattle ranges from 53–60% in cattle and 80–86% in horses.³⁰

Flunixin meglumine was superior to prednisolone and dimethylsulfoxide in providing protection and mitigating the effects of experimental endotoxemia in calves but was only partially protective against the hypotension and hyper l-lactatemia and failed to alter the hypoglycemic effect.³¹ Although flunixin meglumine is the most widely used NSAID in endotoxemia, there is little experimental evidence demonstrating its efficacy over other NSAIDs. Ketoprofen, flunixin meglumine, ketorolac and phenylbutazone have been compared for treating experimental endotoxemia in calves.³² Each drug modified the response to endotoxin but none was clearly superior to the others in modulating the clinical signs. Phenylbutazone given to calves at 5 mg/kg BW/day intravenously for 5 days suppressed the clinical response to experimental endotoxin in neonatal calves with progressively increasing amounts of endotoxin until large amounts were given.³² There were no significant differences between ketoprofen and flunixin meglumine in in vitro studies of the effects of the drugs on equine peripheral blood monocytes.³³ An interesting finding in adult dairy cows with experimentally induced endotoxemia was that flunixin meglumine and phenylbutazone delayed the plasma clearance of endotoxin by 2–3 and 6–12 times respectively,³⁴ suggesting that both NSAIDs may prolong the clinical signs of endotoxemia in cattle, possibly by interfering with hepatic metabolism. The clinical significance of this finding is unknown.

Glucocorticoids

Glucocorticoids (corticosteroids) have been used extensively in the past for the treatment of endotoxemia and shock. The rationale for the use of glucocorticoids includes:

The corticosteroids most commonly used in endotoxic shock were hydrocortisone, prednisolone, methylprednisolone and dexamethasone. However, these corticosteroids have been most beneficial therapeutically when given as a pretreatment in experimental situations. Published evidence, based on controlled clinical trials, that corticosteroids are efficacious in naturally occurring cases of endotoxemic shock in farm animals appears to be lacking.

Glucocorticoids improve capillary endothelial integrity and tissue perfusion, decrease activation of complement and the clotting cascade, decrease neutrophil aggregation, stabilize lysosomal membranes, protect against hepatic injury and improve survival rate. However, there are concerns about their use in septicemic animals because they may cause immunosuppression. Large doses are required, which are cost-prohibitive in farm animals where they are used most commonly in acute cases and in doses such as 1 mg/kg BW of dexamethasone intravenously every 24 hours. It is currently believed that glucocorticoids, if they are to be clinically effective, must be given as early as possible to endotoxemic animals. Glucocorticoids are less frequently administered to endotoxemic animals as a result of a number of studies supporting the use of NSAIDs.

Inotropic agents and vasopressors

Critically ill neonates and adults may require the administration of positive inotropic agents and vasopressor agents. Inotropic agents increase cardiac contractility, thereby increasing cardiac output and oxygen delivery. Vasopressor agents increase systemic arterial blood pressure. Inotropic and vasopressive agents are usually administered for short periods of time during anesthesia or recovery from anesthesia.

Dobutamine (0.5–1.0 μg/kg BW/min in adults and 1–3 μg/kg BW/min in neonates) is the inotropic agent of choice.³⁵ Dobutamine should be diluted in 0.9% NaCl, 5% dextrose or lactated Ringer’s solution and the dose carefully titrated by monitoring heart rate and rhythm and blood pressure. Norepinephrine (0.01–1 μg/kg BW/min) is the vasopressor agent of choice in hypotensive animals that have not responded to intravenous fluid loading or dobutamine.³⁵ Norepinephrine should be diluted in 5% dextrose and the dose titrated as there is marked individual variability in the response to norepinephrine administration.

Polymyxin B

Polymyxin B is a cationic antibiotic that has an appropriate charge distribution to stoichiometrically bind to the lipid A moiety of lipopolysaccharide. Parenteral administration of antimicrobial doses of polymyxin can lead to nephrotoxicity, neurotoxicity and ototoxicity but lower, non-nephrotoxic doses are effective in ameliorating the effects of endotoxin in horses. Specific endotoxin binding agents such as intravenous polymyxin B are therefore theoretically of benefit and have shown efficacy in endotoxemic horses when administered at a recommended dose of 5000 U/kg administered at 8–12-hour intervals^36,37 but definitive efficacy studies have not been completed in endotoxemic calves or horses with naturally acquired endotoxemia. In particular, because the efficacy of polymyxin B is focused against circulating lipopolysaccharide before it is bound to lipopolysaccharide binding protein, it is currently believed that polymyxin B, like glucocorticoids, must be given as early as possible to endotoxemic animals if they are to be clinically effective. Attractive features of polymyxin B are its shelf life and ease of storage, ease of administration (intravenous bolus) cost and 8–12-hour duration of effect.³⁷

Antiserum

Hyperimmune serum is commercially available for the treatment of endotoxemia in the horse. The rationale is that anti-lipid A antibodies bind circulating lipopolysaccharide, thereby preventing the subsequent inflammatory cascade. However, on theoretical grounds it is difficult for an antibody to competitively inhibit the strong binding affinity and high specificity between lipopolysaccharide and lipopolysaccharide binding protein. There are also difficulties with spatial hindrance between immunoglobulin (Ig)G and the R-core subfraction of lipopolysaccharide that contains lipid A. It is therefore difficult to believe that antiserum against core lipopolysaccharide antigens will ever be therapeutically successful in animals with naturally acquired endotoxemia, and large-scale studies in septic humans have failed to observe a decrease in mortality following the administration of hyperimmune core-lipopolysaccharide plasma. However, the administration of antiserum has many theoretical advantages separate from those of endotoxin neutralization, and it may be that plasma transfusion alone is beneficial.

The use of antiserum to the rough mutant of E. coli 0111:B4(J–5) as a treatment of experimental or naturally acquired endotoxemia has been demonstrated in some, but not all, studies in adult horses^38,39 but not in foals and calves.⁴⁰ One study in foals indicated that administration of hyperimmune serum resulted in a worsening of the clinical signs and augmented release of TNF-α and interleukin-6.⁴¹ Antiserum does not appear as rational a treatment for neutralizing circulating lipopolysaccharide as polymyxin B and, for this reason, the administration of hyperimmune serum should probably be reserved for animals that fail to improve after polymyxin B administration.

Anticoagulants

Disseminated intravascular coagulation (hypercoagulative states) can be treated with heparin in an attempt to impair intravascular coagulation. Much of the knowledge regarding DIC in endotoxemia has been extrapolated from species other than large animals, and there is little objective information available to guide the clinical use of anticoagulants in endotoxemic large animals. Instead, the focus of treatment should be aggressive intravenous fluid administration in order to maximize microcirculation.

Hematology

A leukopenia, neutropenia and degenerative left shift occur in acute cases and the degree of change parallels the severity of the disease and reflects the absorption of endotoxin from the uterine lumen.

Vaginal/uterine fluid

Samples of fluid from the vagina and uterus reveal a mixed bacterial flora including E. coli, Proteus spp., A. pyogenes, Staphylococcus spp. and Streptococcus spp., with the predominant bacteria varying mainly with time since parturition. In general, E. coli predominates in the first 5 days after parturition, whereas A. pyogenes and F. necrophorum predominate after the first 5 days in cattle with retained placenta.^8,9 Uterine lochia of cattle with retained placenta had a much higher endotoxin concentration in the first 2 days post partum than did lochia of healthy cattle or cattle that had undergone a dystocia but did not have retained placenta. Endotoxin was not detected in the plasma of cattle with high lochial endotoxin concentrations, indicating effective systemic clearance.⁸

Other samples and tests

Ketonuria may occur in animals that are overconditioned and mobilize excessive quantities of depot fat, resulting in ketosis. Liver function tests reveal a decrease in liver function, which may be irreversible in excessively fat cows.

The fat cow syndrome

This is characterized by excessive body condition, anorexia to inappetence, ketonuria, a marked loss in milk production, decreased rumen movements and delayed involution of the uterus. The temperature is usually normal but the heart and respiratory rates may be increased. The prognosis is poor in cows that are totally anorexic; those that are inappetent will usually recover after 5–7 days of supportive therapy.

Acute diffuse peritonitis

This may occur in cows within a few days postpartum and is characterized by anorexia, toxemia, a spontaneous grunt or one that can be elicited by deep palpation, rumen stasis, fever and the presence of an inflammatory exudate in the peritoneal fluid.

Peracute and acute mastitis

This occurs in cows within a few days after parturition and is characterized by severe toxemia, swelling of the affected quarters and abnormal milk.

Conservative therapy

Uncomplicated cases of retained fetal membranes without any evidence of clinical toxemia usually do not require parenteral or intrauterine treatment. The placenta will usually be expelled within 4–6 days. Cows with retained fetal membranes and tenesmus should be examined vaginally to ensure that there is no evidence of injury to the vagina or cervix. In cows with tenesmus, if the placenta is detached and loose it should be removed by careful traction. Forceful removal of the placenta should be avoided.

Antimicrobial agents

Cows with retained fetal membranes but without systemic illness should be monitored but treatment with antimicrobial agents is not indicated. Antibiotic treatment with oxytetracycline (10 mg/kg BW, daily) before placental shedding delays detachment of the placenta; this finding is consistent with the concept that intrauterine bacterial infection facilitates placental detachment.⁹

Cows with retained fetal membranes complicated by septic metritis and toxemia should be treated with antimicrobial agents daily for several days or until recovery occurs. Death can occur in untreated animals. Because of the mixed bacterial flora in the postpartum uterus with a retained placenta, broad-spectrum antimicrobials are recommended. Intramuscular procaine penicillin (22 000 U/kg BW every 24 h), subcutaneous ceftiofur (2.2 mg/kg BW every 24 h), intramuscular ampicillin (10 mg/kg BW) and intravenous oxytetracycline (11 mg/kg BW every 24 h) are commonly administered for several days until recovery is apparent.^10,11 Ceftiofur increases the cure rate and milk yield, and decreases rectal temperature, when administered to dairy cows with fever and vaginal discharge or dystocia.¹² Subcutaneous administration of ceftiofur (1 mg/kg BW) achieved concentrations of ceftiofur derivatives in uterine tissue and lochial fluid that exceeded the reported minimal inhibitory concentrations for common metritis pathogens.¹³ Ampicillin increased the pregnancy rate and decreased the cure rate, compared to ceftiofur, in cattle that were also treated with intrauterine ampicillin and cloxacillin.¹⁴ In general, oxytetracycline use should be confined to the first 5–7 days post partum when E. coli predominates, as it is likely to be ineffective against A. pyogenes in the endometrium. Oxytetracycline at 30 mg/kg BW intravenously as a single dose in cows with retained fetal membranes resulted in concentrations of the antimicrobial in uterine secretions, placenta and cotyledon for 32–36 hours.¹⁵ Two intramuscular injections of oxytetracycline at 25 mg/kg BW resulted in lower peak concentrations, but these were maintained for 144 hours. Parenteral oxytetracycline appears to decrease endotoxin production, as indicated by the severity of leukopenia in cattle with retained placenta.⁹

In severely affected cases, large amounts of balanced isotonic crystalloid fluids, electrolytes and glucose by continuous intravenous infusion may be necessary and often result in a marked beneficial response within 24–48 hours. The uterus should always be examined by palpation per rectum and vaginally to determine the degree of uterine involution, the thickness of the uterine wall, the volume of the uterus, the nature of the luminal contents and the degree of attachment of the placenta to the cotyledons. This can be done daily to assess progress. Uterine fluids should be drained by creating a siphon, if sufficiently liquid in nature, although care must be taken to ensure that the tube does not penetrate a friable uterine wall. If parenteral antimicrobial and supportive therapy is provided the placenta will invariably be expelled within 6–8 days and usually within 4–6 days. The use of antimicrobial agents must be accompanied by appropriate withdrawal periods for the milk produced by treated animals.¹⁶

Intrauterine medication

The necessity for intrauterine medication is controversial. There is limited evidence, if any, that the intrauterine infusion of antimicrobial agents with or without lytic enzymes and estrogens has any beneficial effect in the treatment of postpartum septic metritis. Nevertheless, a wide variety of antimicrobial agents have been used for intrauterine medication for retained placenta and metritis in cows, although in general, β-lactam-resistant antibiotics should be administered because the uterine lumen can contain β-lactamase-producing bacteria. Intrauterine infusion of 0.5 g of the first-generation cephalosporin cephapirin improved the reproductive performance, but only when administered after 26 days in milk.^17,18 Intrauterine infusion of 1 g of the third-generation cephalosporin ceftiofur in 20 mL of sterile water once between 14 and 20 days of lactation had no effect on reproductive performance but decreased the risk of culling and increased the time to culling.¹⁹ Tetracycline products (5–6 g) are commonly used but should be administered as a powder dissolved in an appropriate volume of 0.9% NaCl, as vehicles such as propylene glycol can irritate the endometrium. Infusion of oxytetracycline decreases lochial odor and the incidence of fever in cattle with retained placenta.²⁰ In cattle with retained placenta, intrauterine administration of a povidone-based oxytetracycline solution (5 g daily until expulsion) combined with fenprostalene (1 mg subcutaneously) did not alter the time to detachment of the placenta but increased the frequency of pyometra;²¹ this finding was consistent with the concept that intrauterine bacterial infection facilitates placental detachment.⁹ Milk from cows treated by intrauterine infusion of antimicrobial agents should be discarded for an appropriate period of time in order to avoid illegal residues.¹⁶

Intrauterine administration of antiseptics (povidone iodine, chlorhexidine, hypertonic saline) has been done but studies demonstrating efficacy are lacking.

Ancillary treatment and control

Portions of retained placenta protruding from the vagina should be wrapped in a plastic rectal sleeve to minimize wicking of fecal bacteria after defecation, although this supposition has not been verified. Alternatively, protruding remnants of placenta can be excised, although this may prolong to the time to expulsion because the decreased weight may interfere with traction on the remaining placenta in the uterine lumen. Complete manual removal is often requested by the producer but is not recommended because studies have not demonstrated its efficacy.

The infusion of collagenase solution (200 000 U dissolved in 1 L of 0.9% NaCl containing 40 mg calcium chloride and sodium bicarbonate) into the umbilical arteries within 12 hours of parturition is an effective treatment for retained placenta. Collagenase injection therefore provides an effective method for preventing septic metritis in cattle with retained placenta. However, the collagenase solution is expensive, not widely available and the technique is difficult in some animals because of difficulty in identifying intact umbilical arteries for injection. As a result, collagenase injection is rarely performed in clinical veterinary practice. The efficacy of umbilical artery infusion with antimicrobial agents has not been adequately evaluated.

Ecbolic drugs have been proposed for the prevention and treatment of retained placenta in cattle. These include prostaglandins, ergot derivatives, oxytocin and β₂-adrenoceptor antagonists.²² The rationale for their use is that they stimulate uterine contractions and physically aid in the expulsion of the fetal membranes. In general, the consensus is that they are ineffective after the diagnosis of a retained placenta is recognized. However, their use may be effective if used immediately after calving. In particular, the frequent intramuscular administration of oxytocin appears to provide the most effective means of preventing metritis, with a recommended protocol of 20 IU every 3 hours for postpartum days 0–3, 30 IU every 2 hours for postpartum days 4–6 and 40 IU every 2 hours for postpartum days 7–10.²³ A large study found that intramuscular injection of oxytocin (30 IU) immediately after parturition and 2–4 hours later decreased the incidence of retained placenta and the calving-to-conception interval.²⁴ Fenprostalene at 1 mg subcutaneously, 25 mg dinoprost tromethamine intramuscularly, or 20 IU oxytocin given to a large number of dairy cows in five commercial dairy herds did not reduce the incidence of retained fetal membranes or improve reproductive performance.⁶ A detailed review failed to identify any evidence supporting the use of estrogen or prostaglandins in the first 7–10 days post partum.²³

The finding that retained placenta can be caused by neutrophil dysfunction at calving⁷ provides the basis for epidemiological evidence that deficiency of trace minerals or vitamins (such as selenium and vitamin E) is associated with an increased incidence of retained placenta. In regions deficient in selenium, supplementation of the diet up to 0.3 ppm can decrease the incidence of retained placenta in herds that are fed a total mixed ration. Selenium can also be administered by intraruminal boluses or parenteral administration of vitamin E/selenium preparations during the dry period.