Chapter 4 Alterations in Body Temperature
CONTROL OF BODY TEMPERATURE
Mammalian species maintain core body temperature within a narrow range despite extremes in environmental conditions. Core body temperature is not constant but exhibits diurnal variation. The normal range of temperature for individuals within a species may vary by as much as 1° C (2° F).
Maintenance of body temperature is under neuronal control in a negative feedback system. Warm- and cold-sensitive neurons within the hypothalamus sense existing core body temperature via peripheral nerve receptors and blood bathing the hypothalamus. Integrative structures located in the preoptic region of the anterior hypothalamus (POAH) that act similarly to a thermostat with a desired “set point” recognize temperatures as either too low or too high and activate both behavioral and autonomic effector responses to either lose or gain heat (Fig. 4-1).1
Heat production occurs primarily from muscle activity, which can vary according to need. Muscle activity may range from inapparent contractions to generalized shivering. Digestion of food also contributes significantly to total body heat and may be clinically important as a means of heat production in ruminants both in low environmental temperatures and in high temperatures when the threshold for heat stroke may be lowered. Heat conservation occurs from adrenergic autonomic stimuli to decrease peripheral circulation and cause piloerection. Behavioral means of heat conservation include adopting a “huddled” posture, group aggregation, and seeking a sheltered environment.
Heat loss occurs from conduction, convection, and radiation from body surfaces and by evaporation. Sympathetic vasodilation of cutaneous vessels contributes to surface cooling. As ambient temperature rises, evaporative heat loss becomes more important. In ruminants evaporative heat loss is confined to the respiratory system; respiratory rate increases concurrently with temperature. In horses, sweating aids evaporative heat loss. Behavioral responses that contribute to heat loss include seeking shade and wind currents and wading into water.
CONDITIONS OF INCREASED BODY TEMPERATURE
Body temperature disorders in which the core body temperature set point is unaltered can occur from increased heat production, absorption of heat, or impairment of heat loss. Central nervous system disorders that disturb the hypothalamic regulatory center, certain drugs, and metabolic disorders may also cause temperature changes. Phenothiazine tranquilizers are a recognized cause of loss of ability to control body temperature.2 Erythromycin may induce hyperthermia during hot weather, particularly in foals.3 Hyperkalemic periodic paralysis of horses has also been associated with episodes of hyperthermia.4
Exercise
During sustained exercise, heat production may exceed the ability of heat loss mechanisms, leading to a stable increase in core body temperature proportional to the intensity and duration of exercise. The elevation in temperature often persists for several hours after exercise, but temperature returns to normal with rest as heat loss mechanisms remain activated. Body temperatures during exercise greater than 2° C (4° F) above normal, especially if reached early in exercise, are usually the result of severe environmental conditions and/or failure in heat loss mechanisms. Peripheral cooling to augment heat loss should be used to lower body temperature, as increases in temperature caused by exercise are unaffected by antipyretic drugs.2,5,6
The intense muscular activity associated with generalized tonic clonic seizures may, like vigorous exercise, cause a rise in body temperature. If central heat regulatory systems are unaffected by the disease process, body temperatures return to normal no longer than 48 hours after the last seizure.7 Elevated temperatures that persist for longer periods should prompt investigation into other causes for the increased temperature.
Malignant Hyperthermia
Malignant hyperthermia consists of a group of inherited skeletal muscle calcium metabolism disorders in which a hypermetabolic state of muscle is induced by the administration of halogenated inhalation anesthetics, depolarizing skeletal muscle relaxants, or, occasionally, local anesthetics. Although malignant hyperthermia is most common in humans and pigs, it has been reported in horses.8-11 Mutation of the ryanodine receptor 1 gene, which is essential in skeletal muscle excitation-contraction coupling, is the basis of malignant hyperthermia in humans, pigs, and dogs. Mutation of this gene has been documented in two horses with malignant hyperthermia.12 Rapid increase in core body temperature (39° C to 42° C), skeletal muscle rigidity, tachycardia, metabolic acidosis, and muscle necrosis may lead to death.
Ergopeptine Alkaloid Toxicosis
Tall fescue infected with the endophyte Neotyphodium coenophialum contains vasoactive ergopeptine alkaloids that cause vasoconstriction and reduced blood flow to the skin of ruminants. These alkaloids also induce bronchoconstriction and pulmonary vasoconstriction, which further compromise ruminants’ ability to lose heat, especially during hot environmental conditions. Affected animals have a poor appetite and other indications of poor performance recognized as part of the syndrome of fescue toxicosis or “summer slump.”13 A related endophyte infesting perennial ryegrass has been found to produce a similar hyperthermic condition in the western United States.14 Claviceps purpurea infestations of annual or perennial ryegrass and of cereal grain heads have also been reported to produce a similar hyperthermic syndrome, which may lead to heat prostration and death when ambient temperatures are high.15-17
Cattle affected by any of these ergopeptine alkaloids have few to no clinical signs when environmental conditions are cool and heat loss mechanisms are not challenged. It is not yet known, however, if all of the effects of the alkaloids are peripheral or if they may also act within the central nervous system.13
Heat Stroke
When animals are exposed to high ambient temperatures, intense solar radiation, and/or high humidity so that heat load increases at a rate faster than heat can be dissipated, heat stroke may develop. Heat stroke is more common in ruminants because of their inability to sweat and thus their diminished evaporative ability for heat loss. Sheep with fleece and large dense cattle are especially prone to heat stroke when denied access to shade or adequate water and/or when physical activity is imposed on them. Rectal temperature will often exceed 41.5° C (107° F), and central body temperature may exceed 44.5° C (112° F). Horses continuously exercised in high heat and humidity may also develop heat stroke. Evaporative heat loss from sweating is the most important means of heat loss as metabolic heat production increases during exercise, especially as ambient temperature and humidity increase.18 Efficiency of evaporative heat loss diminishes when temperature and humidity are high and there is a significant radiation component resulting from strong sunshine.19 Horses’ susceptibility to heat stroke is enhanced if dehydration and electrolyte imbalances occur because of large losses of sweat (see Exhaustion in Endurance Horses, Chapter 42).
As rectal temperature increases above 41.5° C (107° F), the homeostatic mechanisms of temperature regulation fail; peripheral vasoconstriction, decreased blood pressure, and decreased cardiac output occur. The animals are lethargic and have weak, flaccid muscles; prostration and shock occur rapidly. Disseminated intravascular coagulation, liver damage, renal failure, and myocardial necrosis are frequent complications.
Anhidrosis
As many as 25% of horses in hot, humid environments lose their ability to sweat and subsequently suffer from hyperthermia as a result of impairment of heat loss.20 Horses in training have been reported to have a higher frequency of anhidrosis, as are horses shipped to hot environments from more temperate regions; however, horses indigenous to hot, humid areas that perform less rigorously or not at all may also develop anhidrosis.21,22 In addition to hyperthermia, clinical signs are poor performance, total or partial loss of ability to sweat, increased respiratory rates (three to five times normal), and dry, thin hair coats with areas of alopecia (see also Anhidrosis, Chapter 41).
Diseases of the Nervous System
Central nervous system disorders that damage areas of the hypothalamus associated with temperature regulation may lead to either decreases or increases in body temperature, although hypothermia is most common. Hemorrhage, space-occupying masses (abscesses, tumors), infectious or inflammatory diseases, and degenerative disorders have all been implicated in hyperthermia. Central hyperthermia is usually characterized by lack of diurnal variation, absence of sweating, resistance to antipyretic drugs, and excessive response to external cooling.1,2
Certain toxins and drugs may act to increase body temperature by causing an increase in metabolic work (Boxes 4-1 to 4-3). Chlorophenols and nitrophenols, used as herbicides and wood preservatives, cause uncoupling of oxidative phosphorylation within mitochondria and lead to rapid extreme rises in body temperature.23 Chronic and/or low-level exposure to these compounds may manifest clinically as hyperthermia.
FEVER
True fever differs from other hyperthermic states in that the desired core body temperature or set point is elevated. This new, higher set point is vigorously defended by the same mechanisms that maintain body temperature in health. Initiation of the febrile state can occur by a variety of infectious, inflammatory, immunologic, neoplastic, or injurious conditions. In the classic model of fever these stimuli cause the production of multifunctional pyrogenic cytokines by a wide variety of cells, but primarily by fixed or circulating monocytes and macrophages (Fig. 4-2). Currently at least 11 cytokines have been shown to induce the febrile response in humans and animals. Of these cytokines, interleukin 1 (IL-1α, IL-1β) and tumor necrosis factor alpha (TNF-α) are the most potent. Each of these cytokines induces others and stimulates the production of other pyrogenic cytokines (IL-6, interferon [IFN-α, IFN-β, IFN-γ], ciliary neurotropic factor [CNF], and IL-11) that signal cells through a common receptor (glycoprotein 130). Pyrogenic cytokines reach the POAH via the circulation and attach to receptors on the endothelium of the capillaries of the circumventricular vascular organs (CVVOs), which induce the production of arachidonic acid and its metabolism to prostaglandin E2 (PGE2), by the cyclooxygenase (COX)-2 pathway. PGE2, produced on the brain side of the CVVOs, binds to PGE2 type 3 receptors of glial cells and possibly neuronal cells to initiate neuronal signaling by producing a cascade of changes in cyclic nucleotides, calcium, and neurotransmitters that result in a higher “set point” within the hypothalamic thermoregulatory center24,25 (see Fig. 4-2). COX inhibitors, and specifically COX-2 inhibitors, effectively reduce the febrile temperature to normal but have no effect on normal body temperature.2,25
Fig. 4-2 Pathogenesis of fever. OVLT, Organum vasculosum laminae terminalis endothelium; TLRs, toll-like receptors.
This model, however, does not fully explain the presence of fever, because specific blockade of IL-1 or TNF-α activity does not diminish the febrile response to lipopolysaccharide (LPS) or other microbial products in experimental studies or in patients with natural infections. Microbial products from a variety of agents bind to toll-like receptors (TLRs) on the surface of cells. Toll-like receptors and IL-1 receptors share the same signaling areas and, along with other pyrogenic cytokines, a common pathway to activate nuclear factor (NF)–κB. Activated NF-κB in turn results in expression of COX-2 or COX-3 and PGE2 synthesis. Mice deficient in COX-2 and injected with LPS, IL-1, TNF-α, or IL-6 either intravenously or within the central nervous system do not develop a fever.25 Thus the induction of COX-2 and the subsequent production of PGE2 provide a common pathway for divergent pyrogens to produce the febrile response (see Fig. 4-2).
There is an apparent role for the vagal nerve in the production of the febrile response. Studies in laboratory animals in which the hepatic branch of the vagus nerve is severed have shown diminution of the febrile response to a relatively low dose of intraperitoneally injected LPS but not intramuscularly administered LPS or high-dose intraperitoneally injected LPS. Local production of cytokines may stimulate primary hepatic vagal receptors that, via vagal afferent fibers and A1/A2 noradrenergic cell groups in the brainstem, release noradrenaline, which subsequently induces the production of PGE2 and fever.26
In addition to a rise in body temperature, the febrile state is accompanied by a variety of metabolic, hematologic, and immunologic changes. IL-6 and IL-11, induced by IL-1α, IL-1β, and TNF-α, induce the synthesis of fibrinogen, C-reactive protein, haptoglobin, ceruloplasmin, and certain macroglobulins, known collectively as acute phase proteins, by hepatocytes. In addition, these cytokines mediate the accompanying hypoferremia, hypozincemia, and hypercupremia of the acute phase response. Pyrogenic cytokines stimulate the activation and proliferation of T-lymphocytes and of antibody-producing B lymphocytes which, in turn, produce additional cytokines that both enhance and inhibit further production of pyrogenic cytokines.27,28 Pyrogenic cytokines, particularly IL-1 and TNF-α, cause membrane perturbation in a variety of body tissues, with a resultant increase in phospholipases and the production of arachidonic acid. Subsequent production of mediators is dependent on the metabolic pathways for arachidonic acid in the target tissue. Prostaglandins induced by pyrogenic cytokines have been shown to stimulate the muscle catabolism associated with fever and to induce collagenase synthesis from synovial cells.29 These processes contribute to the muscle and joint pain associated with fevers that are relieved by COX inhibitors. Lymphocyte and granulocyte response to IL-1 has been shown to be blocked by inhibitors of lipoxygenase but unaffected by indomethacin.27 Local tissue responses to IL-1β and TNF-α may stimulate afferent neural impulses that are responsible for many of the behavioral changes (increased sleep, decreased appetite, and loss of social behavior) associated with fever. Transection of the visceral vagal afferents has been shown to attenuate febrile behavioral responses, but not the associated temperature elevation, to high-dose intraperitoneal LPS injection in rats.30
Physiologic control of the febrile response is multifactorial and prevents extreme elevations in body temperature that are incompatible with life in most instances. TNF-α inhibits further production of itself. IL-1 and other inhibitory cytokines stimulate the production of IL-1 receptor agonist, which prevents further binding of IL-1. In addition, one of the receptors on cell surfaces for IL-1 (type II receptor) does not result in cell signaling and is thought to serve as a “decoy” receptor to decrease the concentration of IL-1.31 IL-10, induced by pyrogenic cytokines, inhibits IL-1, TNF, and IL-6 production and suppresses the production of IL-2 and IFN-γ by T-helper cells.31,32 Circulating pyrogenic cytokines may be bound to carrier molecules that reduce or prevent the interaction with receptors. For example, IL-1β has been shown to bind to α2-macroglobulin, a protein increased during the acute phase response.1 Glucocorticoids inhibit the transcription of numerous genes encoding the pyrogenic cytokines IL-1β, Il-6, and TNF-α. Within the brain both arginine vasopressin (AVP) and alpha melanocyte stimulating hormone (αMSH) act as potent antipyretic agents. Receptors for AVP, which acts as a neurotransmitter within the brain, are found lateral to the PAOH and decrease fever in both natural and experimentally induced fever, whereas injection of AVP receptor antagonist elevates fever and delays defervescence.33,34 αMSH binds to local melanocortin receptors within the brain and on cell receptors of immune cells to decrease fever and inflammation. When administered systemically to humans, αMSH is 20,000 times more potent on a molar basis than acetaminophen in decreasing fever from endogenous pyrogens.34 In the brain, nitric oxide (NO), by activating soluble guanylate cyclase and increasing cyclic guanosine monophosphate (cGMP) levels, participates in regulation of body temperature. Intracerebral ventricular injection of NO donors depresses fever in rats, whereas inhibition of NO synthesis within the central nervous system enhances fever.31
In summary, the occurrence of fever during disease results from a complex interaction of multiple cytokines and microbial products that act locally (site of tissue injury), systemically (in the circulation) and in the POAH of the brain and affect the immune, endocrine, and nervous systems.
Beneficial Effects of Fever
Body temperature elevation in pyrogenic mediated fevers, in contrast to hyperthermic states, rarely exceeds 2.5° C (5° F) above normal. Although the severity of some viral infections is decreased at these temperatures, most pathogens are not affected by a modest rise in temperature. Studies on bacterial infections in fish, lizards, rabbits, and humans, however, have shown an increase in survival correlated with the presence of fever.2,35,36 One well-studied effect of fever on bacterial proliferation is the effect of hypoferremia. Bacteria, which require iron for multiplication, are inhibited by the reduced availability of iron during the acute phase reaction. This response is augmented by the increased susceptibility of bacteria to low iron at higher temperatures.37,38 Certain neoplastic cells are inhibited during fever, although it is likely that inhibition of neoplastic cell division results from augmentation of immune responses.
Literature on the effect of fever is conflicting owing to the multiple variables present in in vivo studies and the application of heat in temperature ranges exceeding those of natural fevers in in vitro studies. Enhancement of host defenses, however, appears to be the primary beneficial effect of fever. Fever or heat applied in in vitro studies within the physiologic range of natural fevers has a beneficial effect on multiple processes of the adaptive immune response. Neutrophils and monocytes have increased motility and emigration, enhanced phagocytosis, increased oxygen radical production, and enhanced killing of intracellular bacteria. IFN production increases, and its antiviral, antitumor, antiproliferative, and natural killer (NK) cell—stimulating properties are enhanced. Increased T-cell proliferative responses to nonspecific mitogens IL-1 and IL-2, and enhanced T-helper cell activation, expression, recruitment, and cytotoxicity have all been correlated with fever. Enhancement of B cells, with a subsequent increase in production of antibodies, and enhanced expression of Fc receptors occur during fever.39
Activity of pyrogenic cytokines is also influenced by temperatures achieved during fever. For example, in a mouse-endotoxin model, fever enhanced the early expression of TNF-α but limited the duration of its expression. Production of IL-1β was delayed, whereas that of IL-6 (which downregulates production of TNF-α and IL-1β) was enhanced, preventing the simultaneous expression of TNF-α and IL-1β and the potential harmful effects of their simultaneous expression.40 Other studies have demonstrated that the effect of fever on various cytokines is specific for each cytokine and specific to body compartments. Thus fever is an important component of the coordinated and specific cytokine response of the host to various inflammatory stimuli.1,28,39
Adverse Effects of Fever
The beneficial effects of fever during bacterial infections in rabbits have been shown to reverse at temperatures greater than 3° C (5° F) above normal. Cytokine disregulation may result in prolonged or extreme fevers with adverse effects on a variety of body functions in addition to the immune response. Catabolic metabolic processes during fever are markedly different from catabolism of starvation. Protein loss occurs four times as rapidly in individuals with infectious or inflammatory diseases as compared with starvation-adapted individuals. Ketonemia is inhibited, resulting in the oxidation of large amounts of muscle-derived amino acids for energy. This cytokine-driven catabolism, combined with the decreased feeding behavior that accompanies fever, variable anorexia (even if feed is provided), and increased metabolic rate at higher temperatures, can result in rapid and severe muscle wasting, weakness, and atrophy. In humans high fevers frequently cause seizures, especially in children,2 but this is rare in animals unless temperatures reach 42° C (108° F) in neonates. Prolonged high fevers in debilitated animals may lead to failure of the cardiovascular system.
Fever is one of the earliest and most prominent manifestations of the acute phase reaction. Veterinarians have used the clinical thermometer to aid in diagnosis and to monitor the progress of illness in animals since 1770. With the increased knowledge of the pathogenesis of fever has come a better appreciation for the diverse causes of the febrile state. In ruminants and horses, however, infectious disease remains the most common reason for development of fever (Boxes 4-4 and 4-5). Careful evaluation for the presence of infectious disease is always indicated, especially when the onset of a fever is abrupt; the temperature is >39.4° C (103° F); and the fever is accompanied by depression, variable loss of appetite, serous nasal exudate, epiphora, enlargement of lymph nodes, or diarrhea and a decreased or increased leukocyte count. Other causes of fever are neoplasia (Boxes 4-6 and 4-7), immune-mediated diseases (Boxes 4-8 and 4-9), noninfectious inflammation (Boxes 4-10 and 4-11), and certain drugs.
FEVERS OF UNKNOWN ORIGIN
Most febrile illnesses encountered in large animal practice are caused by infectious diseases that are readily diagnosed by careful evaluation of history and physical examination or are of short duration, run their course, and progress to complete recovery within 2 weeks without a specific etiologic diagnosis having been made. Some febrile conditions, however, continue for weeks or months, accompanied only by nonspecific signs of depression, variable anorexia, and weight loss, while the diagnosis remains obscure. Patients with prolonged febrile episodes of 3 weeks’ duration or longer in which a diagnosis has not been made after a week of routine diagnostic efforts or after 3 days of hospitalization and diagnostic tests are considered to have fever of unknown origin (FUO). The majority of cases that meet the definition of FUO have infectious causes. Neoplastic diseases, immune-mediated vasculitides, and autoimmune diseases are the next most common causes. Adverse drug reactions and other miscellaneous diagnoses are the least common documented causes of FUO. Most cases of FUO are caused by common diseases with an unusual presentation; an ordered, problem-oriented approach to diagnosis will render a diagnosis in 90% of cases.37,41 The following steps are suggested (Fig. 4-3).
Document Fever
A temperature chart consisting of at least twice daily determination of rectal temperature should be completed to characterize the fever pattern. Intermittent fevers are characterized by diurnal variation in which a peak elevation of temperature of >0.75° C (1.5° F) occurs, followed by a decline in temperature, which in some patients falls within the normal range. Most intermittent fevers peak in late afternoon or evening, with the lowest temperatures occurring in the morning; but approximately 10% of cases will have a reverse pattern. Intermittent fever is most commonly associated with pyrogenic infections, although it may occur in neoplasia, especially if tissue necrosis and inflammation are concurrent. Remittent fevers are characterized by a period of days in which elevated temperatures occur, followed by several days of normal temperature, only to have the cycle repeat again. Brucellosis in ruminants, equine infectious anemia (EIA) in horses, and blood-borne protozoal diseases such as babesiosis may exhibit this type of pattern. Sustained fevers are characterized by a consistently raised temperature without variation and appear as a “flat line” on a temperature chart. Fevers caused by drug administration and certain toxins may be of this type, especially if the patient does not exhibit any other signs of illness.2 Any pharmacologic agents being administered to the patient should be discontinued. Defervescence of fever from drug administration should occur in 48 hours.
Consideration of Epidemiology
Repeated efforts to obtain a complete history in chronologic order of development of clinical signs may be necessary to extract all the information pertaining to the individual animal. A knowledge of forage available, presence of nutrient deficiencies and excesses, toxic plants, and infectious organisms indigenous to the area, as well as the threat of exotic diseases, is necessary for the present and past geographic environment of the animal.
Physical Examination
A physical examination (see Chapters 1 and 2) should be carefully performed to evaluate all body systems as thoroughly as possible and repeated as often as practical, because it is unusual for a disease to cause a prolonged fever without the occurrence of some physical signs. Examination should include the following:
Diagnostic Aids (Table 4-1)
All cases of FUO should have a laboratory database consisting of a complete blood count (CBC), urinalysis, and biochemical profile. The CBC should include morphology of red blood cells and white blood cells (WBCs), WBC differential, and fibrinogen determination. Chronic inflammatory disease produces characteristic changes in the CBC (see Chapters 24 to 26), and morphologic evaluation of the blood smear may reveal blood-borne parasites.
Table 4-1 Fever of Unknown Origin: Diagnostic Procedures
| Procedure | Indications |
|---|---|
| Abdominocentesis | Abdominal pain Abnormal rectal examination (e.g., mass) Fluid wave on ballottement or ultrasonography |
| Biopsy | Enlarged lymph nodes or other mass found Abnormal renal or liver function test results Vesicular or ulcerative skin lesions |
| Blood culture | Intermittent fever, especially in a neonate with failure of passive transfer Neutropenia or neutrophilia ± bands Increased fibrinogen Cardiac murmurs (bacterial endocarditis) |
| Radiography | Any musculoskeletal pain, heat, swelling Thorax, see transtracheal aspirate |
| Synovial fluid aspirate | Joint effusion, heat, pain |
| Thoracocentesis | Abnormal percussion of chest Fluid line thoracic radiographs Fluid found on ultrasonography |
| Transtracheal aspirate | Persistent cough or nasal exudate with normal upper respiratory tract Abnormal auscultation or percussion of thorax Persistent increased respiratory rate |
| Bronchial alveolar lavage | Exercise intolerance with normal cardiovascular system |
| Immunodiagnostic screening | |
| Serum protein electrophoresis | Abnormal serum protein |
| Serum protein immunoelectrophoresis | Hypergammaglobulinemia Hypogammaglobulinemia (horses) |
| Direct Coombs’ test | Hemolytic anemia RBC autoagglutination |
| Skin biopsy direct immunofluorescence | Vasculitis, purpura Bullous or ulcerative skin lesions |
| Antinuclear antibody | Multiple noninfectious arthritis |
| ECG | Dysrhythmia, congestive heart failure |
| Bone marrow aspiration | Anemia Thrombocytopenia |
| Gastrointestinal absorptive tests (horse) | Hypoproteinemia with normal kidney, liver |
| Serology | Persistent undiagnosed disease |
| Exploratory laparotomy | Abnormal rectal examination, ultrasonography Chronic abdominal pain Abnormal peritoneal fluid |
| Ultrasonography | Cardiac murmurs, dysrhythmias Abnormal liver or kidney function tests Abdominal mass Suspect fluid in thorax, pericardium, abdomen |
ECG, Electrocardiogram; RBC, red blood cell.
Serum protein and albumin determinations characterize either hypoproteinemia or hyperproteinemia. Serum protein electrophoresis and immunoelectrophoresis further classify deficiencies or increased production of proteins. Serum enzyme determinations and bile acid concentration for liver evaluation are also warranted.
Because much of the abdomen is unavailable to rectal palpation, abdominocentesis and evaluation of peritoneal fluid for protein, cellularity, and cell morphology are justified. Peritoneal fluid is obtained more consistently in horses than in ruminants with abdominal disease because of the presence of the greater omentum and the rapid formation of fibrinous adhesions in ruminants with inflammatory abdominal disease. Peritoneal fluid evaluation is usually most helpful in inflammatory diseases, but it may be diagnostic in some cases of abdominal neoplasia. Bacterial culture and sensitivity of peritoneal fluid are indicated in inflammatory diseases when WBCs show degenerative or toxic changes but are rarely positive unless gross bowel contamination has occurred. Polymerase chain reaction (PCR) for Streptococcus equi and/or Rhodococcus equi may be warranted in horses with evidence of chronic inflammation of the abdominal cavity.
Blood cultures are best used after characterization of a remittent fever and evidence of pyogenic inflammatory disease from the laboratory database. Any antimicrobial therapy should be discontinued 48 to 72 hours before sampling. Three to five samples should be collected at least 45 minutes apart and are best taken directly into culture media. Sampling just before and during a temperature rise is more likely to yield positive results than sampling at the temperature peak and decline.
Serologic evaluation for infectious diseases common in the geographic area and/or patient population should be performed. Single serologic determinations usually are of value only in those diseases in which one positive titer is significant and when the disease is characterized by persistent infection such as EIA, brucellosis, or Johne’s disease. In many instances vaccination history and/or accompanying clinical signs must be correlated with titer determinations. Paired samples for toxoplasmosis, babesiosis, and various mycotic diseases (especially coccidioidomycosis) are indicated when the diagnosis remains obscure. Serologic determination of antibody titers to the SeM protein of S. equi can aid in the diagnosis of internal abscessation.42 Virus isolation and/or PCR, particularly in persistent bovine viral diarrhea (BVD)–infected cattle, may be helpful.
Evidence of gastrointestinal protein loss, chronic diarrhea, or persistent melena warrants several fecal or rectal biopsy cultures for salmonella in horses and calves, whereas such signs in adult dairy cattle warrant ruling out bovine leukosis as the cause.
Also helpful are biopsies of enlarged lymph nodes, accessible abdominal masses, and the liver and kidney when laboratory data indicate abnormalities. Liver biopsies should be cultured and evaluated histologically, because bacterial cholangiohepatitis can be a cause of FUO. Evaluation of biopsies for the presence of immunoglobulins, particularly if skin lesions are present, may add in diagnosis of immune-mediated disorders. Antinuclear antibody determinations and a Coombs’ test are also indicated in suspected immune-mediated diseases.
Radiographic evaluation, particularly of the thorax, should be performed in horses and small ruminants and is often possible in dairy cattle. Ultrasonographic examination of the heart may definitively diagnose cardiac abnormalities and may provide more complete scrutiny of other organs in the thorax and abdomen, as well as deep structures of the musculoskeletal system. Ultrasonographic examination also aids in percutaneous biopsy of internal structures and may help the practitioner make the decision for exploratory laparotomy.
Exploratory laparotomy without direct evidence of abdominal disease should be performed only in patients that are becoming progressively debilitated and in which all other avenues of diagnosis have been exhausted. Blind exploratory laparotomies usually do not contribute to diagnosis, are costly, and are not without risk. Exploratory laparotomy is used for diagnostic purposes more routinely in ruminants than in horses.
Nuclear imaging and imaging using autologous WBCs labeled with technetium-99m or indium-111 are increasingly used in human and small animal medicine.43 These procedures may be helpful in localizing abscesses, particularly osteoarticular infections. These modalities may prove to be of benefit for large animals as the modalities’ availability increases.
The use of therapeutic trials of antimicrobials in FUO should be restricted to cases in which strong evidence of a bacterial infection exists. The therapeutic regimen should be as specific as possible and administered for a predetermined amount of time. Inappropriate use of broad-spectrum antimicrobials for all febrile diseases contributes to interference in accurate diagnosis.
HYPOTHERMIA
Decreases in body temperature may occur when environmental stresses (cold, wet, wind) overwhelm the body’s capability of heat production (especially when the body is weakened from disease), when central nervous system disease has resulted in damage to the regulatory centers within the hypothalamus, or when adrenergic or sympathetic effector systems have been damaged. Newborns, cachexic, and very aged animals are most susceptible to heat loss caused by cold exposure (see neonatal sepsis and weak calf syndrome, Chapter 20). Concurrent signs of septic disease in hypothermic animals signify a guarded prognosis because the body’s defense mechanisms are often overwhelmed when core body temperature declines. Severely hypothermic animals (core body temperature >30° C) are profoundly depressed and have marked reduction in ventilation, absence of muscle activity, and decreased reflexes. Decreased intravascular volume and depressed cardiac function lead to hypoxia, acidemia, and cardiac dysrhythmias. Newborns are often hypoglycemic and have potassium imbalances. These animals should be warmed by protecting them from wind or drafts, drying them, and providing a microenvironment of high ambient temperature. Applying thermal blankets and housing them in an insulated stall, with or without supplemental heat, are superior to direct external heat from heat lamps or other sources. Direct external heat without environmental control causes cutaneous vasodilation, often exacerbates central hypothermia, and contributes to cardiovascular compromise.
Animals with severe hypothermia should be warmed gradually over 24 hours, with careful monitoring of body temperature and the cardiovascular system. Maintenance of adequate systemic perfusion is the most important means of preventing cardiac failure.44,45 Acidosis and potassium imbalances are common and may fluctuate rapidly. Consequently, repeated measurements, especially when a patient’s clinical condition worsens in the process of warming, are often necessary. Appropriate crystalloid fluids, warmed to body temperature, are usually necessary throughout the warming process. Evaluation of blood glucose and concurrent dextrose therapy, especially in neonates, should also be performed.
Warmed humidified oxygen therapy both as an aid in treatment of hypoxia and as a means of warming is helpful. Gastric (rumen) or rectal lavage with warmed fluids may also be used. However, care should be taken in rapid rewarming, because an imbalance in the basal metabolic rate (which is temperature dependent) and systemic perfusion may result in life-threatening cardiac dysrhythmias and worsening of metabolic acidosis and hypoxia. Hypothermia attenuates the inflammatory response by a multiplicity of effects on cytokines and other key signaling mechanisms.46 Thus the adverse metabolic effects of disease are slowed at low body temperatures, and, as body temperature elevates, signs of systemic disease become apparent.47 In hypothermic animals in shock, particularly neonates, severe anoxic changes in the bowel wall may result in severe diarrhea, sloughing of mucosa, or clostridial growth in the bowel.
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