Chronic Exertional Rhabdomyolysis

SELECTED NEUROLOGIC AND MUSCULAR DISEASES

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CHRONIC EXERTIONAL RHABDOMYOLYSIS Jill Beech, VMD

Chronic intermittent rhabdomyolysis (CIR) or exertional myopathy has long been recognized in horses performing various types of exercise. It once was referred to as Monday morning disease or hemaglobinemia paralytica 14 because of its association with draft horses being rested but fed normal rations on Sunday and then resuming work on Monday. Although this is still the scenario for some horses with exertional rhabdomyolysis, many cases do not fit this pattern. Azoturia and paralytic myoglobinuria, and tying up were other terms for the condition. The term tying up or chronic intermittent (exertional) rhabdomyolysis is a broad clinical description. Although opinions and hypotheses abound, in many cases the cause and pathogenesis are unknown. Considering the varying causes for this clinical syndrome, it is not surprising that treatments and prophylactic measures are numerous, usually of undocumented efficacy, and frequently decided by trial and error. Exertional myopathy in endurance horses following prolonged exercise is probably different from rhabdomyolysis in the racehorse walking out to the track preceding any strenuous exercise. This article describes the clinical signs of CIR and presents current knowledge of conditions contributing to its manifestation, useful diagnostic tests, prophylaxis, and treatment of the acutely affected horse. Postanesthetic myopathy, exertional capture myopathy, and ear tick-associated muscle cramping42 are not included. Likewise, atypical myoglobinuria and acute

From the Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, Pennsylvania

VETERINARY CLINICS OF NORTH AMERICA: EQUINE PRACTICE VOLUME 13 • NUMBER 1 • APRIL 1997

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myopathy, reported as outbreaks in grazing horses on a poor plane of nutrition often following adverse weather,82 are not included.

CLINICAL SIGNS

Clinical signs of CIR are highly variable. Some horses show only suboptimal performance and a slightly restricted gait; clinical laboratory testing may be needed to document elevated serum creatine kinase (CK) or aspartate aminotransferase (AST) concentration. Although the hindquarters usually are affected most often and most severely, the forelimbs may show similar, or even more marked, signs. Occasionally, horses are affected most severely in a single limb. Horses may resist work, and their shortened stride may be mistaken for a skeletal lameness. Some horses show transient stiffness, which resolves with just rest but recurs when exercise is resumed. If signs occur when the horse returns to its stall after exercise, one may initially notice weight shifting, an anxious expression, and partial posturing as if to urinate. Signs may be inconsistent; some horses may exercise strenuously without problems one day and then tie up with less strenuous exercise the next. Some horses become violent and appear to have colic; however, evaluation reveals no primary gastrointestinal problem except ileus; in such horses, the diagnosis of exertional rhabdomyolysis is made based on high serum CK and AST and myoglobinuria. In one survey, 48% of the replies reported abdominal discomfort as a sign of exertional rhabdomyolysis. 25 The muscles inconsistently may be firm or swollen. The serum enzyme elevation does not always correlate with what one would expect based on the horse's gait and the appearance of its muscles. Horses may sweat profusely and become extremely tachypneic, tachycardic, and hyperthermic. They may collapse and be unable to rise. Rarely, an owner might misinterpret reluctance to move and stiffnes~ as tying up when the horse actually has pleuritis, peritonitis, or severe back or neck pain. In a horse showing severe pain and lameness in one limb, an underlying skeletal lesion or circulatory impairment must be considered. In human beings, local irritation or pain in an underlying structure can lead to painful muscle cramps, and this could occur in horses. Intermittent claudication with thrombosis of the iliac vessels and impaired blood supply to the hind limb(s) could cause similar signs. The affected limb is usually cool, however, and palpation and ultrasonography per rectum are usually diagnostic. Port wine-colored urine is seen in some but not all. In a survey of horses in the United Kingdom, 38% of reported episodes of exertional rhabdomyolysis occurred after exercise as the horse returned home or as it rested after work. A total of 54.5% occurred

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during work, and 4% occurred on leaving the stable. In 16 %, signs occurred during light work, and 9.5% of cases occurred while warming up. Signs at more than one stage of exercise were reported in 3.5%. 25 Division into three grades based on severity of signs and enzyme elevations has been suggested: The light form might be overlooked because muscle spasms are transient, and the CK concentration 1 to 4 hours postexercise is less than 1500 IV /L and AST less than 500 IV /L; in the intermediate form, profuse sweating and pronounced stiffness occur usually after 20 to 30 minutes of exercise, and serum CK varies from 1500 to 10,000 IV/L and AST from 500 to 2000 IV /L; the severe form occurs rapidly after onset of exercise, signs are more advanced, and serum CK exceeds 10,000 IV /L. Myoglobinuria occurs in all but the light form. 37 CAUSE AND PATHOGENESIS

There are many proposed causes, some of which have been confirmed: hormonal imbalance including hypothyroidism, electrolyte deficiencies, viral infection, high carbohydrate diets, irregular exercise schedules, mitochondrial enzyme abnormalities, abnormal sarcolemmal function including malignant hyperthermia, vitamin E and selenium deficiency, and polysaccharide storage disease. Although many dietary factors could be important, to the author's knowledge to date, there have been no definitive studies linking certain diets to the condition. Likewise, although the type of exercise program is known to be an important influence, the mechanism has not been shown. It is unclear why certain horses are more sensitive to disruptions in their exercise schedule, whereas other horses tolerate even more irregular programs. Abnormal Sarcolemmal Function

Abnormal sarcolemmal function has been documented in some performance horses, although the underlying cause is unknown. 3 ,5 These horses have no histologic evidence of a specific myopathy and have been responsive to drugs that affect ion movement across membranes. Specific information is included under the section on muscle biopsies. Diagnosis is based on testing muscle in vitro. Electrolyte Imbalance and Diet

; High-carbohydrate diets have been blamed as a cause, usually in conjunction with interrupted exercise. To the author's knowledge, how-

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ever, there are no data on specific dietary factors as a cause. Time of feeding grain relative to exercise also has been thought to be a factor. At least in normal horses performing repeated bouts of high-intensity treadmill exercise, neither a positive nor a negative effect of feeding corn 2.5 to 3 hours before exercise versus a 16-hour fast was seen. 3S Electrolyte imbalance has been theorized to be important. Potassium particularly has been of interest. Potassium-depleted dogs that develop rhabdomyolysis when exercised have decreased muscle potassium concentration and release and decreased muscle blood flOW. 32 Alterations in muscle potassium also can affect intracellular metabolism and membrane permeability. The effects of potassium deficiency, however, vary with species. Horses effectively conserve potassium when fed a lowpotassium diet, although acute loss could occur subsequent to administration of certain drugs. Furosemide and sodium bicarbonate administration was followed by a fall in calcium, chloride, magnesium, and potassium. Subsequent exercise resulted in an increase in serum CK activity in two of six horses. One horse had a transiently stilted gait after exercise, and three had synchronous diaphragmatic flutter. 22 Most equine diets are replete with potassium because of hay and use of commercial mixed feeds. Plain oats, however, are low in potassium as well as sodium and magnesium. Histologic changes (vacuolar myopathy) frequently associated with potassium deficiency have not been seen in biopsy samples from horses with exertional rhabdomyolysis. s,6 In other species, these changes are inconsistent, and because muscle may appear normal or have nonspecific changes in potassium-depleted states, absence of these changes does not eliminate potassium depletion as a potential cause. Current information on evaluation of electrolyte balance in affected horses is presented in the section on diagnosis. Although electrolyte imbalance could be a factor and induce rhabdomyolysis, to the author's knowledge, no one irrefutably has shown it to be a cause of CIR in horses. Hyponatremia in humans is associated with fatigue and muscle cramps but, to the author's knowledge, has not been associated with rhabdomyolysis. Although calcium-phosphorus imbalance may occur in horses' diets and could contribute to muscle dysfunction, there are no data proving this is the cause of exertional rhabdomyolysis. To date, theorizi1).g about the potential role of electrolytes and anecdotal clinical response to electrolyte supplementation, with correction of urinary clearance ratios in some cases,27 appears to have been the basis for continued interest in dietary electrolyte imbalance as a factor in chronic intermittent cases. Climatic factors may be important, although, in the author's experience, case histories usually do not support this. Hot weather results in increased sweating and hence electrolyte loss, which is documented as

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a cause of muscle cramps and rhabdomyolysis in other species. Heat also may be a problem during prolonged submaximal exercise because, at least in humans, there is an effect on skeletal muscle metabolism. Heat induces an increase in plasma and muscle lactate, which could be lowered by acclimation. 84

Vitamin E and Selenium Deficiency

Vitamin E and selenium are closely interrelated in decreasing lipid peroxidation. Free radical activity and lipid peroxidation could cause Ca2+ leakage into the cytosol and subsequent muscle damage. Nutritional myodegeneration or white muscle disease has been described but often has been accompanied by steatitis and other signs. 82 In adult horses, several different entities have been described. Colic, myocardial disease, rhabdomyolysis, muscle pain, and sometimes recumbency, myoglobinuria, and edema of the head and neck have been reported. 52 Masseter myonecrosis or maxillary myositis in horses on a poor plane of nutrition has been described; myoglobinuria can be seen, and although many muscles can be affected, the masticatory muscles are clinically the most severely affected. 24,65 Vitamin E intake is influenced by handling, processing, and storage of feeds. Even with normal drying, the vitamin E content in hays can decrease by more than 50%. 45 Winter grass and some pelleted feeds have low levels. Some fresh legume pastures and hay contain a succinooxidase inhibitor that interferes with vitamin E, and this further increases if hay becomes damp.58 Lack of access to green pasture, unsupplemented feeds, and deficient grains cause low vitamin E status. The prevalence 6f vitamin E and selenium deficiency-associated diseases in animals has been associated with areas having less than 0.05 ppm plant selenium content, but one study showed no good correlation between soil selenium levels, horses' serum vitamin E and selenium levels, and clinical signs of myopathy.52,76 Deficiency is unlikely to occur in horses fed a high-quality diet and, in the author's experience, has not been documented to be a factor in well-managed performance horses. Serum samples and muscle biopsy samples from 12 clinically healthy Standardbreds with normal serum AST concentrations had lower vitamin E concentrations than those from 6 Standardbreds that were tying up and had elevated serum ASTs. The blood glutathione peroxidase activity was also higher in the affected horses. 55 These horses probably had received vitamin E and selenium supplementation, but these results indicate that deficiency was not a trigger for the clinical syndrome.

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Hormonal Influence

Studies have reported a higher incidence in females than males. In one survey of the distribution of cases having a referral history of rhabdomyolysis compared to other conditions, although there was a higher number of males affected, there was an increased proportion of females in the exertional myopathy group compared with the control group.25 In one report, 28 of 59 affected Standardbreds were females,39 and in a mixed population of 46 horses with exertional myopathy, 27 were females and 19 were males. 21 In another study, 17 of 22 Thoroughbreds but only 5 of 19 Standardbreds referred for evaluation of CIR were females. 5 To date, more females than males have been reported with polysaccharide storage myopathy-associated rhabdomyolysis. 67f 72 The reason underlying a preponderance of females in some studies is unknown. No correlation between estrus cycles and elevated CK levels was found in a group of Thoroughbred horses in training. 20 Hormones can directly affect muscle metabolism and membrane function, but potential effects could be mediated via neural or other neuroendocrine pathways. Hypothyroidism has been associated with myopathies in other species. It was implicated as a cause of tying up in horses primarily based on low serum levels of triiodothyronine (T3) or thyroxine (T4 ).79 Serum concentrations of T3 and T4, however, can be low in normal horses. 63 Low basal levels may exist in euthyroid states and in themselves are not diagnostic of hypothyroidism. A thyroid-stimulating hormone or thyroid-releasing hormone challenge test is needed for diagnosis. In the author's experience with performance horses, none of the horses showed other signs suggesting hypothyroidism, and basal concentrations of T3 and T4 were not low in the small number evaluated.

Infectious Causes

Viral diseases can cause myalgia, but recurrent intermittent bouts of rhabdomyolysis and muscle soreness have not been associated clearly with viral infections. Equine herpesvirus 1 infection was implicated as the cause of an outbreak of muscle stiffness and poor performance with elevation of serum CK and AST in a group of Thoroughbred racehorses in training26; this was based on a reported increase in serum antibody titers highly suggestive for equine herpesvirus 1 infection in some horses during the time period of clinical signs. More data are needed to substantiate the potential role of viruses in this condition. Although sarcocysts can encyst in muscle, to the author's knowledge, sarcocyst infections have not been associated with recurrent bouts

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of rhabdomyolysis. There is one report of widespread Sarcocystis fayeri in a horse with weight loss, lethargy, difficulty chewing and swallowing, muscle weakness and fasciculations, and a mildly increased AST. That horse acutely became recumbent with marked increases in AST and CK when treated with thiabendazole. There was no history, however, of intermittent rhabdomyolysis. 21 Infections with bacteria such as Clostridium or Streptococcus may cause acute myositis but not recurrent bouts of rhabdomyolysis.

Metabolic Myopathies

Polysaccharide storage myopathy has been described in several breeds as a cause of exertional rhabdomyolysis. 67/ 73 At least in quarter horse-related breeds, a familial basis has been suggested. 72 A familial basis may also exist in the Belgian Draft breed (BA Valentine, personal communication, 1996). Affected horses usually develop signs of rhabdomyolysis and muscle pain at a young age. Signs can vary in duration and severity. When these horses have been evaluated on the treadmill, their maximal achievable speed is low, and lactate accumulation and oxygen consumption are 50% lower than in clinically normal horses. 71 Diagnosis is based on characteristic histopathologic changes seen in muscle. Accumulation of glycogen in muscle is seen but is not specific for this entity because high glycogen content in muscle has been reported in other studies on horses with recurrent rhabdomyolysis not associated with this specific disease. Widespread subsarcolemmal vacuoles may represent small areas of myofibrillar lysis caused by repeated episodes of rhabdomyolysis. 67 Up to 5% of the type 2A and B fibers contain variably sized mucopolysaccharide inclusions that stain with periodic acid-Schiff (PAS) stain. Numbers of inclusions vary but may be so great as to disrupt normal myofibril architecture. 67 In contrast to glycogen, the polysaccharide is not removed during incubation in an anaerobic medium, indicating it is stored in a nonbioavailable form. The mechanism underlying the disease is unknown, although some enzymatic defect in glycolysis is postulated. Affected animals should not be used for breeding. Breeding affected horses has resulted in affected foals showing signs at several months of age (SJ Valberg, personal communication, 1996). Defects in mitochondrial metabolism have received limited evaluation as causes of exertional rhabdomyolysis. One Standardbred filly with chronic repeated attacks was found to have loosely coupled mitochondria in muscle biopsied after exercise, leading the authors to suggest a potential metabolic defect. 75 Subsequently, six horses with recurrent rhabdomyolysis were compared with three clinically normal control

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horses. Specifically, the activities of complex 1/ 11/ 111/ and IV of the mitochondrial respiratory chain and the carnitine system were examined. No dysfunction was detected in these horses. 59 A deficiency of the complex I respiratory chain enzyme, however, was described in a 3year-old Arabian female with profound exercise intolerance and muscle stiffness.7° Even light exercise induced a lactic acidosis. Muscle biopsy samples revealed ragged red fibers, a feature of mitochondrial myopathies in humans; abnormal mitochondria seen on electron microscopy; and a low activity of NADH cytochrome C reductase, the first enzyme complex in the mitochondrial respiratory chain. Neither the dam nor several siblings were clinically abnorma1. 7o As the ability to evaluate horse muscle for various metabolic errors is expanded, it is possible that additional disorders will be described. In cattle, for example, myophosphorylase deficiency has been associated with exercise intolerance and rhabdomyolysis. 1

DIAGNOSIS

Diagnosis is based on history; complete physical, neurologic, and musculoskeletal examinations; and clinical laboratory testing.

Creatine Kinase and Aspartate Aminotransferase Concentrations

The most commonly used diagnostic tests are determination of serum or plasma CK, AST, and sometimes lactic dehydrogenase (LDH) concentrations. CK originates primarily from skeletal and cardiac muscle/ whereas AST and LDH are high in skeletal and cardiac muscle as well as liver. If the CK is normal but the AST or LDH is elevated and the horse has other compatible signs, further workup to rule out hepatic disease should be undertaken. Horses affected with CIR do not always have high resting or exercise-associated increases in these enzymes, and the increase in serum and plasma enzyme concentrations does not always correlate with the severity of clinical signs. Concentrations of these enzymes can be influenced by stage of training, exercise program, and the time at which the horse is tested relative to exercise. In early stages of training, CK and AST enzyme concentrations are relatively high. In some cases, a dramatic decrease may be seen between the first and fifteenth day of training. 13 In addition, 2-year-old Thoroughbred fillies in training had higher levels than 3-year-old fillies and colts. 20 Serial serum samples obtained from horses in training have shown that enzyme levels are higher postexercise following a day of rest than

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following the same exercise preceded by days of regular exercise. Even when this exercise/rest effect caused markedly increased CK levels, however, signs of exertional myopathy occurred unpredictably.2o Interpretation of elevated enzyme concentrations, especially when the increase is mild, can be difficult. An increase does not always indicate that exertional myopathy is the horse's major problem. A study on kinetics of CK indicated that the normal circulating CK concentration corresponds to the total CK quantity in approximately 1 g of muscle, and even a three to five fold increase in activity corresponds to apparent myolysis of only approximately 20 g of muscle, a very small amount of tissue?? When evaluating a horse suspected to have a myopathy, blood samples should be drawn before exercise and at set times afterward to evaluate any elevations. Because of the delayed rise in AST, if one is sampling a horse suspected to have had rhabdomyolysis 1 to 2 days previously, the AST is a better indicator than CK. The CK concentration may have been high following the episode of rhabdomyolysis but may be markedly decreased 24 to 48 hours later. Evaluation of both enzymes is preferred. Although resting AST may be elevated in horses with exertional rhabdomyolysis, activities are not predictive of an episode.68/69 Frequently, resting enzyme concentrations are normal in predisposed horses, and exercise does not evoke consistent elevations. In a normal horse, CK peaks approximately 5 hours after exercise and returns to preexercise levels. In most horses with exertional rhabdomyolysis, it peaks within the first 24 hours and declines within the next 3 to 4 days, unless there is continued rhabdomyolysis to contribute to further rise. CK concentration may not return to normal values for 7 to 10 days following rhabdomyolysis.13/83 In contrast, the AST rises more slowly and is usually higher several days later than in the acute stage of rhabdomyolysis. AST levels may not return to normal for 15 days or more and sometimes have remained elevated up to 4 weeks in horses with exertional rhabdomyolysis.13/83 Myoglobin Concentration in Serum and Urine

A correlation between serum concentrations of myoglobin and clinical severity of rhabdomyolysis has been made. 8o Myoglobin increases rapidly in serum of affected horses, and ready availability of an accurate specific and sensitive commercially available test would be helpful. Carbonic Anhydrase III Isoenzyme Concentration

Because carbonic anhydrase isoenzyme III is fairly specific for skeletal muscle, it has been postulated to be useful as a marker for muscular

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diseases, although in humans it can also increase with prolonged running. 51 In one study, concentrations of serum carbonic anhydrase III were markedly elevated in horses with a history of rhabdomyolysis and except in one horse correlated with severity of signs. 50 Carbonic anhydrase III elevation correlated with CK rise but more rapidly decreased. 50 It is as yet unknown what changes might occur in horses following short-term strenuous exercise or longer duration exercise. The latter would be more likely to result in an increase because of the distribution of enzyme primarily within slow-twitch oxidative fibers.

Vitamin E and Selenium Levels

Although deficiency is unlikely to be a factor in most horses, measurement of serum levels is advisable when the diet is poor or high in fat or when there are multiple affected animals from the same farm. Low levels of selenium, glutathione peroxidase activity, and vitamin E can occur in animals with no signs of muscle disease. In one study, although blood glutathione peroxidase activity was highly variable, pasture-fed asymptomatic horses grazing in areas where foals had died with muscular dystrophy had low activities. 12 To evaluate selenium status, either red blood cell glutathione peroxidase or serum or plasma selenium concentration can be used. Although a positive correlation between the two has been reported,12 other studies showed that red cell glutathione peroxidase activity reaches a plateau when a certain serum or blood level is reached and, therefore, may not adequately reflect dietary selenium intake in mature horses. 8,61 Increases in red cell glutathione activity occur during erythropoiesis, and, therefore, increases in enzyme activity lag 5 to 6 weeks from the time of initiating selenium supplementation. 45 Likewise, because of red cell turnover time, blood selenium is a less sensitive indicator of selenium intake than plasma selenium. 43-45,61 Serum vitamin E levels may vary significantly throughout the day in normal horses; therefore, using several pooled samples may provide a more accurate reflection of the horse's status. 16 Also, the range in normal horses is wide. 64 Low levels may be found in clinically normal horses and by themselves do not indicate vitamin E deficiency is the cause of rhabdomyolysis. Levels can vary seasonally in pastured horses and with intake. No seasonal variation was reported for stabled horses. l1 Ponies are reported to have lower levels than Thoroughbreds. 17 Serum or plasma levels of vitamin E do not correlate with selenium concentrations. l1 Therefore, both should be measured if deficiencies are suspected. The patient's parameters should be compared with the ranges used by the laboratory performing the tests.

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Determination of Electrolyte Status

Determination of electrolytes and urinary fractional excretion of electrolytes has been used in attempts to ascertain whether electrolyte imbalance may be the underlying cause. Usually, serum or plasma electrolytes are normal in horses predisposed to intermittent rhabdomyolysis. Fractional urinary electrolyte excretion has been used to determine whether horses are excreting normal amounts of various electrolytes. A decreased concentration implies inadequate intake or conservation, whereas excessive excretion usually indicates excess intake. Although there is some daily variation in excretion of electrolytes47 and a 24-hour collection is most accurate, single samples usually suffice for revealing gross changes, provided that there were no major changes in food, water, or electrolyte consumption preceding collection. Urine samples obviously should not be obtained following use of a diuretic. The fractional excretion is determined by the formula: urine electrolyte plasma electrolyte

X plas~a

creatinine urIne creatine

X

100°10

Ranges and 95°10 confidence intervals for the various electrolytes have been reported. 47 For sodium, single samples' excretion values varied between 0.01 °10 and 0.91 °10. For potassium, a 95°10 confidence interval of 23°10 to 48°10 has been reported,47 but in the author's experience, normal horses often have much higher percent excretion, and less than 25°10 is low. The excretion for chloride ranges from 0.86°10 to 1.24°10 with a 95°10 confidence interval of 0.59°10 to 1.86°10. It can be variable within individual animals. Calcium excretion varies widely over a 24-hour period, and in some time periods the 95°10 confidence interval was 0.09°10 to 6.72°10. 47 Another study reported the following ranges for single samples: 35°10 to 80°10 for potassium, 0.04°10 to 0.52°10 for sodium, 0.7°10 to 2.1 °10 for chloride, and 0 to 0.2°10 for phosphate. 27 Because extracellular concentrations of potassium poorly reflect intracellular concentrations and urinary excretion is an indirect crude assessment of the body's status, red blood cells and muscle biopsy specimens have been evaluated. Red blood cell potassium determination is a relatively simple noninvasive test and once had been proposed to reflect myoplasm concentrations. Several studies, however, have shown no correlation between erythrocyte and muscle red blood cell concentrations. 6, 31, 34 The red blood cell potassium concentration does not provide a valid estimate of the horse's potassium status. There is one report of lower red blood cell potassium concentrations in 2-year-old fillies that had tied up within 48 hours of sampling,2 but another study showed no difference in erythrocyte potassium concentrations of horses that had CIR compared with normal horses. 6 Likewise, other studies have shown

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no consistent correlation between red blood cell potassium concentrations and poor performance. 49 Small muscle biopsy specimens can be used to determine intracellular potassium concentration (as well as other electrolytes) on a dry and a wet weight basis. The technique for potassium determination has been published. 6,40 Measurements of normal equine middle gluteal muscle potassium concentration on a wet weight basis have been reported as 91.06 ± 2.96 f-Lmol/ g31 and 86.2 to 94.0 mEq/kg in horses older than 1 year of age. 38 Semimembranous muscle potassium concentration on a wet weight basis was 93.8 ± 5.6 mmol/kg and on a dry weight basis 353.7 ± 17.5 mmol/kg in normal horses. 6 Sodium concentration in equine muscle was reported to increase with age (21.2±4.46 mEq/kg wet muscle in those <4 years versus 25.8 ± 4.72 in those between 4 and 8 years of age).38 Magnesium content reportedly does not change with age and ranged from 16.8 to 22.4 mEq/kg wet muscle. 38 A positive correlation between muscle potassium and magnesium concentration has been reported. In mature horses, age does not appear to influence muscle potassium concentrations,6,34 although horses younger than 1 year of age were reported to have higher values than older horses. 38 The muscle potassium concentration on a dry weight basis was significantly lower in 13 horses with CIR than in 15 normal horses (320 ± 14 mmol K/kg versus 354 ± 18 mmol K/kg; P<0.0001).6 On a wet weight basis, the potassium concentration was insignificantly (P<0.06) lower (89.2±9.2 versus 93.8±5.6 mmol/kg). There was no correlation between red blood cell potassium concentration and muscle potassium concentration. There was no histologic change in the muscle to suggest a hypokalemic myopathy despite the lower concentration on a dry weight basis. Whether the lower potassium concentration showed in this study occurs in all muscles is unknown because in other species variation can occur between different muscles. 7, 46, 62 There is one report comparing urinary fractional excretion of potassium, sodium, and chloride; red blood cell potassium concentration; and semimembranous muscle potassium concentration in normal horses with values from horses with CIR.6 There was no significant difference in red blood cell potassium concentration or urinary fractional excretion values between the two groups. Within the rhabdomyolysis group, however, 12 of 38 had a potassium fractional excretion of less than 30%, and in 7 it was less than 20%. In 12 of 32 horses with CIR, percent fractional excretion of chloride was below the published 95% confidence interval. Muscle Biopsy Samples

Use of biopsy specimens for evaluation of electrolyte concentration has been discussed in the preceding section. Biopsy for histology, histo-

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chemistry, and biochemistry can reveal underlying pathology or metabolic defects (or both). When there is access to laboratories performing in vitro testing, tests of calcium regulation in the sarcoplasmic reticulum and twitch and contracture studies under various conditions including testing for malignant hyperthermia can be performed. The muscles most frequently used for histology and histochemistry are the middle gluteal and semimembranous muscles. The latter is used for samples for in vitro testing because it is possible to obtain sections of aligned muscle fibers of sufficient length with no detrimental effect on the horse. Both muscles are primarily type II fiber types. If a generalized myopathy is the basis for chronic exertional rhabdomyolysis, these muscles should be representative. If the case is unusual and the forelimb muscles primarily are affected, one of this group should be biopsied. For histologic evaluation, the author advises sending the muscle biopsy specimen to a laboratory specializing in muscle pathology and biochemical testing. The laboratory should be consulted before obtaining the biopsy specimen so that processing is done according to their specifications. Even if a veterinarian cannot send an isopentane frozen specimen to the laboratory, a section placed on lightly moistened gauze in an airtight container sent on ice packs by overnight mail to the laboratory usually yields samples suitable for histology and histochemistry. Routine formalin fixation and processing is not advised. Histology may reveal no changes or low-grade to moderate degenerate myopathy with internalized nuclei, focal necrosis, fiber splitting, and sometimes fibrosis and fatty infiltration. s Obviously, the changes are affected by time between the biopsy and last bout of rhabdomyolysis as well as severity. Focal hyalin degeneration with necrosis, slight inflammatory reaction, and degenerative changes are seen in horses with acute rhabdomyolysis. 39 The fast-twitch (type II) fibers are more severely affected than type I. Biopsy specimens have been the basis for diagnosis of a mitochondrial myopathy in a horse with exercise intolerance and stiffness70 and polysaccharide storage myopathy.67,73 In vitro testing has shown prolonged relaxation of the electrically elicited twitch and shortened relaxation time of caffeine-induced contractures in horses with CIR. The threshold of calcium-induced calcium release in heavy sarcoplasmic reticulum fractions was also lower in affected horses. s Although none of the horses in that study tested positive for malignant hyperthermia using criteria of the North American Malignant Hyperthermia group, increased sensitivity to halothane and caffeine has been reported for gracilis muscle. 78 A more recent study on biopsy samples from omobrachialis muscle, from 10 horses with chronic exertional rhabdomyolysis, showed none had positive responses to 2% and 4% halothane. 29 Occasional horses, those with CIR and those without histories of muscle dysfunction, and some with hyperkalemic periodic

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paralysis have biopsy samples that have contracture responses characteristic of malignant hyperthermia. The basis for the disordered ion regulation in muscle from horses with CIR is unknown at this time. In vitro test responses, however, have been the basis for prophylactic drug therapy in affected horses. Electromyography

Electromyography can detect abnormal electrical activity in muscles. Certain myopathies may be associated with certain patterns, and denervation also can result in characteristic alterations. For example, horses with hyperkalemic periodic paralysis and those with a myotonic dystrophy-like condition have high-frequency repetitive myotonic discharges. The technique, however, is unlikely to receive wide application in evaluation of most horses with rhabdomyolysis. Scintigraphy

Radiopharmaceutical 99mTc-MDP uptake occurs in damaged bone and skeletal muscle. It has not been used widely for evaluating horses with exertional rhabdomyolysis. Of 109 racehorses undergoing scintigraphy after treadmill exercise, 10 had abnormal skeletal muscle uptake, and in 8 horses in which serum CK was measured there was an abnormal exercise-associated elevation. 48 Eight horses were reported to have had subtle hind limb gait deficits, but only two had a history suggesting muscle stiffness and showed muscle soreness after treadmill exercise. Scintigraphy was suggested as helpful in identifying localized exertional rhabdomyolysis. What is not known at present is whether horses with recurrent intermittent rhabdomyolysis would have consistent radiopharmaceutical uptake following repeated exercise tests. The technique may be helpful in localizing muscle pathology, especially when plasma CK and AST are normal or interpretation of a mild increase is difficult. PROPHYLAXIS Exercise

A regular exercise program appears to be one of the most important factors in management. Although there are no published studies, anecdotal evidence indicates that horses that tie up with an irregular exercise program or following an interruption in their regular exercise schedule often stop having problems if they are exercised daily. Sometimes,

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several exercise periods per day have appeared effective. The author advises that horses with eIR receive daily exercise and not just shortduration, high-speed exercise. Tranquilization

Low-dose tranquilization has frequently been used, especially if horses are nervous. Acepromazine (PromAce, Ft. Dodge Laboratories, Ft. Dodge, 10) is commonly used, but other substances are also used. Although fluphenazine (Prolixin, Princeton Pharmaceutical Products, Princeton, NJ) is sometimes used because of its longer duration of action, occasional horses have bizarre side effects, showing extrapyramidal signs of restlessness, including walking backwards, facial grimacing, bowing, and pawing. Although transient, these signs can be dramatic. There is one report of diphenhydramine hydrochloride (Benadryl, Park Davis, Morris Plains, NJ) 250 mg intravenously normalizing signs in a horse showing bizarre neurologic signs following fluphenazine use. 10 The diphenhydramine was used because its centrally acting anticholinergic activity is effective in restoring dopamine / acetylcholine balance, and extrapyramidal signs are thought to be due to dopamine block in an area of the brain. Vitamin E and Selenium

Vitamin E and selenium are closely interrelated and important as antioxidants in preventing lipid peroxidation of cell membranes. Despite lack of data substantiating efficacy, they are widely used for prophylaxis, even when a deficient state has not been demonstrated. In one study evaluating selenium supplementation for 4 weeks in horses undergoing exercise tests, there was no evidence that the selenium decreased the exercise-induced peroxidation, suggesting that supplementation at least in normal horses does not provide antioxidant protection. 9 The author is unaware of any reports on effects in horses with rhabdomyolysis. Oral supplementation of 1 mg of selenium daily increased blood selenium concentrations above those associated with myodegeneration in both foals and horses. 45 The minimal oral selenium requirement for horses is 2.4 J.Lg/kg. 66 A study on adult Standardbred horses suggested that 1.5 to 4.4 mg/kg of alpha-tocopherol acetate per day should be given in those fed a diet low in vitamin E (for reference, 1 mg vitamin E = 1.3 IV vitamin E).56 Horses fed a high-fat diet may require higher levels of vitamin E. Although injectable vitamin E and selenium can be used, feeding is safer. Many feeds already contain adequate amounts of selenium, and horses do not require additional supplementation.

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Miscellaneous Feed Additives

Various substances have been added to the feed. Dimethylglycine has been claimed to decrease lactic acid production and enhance performance of horses and Greyhounds. 23,36 Although it is used commonly by trainers and owners, to the author's knowledge, there are no data substantiating its efficacy as prophylaxis for equine rhabdomyolysis. Other substances also have been used to decrease lactic acid production. Sodium bicarbonate is probably the most widely used substance, but to the author's knowledge, there is only one case report substantiating its efficacy.54 Seven switchback trials with and without addition of dietary sodium bicarbonate (2% of dry matter) showed a beneficial but not curative effect in this mare. This mare's clinical syndrome, however, was unlike that of most racehorses, and she had an abnormally high lactate response to only light aerobic exercise. When muscle lactate concentrations have been determined before and immediately after submaximal and near-maximal exercise tests in horses prone to recurrent rhabdomyolysis, values were similar or lower than those of similarly exercised normal horses. 68 Similarly, when gluteus medius biopsy specimens from 33 Standardbred racehorses were evaluated at different time periods (1 to 4 hours, 18 to 24 hours, and 2 to 20 days) following acute rhabdomyolysis, lactate concentrations were similar to normal values except in 4 of 12 horses, which in the early period had increased lactate concentrations. 38,39 Although horses that suffer from exertional rhabdomyolysis have been shown to have higher muscle glycogen concentrations,68 the early hypothesis that its excessive breakdown during exercise leads to a profound lactic acidosis 14 appears untenable for most light breeds. To the author's knowledge, there are no published reports on biochemical studies in muscle from draft breeds with recurrent rhabdomyolysis. It is possible that enhanced buffering of sodium bicarbonate may be beneficial in certain cases, as in the one case report, but it is frequently unpalatable when fed in amounts required to enhance buffering capacity. There is no evidence that administration immediately before exercise has prophylactic efficacy, although it is frequently given for possible enhancement of stamina and performance. The author does not advocate its use except when medically justified.

Diet

There are no published data on rhabdomyolysis and diets on which to base specific recommendations about different feeds. High-fat diets have been suggested for horses with polysaccharide storage myopathy. How helpful these diets would be in other types of exertional rhabdomy-

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olysis has not been determined. Although vegetable oil can be added gradually to a total of 20% of the caloric intake (or 2 cups/ d in a 450kg horse), many horses find large amounts of oil unpalatable. Several commercial high-fat diets are available. Vitamins E and A should be supplemented with high-fat diets.

Drugs that Affect Estrus or Estruslike Behavior

In some fillies, there are anecdotal reports of prevention of rhabdomyolysis following use of altrenogest (Regumate, Hoechst-Roussel, Somerville, NJ) and progesterone. Regumate does not always prevent ovarian activity. Progesterone implants have been used to modify behavior but, to the author's knowledge, have not been evaluated in fillies with rhabdomyolysis. Their efficacy of progesterone release is controversial. Progesterone in oil can be administered intramuscularly, but tissue reaction and soreness at the injection site usually preclude its use.

Dantrolene

Dantrolene, a hydantoin drug that inhibits calcium release from the sarcoplasmic reticulum in muscle, has been used for prophylaxis. There are no controlled trials, however, to prove its efficacy. The dose used in many horses is extremely low, and blood levels are unlikely based on bioavailability studies. A dose of 4 mg/kg orally was reported to yield a peak blood concentration of 1.4 f-1g/mL after 60 to 120 minutes. Is The concentration needed to affect abnormal calcium regulation in equine muscle is unknown. The author advocates its use only when in vitro muscle studies have documented abnormal calcium regulation and contracture testing positive for malignant hyperthermia. There are anecdotal reports of weakness associated with its use and one report associating it with prolonged anesthetic recumbency.74 There is a report of its successful use (50 mg orally three times a day) in a woman with recurrent rhabdomyolysis thought to be caused by a loosely coupled oxidative phosphorylation in mitochondria. 28

Phenytoin

Phenytoin or diphenylhydantoin affects ion channels. It appears to affect the threshold for calcium-induced calcium release in sarcoplasmic reticulum fractions from muscle homogenates when it is abnormally low, and the author has documented its increasing a low threshold for

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calcium-induced calcium release toward normal or normalizing it. 3 ,4 In vivo administration has also resulted in altering a horse's malignant hyperthermia contracture test response from positive to negative. 4 Muscle from some horses with CIR had prolonged relaxation times following an electrically elicited twitch in vitro, and administration of phenytoin normalized these prolonged times. 3 Although there are no switchback studies, phenytoin administration has been clinically effective as prophylaxis in horses that have chronic problems with rhabdomyolysis. 3,4 Its exact mechanism of action on muscle from these horses is unknown, although an effect on muscle triglyceride metabolism has been documented, and fatty acids are known to affect ion channels. 19 The dosage of phenytoin is adjusted to the horse's response, and monitoring serum or plasma levels is advised. Initial oral dosage is 6 to 8 mg/kg twice daily for several days, and the dose is then frequently increased to 10 to 12 mg/kg twice daily. Attempts are usually made to maintain serum levels between 5 and 10 J..Lg/mL as assessed by samples obtained 3 to 4 hours postadministration. Bioavailability appears to vary with the form or brand. The prompt and extended forms have been used, but there are no comparative trials. Although the extended form may be preferable, it is usually considerably more expensive. Because the same dosage can produce divergent blood levels among horses, serum drug monitoring is advised, but when this is not possible, clinical response and signs and serum CK and AST concentrations are the basis for dosage adjustment. The drug does have a tranquilizing effect, which varies among horses. Overdosing a horse that is tranquilized or drowsy can result in ataxia and other neurologic signs, including focal seizurelike activity and recumbency. If a horse does show signs of sedation or drowsiness, dosing should not be resumed until the horse appears normal and then should be decreased by 50% and further adjusted. If a horse is receiving other medication, one should ascertain whether there are any interactions that could potentiate toxicity or decrease efficacy by affecting clearance or protein binding. Concurrent use of phenylbutazone has not caused apparent problems. Drugs such as trimethoprimsulfa combinations can potentiate toxicity by competitively binding protein, resulting in a higher concentration of free phenytoin. Horses have been maintained on phenytoin for months without apparent ill effect, but shorter treatment periods are more desirable. Even after 7 to 10 days of in vivo administration, in vitro and biochemical effects on muscle are apparent. 3, 4, 19 The drug is not palatable and is best administered by dose syringe as a suspension. Withdrawal times before competition for phenytoin and dantrolene are not definitively known and vary with both dosage and the individual horse.

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Electrolyte Supplementation

Horses that are heavily sweating require electrolyte supplementation in the feed or water. Commonly used amounts are 0.5 to 1.5 ounces sodium chloride twice daily and sometimes 0.5 ounce potassium chloride twice daily. When urinary phosphate excretion is elevated, suggesting possible calcium imbalance, adding 11 to 22 g calcium or 1 to 2 ounces ground limestone daily may be useful. 27 Although magnesium is important in muscle function, specific recommendations regarding its supplementation for horses with rhabdomyolysis are not available. Supplementation depends on the diet, type of exercise, and whether any drugs that may affect excretion are being administered. Treatment of the Acutely Affected Horse

Treatment goals are to alleviate pain and anxiety, prevent further muscle destruction, and maintain fluid and electrolyte balance. Severity of signs determines one's treatment regimen. Except in mild cases, horses should not be walked. If they are cramped and far from a stable, they should be transported back to the barn. Therapy in severe cases should be initiated before attempting to move the horse because transport could exacerbate the condition. 57 Transport-induced rhabdomyolysis has been reported. 3D Mildly affected horses may spontaneously recover or require only analgesics or tranquilizers. Flunixin meglumine (1 mg/kg intravenously) is helpful. Ketoprofen (0.5 mg/kg) has also been used as has phenylbutazone. 57 Drugs such as acepromazine can help alleviate pain and anxiety, and its peripheral vasodilatory effects may be helpful. High doses should be avoided, however, and are definitely contraindicated in a hypovolemic horse. In some cases in which pain is extreme, intravenous butorphanol (0.01 to 0.02 mg/kg) combined with xylazine (0.3 to 0.6 mg/kg) is needed. Detomidine (0.005 to 0.020 mg/kg) has also been suggested when rapid restraint and pain relief are needed. 57 If horses are recumbent and violent, longer-acting drugs have been suggested. Intravenous phenobarbital to effect may be useful. A dose of 12 mg/kg produced mild to moderate sedation in mature normal horses. 53 Infusion over 20 minutes was not associated with heavy sedation in normal mature horses. I8 Dosage should be titrated to each patient, especially because other medications may influence response. After a loading dose, lower doses may well be effective. Mildly affected horses that are drinking well may require only careful monitoring of intake and provision of both plain water and electrolyte-supplemented water. Intravenous polyionic fluids are indicated in moderate to severe cases and should be administered when

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there is myoglobinuria. Fluids are also mandatory in a horse that is profusely sweating. In addition to dehydration, sweating results in loss of sodium, chloride, and lesser amounts of potassium. Failure to administer fluids and diurese horses with myoglobinuria can lead to renal ischemia and renal failure. Supplementation of fluids by nasogastric tube, although less expensive and providing a large volume of fluid, is less desirable in severely or moderately affected horses because these animals often have ileus. Unless clinical laboratory data indicate the horse is acidotic and requires sodium bicarbonate, the latter should not be administered; affected horses may already be alkalotic and sodium bicarbonate is contraindicated. Endurance horses are usually alkalotic. 33 Although muscle relaxants such as methocarbamol are used in acute cases by some veterinarians, to the author's knowledge, there are no data proving their efficacy or synergistic action with analgesics and tranquilizing drugs. A dosage of 15 to 25 mg/kg of methocarbamol administered slowly intravenously has been suggested. 57 More commonly, it is administered orally. Elevated myoplasmic calcium has been demonstrated in muscle from recently tied up horses. 39, 41 Free intracellular calcium causes major damage to many cellular functions, leading to cell death; therefore, decreasing calcium release from the sarcoplasmic reticulum should be beneficial in treatment. Dantrolene prevents Ca2 + release from the sarcoplasmic reticulum, and its use was associated with decreasing recovery time of horses with rhabdomyolysis. 41 Six horses given 1.5 mg/kg intravenously the first 24 hours, followed by 2 mg/kg orally for the next 48 hours, had a more rapid clinical improvement and decrease in plasma creatine kinase concentrations than four untreated horses. The myoplasmic calcium levels also had a greater decline in treated horses. Unfortunately, blood levels of dantrolene were not reported in Lopez's horses. Pharmacokinetic data suggest that an intravenous dose of 1.9 mg/kg would maintain blood levels greater than 2.8 f.Lg/mL for only 20 minutes. 15 The therapeutic blood concentration is unknown in horses. Unfortunately, intravenous forms of dantrolene are not readily available and are expensive. Transient weakness and ataxia can be side effects, and confusion should be slow. Oral dantrolene could be administered by nasogastric tube, although the therapeutic dosage has not been determined. A dose of 2 mg/kg is unlikely to be effective as a loading dose, especially because bioavailability is low. Pharmacokinetic data suggest an oral dose of 10 mg/kg as a single loading dose or 2.5 mg/kg every 60 minutes. 15 The former dose was reported to achieve peak blood levels approximately 1.5 hours following administration and maintain levels for an additional 2 hours. The author has no personal experience using dantrolene in the acute case. To the author's knowledge, its assay is not widely available, so one cannot monitor serum or plasma concentrations.

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The benefits of steroids and dimethyl sulfoxide have not, to the author's knowledge, been demonstrated. The analgesic properties of dimethyl sulfoxide reported in some other studies combined with its radical scavenging activity (and hence its anti-inflammatory and antiischemic properties) are the basis for its use. The role of free radicals in most cases of equine rhabdomyolysis is unclear. Free radical generation has, however, been documented following experimental postischemic muscle reperfusion in a horse. 6o Vitamin E is used because of its interaction with free radicals and perhaps other oxidizing intermediates, thus preventing peroxidation of membrane phospholipids and subsequent cell damage. The radical scavenging dosage in horses, however, is unknown. To the author's knowledge, its therapeutic benefit remains unproven except when a deficient state is the cause for rhabdomyolysis. In cases of rhabdomyolysis caused by polysaccharide storage myopathy, administration of lipids might be helpful. In severe cases, 10% lipid solution (1 g/kg over 12 to 24 hours) could be administered intravenously with polyionic fluids. Hyperlipemia is unlikely, but the serum should be periodically evaluated and treatment altered if needed. Although corn oil can be added to the feed, it is often unpalatable, and the author has no experience with administration of large amounts by nasogastric tube to a horse naive to its presence in its diet.

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12. Caple IW, et al: Blood glutathione peroxidase activity in horses in relation to muscular dystrophy and selenium nutrition. Aust Vet J 54:57-60, 1978 13. Cardinet GH, et al: Comparative investigations of serum creatine phosphokinase and glutamic-oxaloacetic transaminase activities in equine paralytic myoglobinuria. Res Vet Sci 8:219-226, 1967 14. Carlstrom B: Uber die atiologie und pathogenese der kreuglahme des pferdes (Haemaglobinaemia paralytica). Scand Arch 62:1-69, 1932 15. Court MH, et al: Pharmacokinetics of dantrolene sodium in horses. J Vet Pharmacol Therap 10:218-226, 1987 16. Craig AM, et al: Variations of serum vitamin E, cholesterol and total serum lipid concentrations in horses during a 72 hour period. Am J Vet Res 50:1527-1531, 1989 17. Dewes HF: A possible vitamin E responsive condition in adult horses. NZ Vet J 29:83-84, 1981 18. Duran SH, et al: Pharmacokinetics of phenobarbital in the horse. Am J Vet Res 48:807-810, 1987 19. Fletcher JE, et al: Phenytoin increases specific triglyceride fatty esters in skeletal muscle from horses with hyperkalemic periodic paralysis. Biochem Biophys Act 1168:292298, 1993 20. Fraunfelder HC, et al: Changes in serum muscle enzyme levels associated with training schedules and the oestrus cycle in Thoroughbred racehorses. Equine Vet J 18:371374, 1986 21. Freestone JF, Carlson GP: Muscle disorders in the horse: A retrospective study. Equine Vet J 23:86-90, 1991 22. Freestone JF, et al: Exercise induced alterations in the serum muscle enzymes, erythrocyte potassium and plasma constituents following feed withdrawal or furosemide and sodium bicarbonate administration in the horse. J Vet Intern Med 5:40--46, 1991 23. Gannon JR, Kendall RV: A clinical evaluation of N,N dimethylglycine (DMG) and diisopropylammonium dichloracetate (DIDA) on the performance of racing Greyhounds. Canine Prac 9:7-11, 1982 24. Hadlow WJ: Myopathies of animals. In Pearson CM, Mostofi FK (eds): The Striated Muscle. Baltimore, Williams & Wilkins, 1973, pp 364--409 25. Harris PA: The equine rhabdomyolysis syndrome in the United Kingdom: Epidemiological and clinical descriptive information. Br Vet J 1474:373-384, 1991 26. Harris PA: An outbreak of the equine rhabdomyolysis syndrome in a racing yard. Vet Rec 127:468-470, 1990 27. Harris P, Colles C: The use of creatinine clearance ratios in the prevention of equine rhabdomyolysis: A report of four cases. Equine Vet J 20:459--463, 1988 28. Haverkort-Poels PJE, et al: Prevention of recurrent exertional rhabdomyolysis by dantrolene sodium. Muscle Nerve 10:45--46, 1987 29. Hildebrand SV, et al: Contracture test and histologic and histochemical analyses of muscle biopsy specimens from horses with exertional rhabdomyolysis. J Am Vet Med Assoc 196:1077-1083, 1990 30. Ito S, et al: Four cases of rhabdomyolysis in the Thoroughbred during transportation. Bull Equine Res Inst 29:1-5, 1992 31. Johnson PI, et al: Effect of whole body potassium depletion on plasma, erythrocyte and middle gluteal muscle potassium concentration of healthy adult horses. Am J Vet Res 52:1676-1683, 1991 32. Knochel JP, Schlein M: Mechanism of rhabdomyolysis in potassium depletion. J Clin Invest 51:1750-1758, 1972 33. Koterba A, Carlson GP: Acid base and electrolyte alterations in horses with exertional rhabdomyolysis. J Am Vet Med Assoc 180:303-305, 1982 34. Larsen J, et al: Relationships between the potassium concentrations of plasma red blood cells and muscle, and the concentrations of magnesium and calcium in plasma and muscle in Standardbred trotters. In Proceedings of the 41st American Association of Equine Practitioners, San Antonio, 1995, pp 266-267 35. Lawrence LM, et al: Effect of feeding state on the response of horses to repeated bouts of intense exercise. Equine Vet J 27:27-30, 1995

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