Respiratory Disease: Medicine and Surgery
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Exercise-Induced Pulmonary Hemorrhage Corinne Raphel Sweeney, DVM*
In 1980, Pascoe and colleagues 23 stunned the racing industry with the results from their postrace endoscopic examination of racehorses. Forty percent of the Thoroughbreds and 27% of the Standardbreds examined after racing were identified with exercise-induced pulmonary hemorrhage (EIPH). Before Pascoe's report, bleeding was though( to occur in fewer than 3% of racing horses on the basis of studies noting the incidence of epistaxis in horses in Great Britain, 29 South Africa, 26• 27 Australia, 5 and Singapore. 3 Since this initial endoscopic study, many studies have been conducted around the world to attempt to gain a better understanding of the causes, pathogenesis, and treatment of this widespread condition. Although this article reviews many aspects of EIPH, it may fail to acknowledge every investigator who has contributed to the body of knowledge about EIPH.
PREVALENCE Table 1 is taken from racing records and shows the prevalence of bleeding among racehorses. These figures are based on observation of blood at the nostrils at the completion of a race. Endoscopic surveys indicate that the prevalence of EIPH is significantly higher than indicated in studies that base the diagnosis on epistaxis (Table 2). The figures in Table 2 were derived from endoscopic examinations on Thoroughbreds, 23• 28• 42 Standardbreds, 23 polo ponies, 42 Quarter Horses, 10 Appaloosas, 11 and mixedbreed horses 36 within 2 hours of completing exercise. These results indicate that although pulmonary hemorrhage is experienced by a large number of exercising horses, epistaxis is a relatively infrequent manifestation of this *Diplomate, American College of Veterinary Internal Medicine; Assistant Professor of Medicine, University of Pennsylvania School of Vete rinary Medicine, Kennett Square, Pennsylvania Veterinary Clinics of North America: Equine Practice-Vol. 7, No. 1, April 1991
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CORINNE RAPHEL SWEENEY
Table 1. Reported Prevalence of Bleeding in Thoroughbred Horses Based on Observation of Blood at One or Both Nostrils PREVALENCE OF EPISTAXIS YEAR
COUNTRY
(%)
REFERENCE
1913 1950 1973 1973 1973 1976
United Kingdom South Africa Australia Singapore South Africa South Africa
0.25 1.2 0.8 2.5 2.5 2.4
Robertson Pfaff 1990 Cook 1974 Choy Cook 1974 Pfaff 1976
phenomenon. It is well accepted that EIPH is a problem of exercising horses and not any specific breed of horses or type of activity. Results of cytologic examination of tracheobronchial aspirates suggest that most Thoroughbred horses in race training bleed after exercise. 43 Repeated endoscopic examination of horses after exercise reveals a higher incidence of EIPH than is indicated by a single examination alone. In a group of 51 horses examined on three or more occasions, Mason et al14 found that 82% had EIPH at least once. Burrell2 found that 18 of 19 (95%) horses examined two or more times bled on at least one occasion. In an effort to determine the prevalence and repeatability of EIPH in horses, the author endoscopically examined 42 horses after breezing. Horses were examined 4 to 12 times. The overall prevalence of EIPH in Thoroughbreds in this training center was 62%. Of the horses initially found to be bleeders, approximately one-third were positive for EIPH on all subsequent endoscopic examinations after breezing; one-third were EIPH-posiTable 2. Incidence of Exercise-Induced Pulmonary Hemorrhage (EIPH) in Horses After Different Types of Exercise EXERCISE
BREED*
NO.
NO. WITH
%WITH
NO. WITH
%WITH
EXAMINED
EIPH
EIPH
EPISTAXIS
EPISTAXIS
Racing
TB
llBO
497
42
15
3
Racing Racing Racing Racing Breezing Pacing
TB TB
191
75
QH
231
144 16 144 49 62 66
62 52 45 26
13 0 12 2 1 9
9 0 8 4 2 14
Steeplechase Flat turf racing Timber races Endurance
TB TB
31 14
21 2
68 14
3 0
14 0
TB Mixed
3 10
2 0
67 0
2 0
100 0
Polo Cross-country
TBtrB-X Mixed
27 45
3 6
11
13
0 1
0 17
App TB STDBD
25 94
139 249
64
REFERENCE
Pascoe and Wheat Raphel Voynick Hilledge et aJI0 Hilledge et al 11 Raphel Pascoe and Wheat Raphel Raphel Raphel Sweeney and Soma 1983 Voynick Voynick
event
*TB = Thoroughbred, TB-X Quarter Horse, App = Appaloosa
=
Thoroughbred cross, STDBD
=
Standardbred, QH
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tive 50% to 75% of the time; and one-third were EIPH-positive 25% of the time or less. Following the results of the postexercise endoscopic examination of this group of bleeders over several months, it was apparent that the EIPH score frequently changes by one grade (either an increase or decrease). Obviously, horses that were categorized as grade -1 could fluctuate between grade O (EIPH-negative) and grade 1 (EIPH-positive).24 Although there are differences of opinion on the effects of age on the incidence of EIPH, most studies report a trend of increasing incidence of EIPH with increasing age. This age association may reflect the chronicity and possible progression of an underlying lung condition.
EIPH AND PERFORMANCE
If performance is based solely on the finishing position in a race, there is no clear association of EIPH and impaired performance. 23• 24• 28• 3.5, 36 Although it is widely accepted that EIPH is deleterious to racing performance, studies to determine the effect of EIPH on performance and ability have not been done. One study34 in which each horse's racing times were standardized for distance and adjusted for track variance reported the poorest performance (based on racing times) in that race in which EIPH was recognized. Because results of an endoscopic examination were unavailable for previous races, it still is not possible to determine the actual effects of EIPH on the performance of horses in this study.34 Although methods are available to compare an individual horse's performance between races, repeated endoscopic examinations to determine the onset of EIPH and an acceptable method of determining the presence of EIPH are necessary.
CLINICAL SIGNS Other than endoscopic observation of blood in the airways, a clearly definable set of clinical signs on which to base a diagnosis of EIPH has not been documented. Most clinical signs are nonspecific. Ascribing a pattern of clinical signs is complicated further by the variable response of individual horses to the presence of blood in the airway and the lack of knowledge concerning the lesion, if any, that predisposes to EIPH. Exercise intolerance frequently is believed to be a clinical sign associated with EIPH, however, it is difficult to determine how frequently exercise intolerance is a result of EIPH. For example, when a horse's training or racing performance is considered unacceptable, routine diagnostic evaluation often includes a postexercise endoscopic examination. If a horse that previously was considered to be a nonbleeder is found to have blood in the trachea, it usually is assumed that the exercise intolerance is a result of the EIPH. However,
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research studies of horses with satisfactory exercise performance often found blood in the trachea during endoscopic examination after breezing or racing. These findings suggest that the presence of EIPH is not always associated with the trainer's perception of poor performance.
DIAGNOSIS
The ability to diagnose EIPH is dependent on the definition of the condition. If EIPH is defined as the presence of blood in the tracheobronchial tree of a horse, then confirmation of EIPH requires direct observation of blood in these airways after exercise. If the diagnosis of EIPH is more liberal and includes the acceptance of hemosiderophages in respiratory secretions, then diagnosis of EIPH can be made by identification of such cells in tracheobronchial aspirates or bronchoalveolar lavage fluid. Roszel et al33 caution against presuming that siderophages are diagnostic of hemorrhage. Although the heme from hemoglobin in the presence of hemorrhage is a common source for iron in siderocytes, it may originate from plasma in the absence of hemorrhage. Alveolar macrophage filled with macropolysaccharides can bind with plasma iron to form an iron pigment resembling hemosiderin, which stains positively with Perl's Prussian blue. Although Perl's Prussian blue often is considered a stain for hemosiderin, it is a stain for inorganic iron and does not discriminate between its sources. Roszel33 believes that this process may occur with cardiac-related pulmonary chronic passive congestion, in which large numbers of cells with pigment may be present in the tissue. Mucus, which is reported in the trachea of some horses after exercise, also may be the source of mucopolysaccharides for alveolar cell engulfment. 33 In the author's experience, tracheobronchial aspirates and bronchoalveolar fluid (BAL) aspirates from horses with excessive mucus in the respiratory tract (horses with chronic obstructive pulmonary disease [COPD]) do not have hemosiderophages. Cardiac-related pulmonary chronic passive congestion has not been determined to occur in most bleeders. Thus, the author believes that the presence of hemosiderophages in a tracheobronchial aspirate or BAL sample, although not specific, is an acceptable means to diagnose EIPH. Lung lavages from the caudodorsal lung field of horses shortly after breezing demonstrate large numbers of red blood cells and hemosiderophages. Similar samples from nonexercising horses do not have the same findings. These findings are circumstantial evidence that the presence of hemosiderophages is directly correlated with the occurrence of EIPH. The presence of blood at the nares is strongly suggestive of EIPH, whereas failure to identify blood on endoscopic examination immediately after exercise does not rule out EIPH. Because the severity of the lung hemorrhage may vary, the time between bleeding and the observation of
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blood in the trachea also varies. Some horses have blood at the nares and in the trachea at the completion of their exercise, but most horses require between 30 and 120 minutes after completion of the exercise before blood is apparent in the trachea. Considering that the tracheal mucus transport rate in the horse is approximately 1. 9 cm/min, 40 and blood in the trachea can be seen "in streams" as if being transported on a mucus elevator, this time differential is not unexpected. Horses with severe pulmonary hemorrhage have been observed to have streams of old discolored blood in the trachea up to 4 days after exercise. Most typical bleeders have blood apparent in the trachea 60 minutes after exercise. If no blood is present in the trachea and EIPH is highly suspected, a repeat endoscopic examination 60 to 90 minutes later is recommended.
RADIOGRAPHY
Radiographic examination of the thorax of bleeders indicates that despite serious and widespread lung involvement, EIPH lesions are responsible for only a vaguely discernible increase in interstitial density. 21 The predominant radiographic location is in the dorsocaudal lung field . As most bleeders have no radiographically discernible lesions several days after bleeding, an increase in soft tissue density noted in the dorsocaudal lung field at this time is suggestive of a severe episode of EIPH. Resolutions of these radiodensities can be rapid, suggesting that these changes are the result of hemorrhage rather than pneumonia, lung consolidation, or lung abscesses. Radiography is not an effective method to diagnose EIPH.
SCINTIGRAPHY
Scintigraphic imaging of ventilation and perfusion function in horses with EIPH demonstrates consistent patterns of reduced pulmonary perfusion in the caudodorsal lung fields. 21 These areas of relative perfusion deficit are confined to the dorsocaudal lung field and demonstrate a horizontal ventral margin with the normally perfused and ventilated lung below. The use of scintigraphic imaging has been reported to detect approximately 95% of horses with EIPH compared with 10% of bleeders detected by standard radiographic evaluation. 22 In addition, nuclear imaging can detect EIPH at an earlier stage of the disease, because it detects functional changes in the lung as opposed to structural changes. 22 O'Callaghan and Goulden 16 were the first to record a distinctive area of change in the peripheral extremity of the caudal lobe of the lungs associated with EIPH. An apparent progression in the radiologic changes associated with EIPH was described. An alveolar interstitial pattern progressed to superimposition of coarse bronchial densities with peribronchial cuffing and hazy, indistinct internal
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CORINNE llAPHEL SWEENEY
margins indicative of mucosal edema and inflammation. Ultimately, a chronic bronchointerstitial pattern was observed. Clarke 4 reported that histologic evidence of EIPH could be found without radiologic changes in the excised lung. The size and extent of lesions, the presence of lung tissue above the relatively dense ventral processes of the thoracic vertebra, and the density of the thoracic wall may all contribute to the failure to observe a radiologically distinct change.
PATHOLOGY
In 1974, Cook5 described a necropsy of a racehorse examined 1 month after its last episode of EIPH. Chronic bronchitis and pulmonary emphysema in the cranial third of both lungs were noted. The site of hemorrhage was described. Death after pulmonary hemorrhage is an uncommon occurrence. 5 • 9• 35 Most bleeders survive; therefore, postmortem findings associated with an episode of EIPH rarely are available. In an effort to address many of the questions associated with the pathophysiology of EIPH, a correlated clinical and pathologic study of 26 Thoroughbred racehorses with histories of EIPH was conducted in Hong Kong. 17 The mean time interval from last recorded bleeding episode to necropsy was 156 ± 141 days, range 12 to 513 days. 17 Necropsy revealed that the lungs had bilateral, symmetric, subpleural staining of the parenchyma that was preferentially distributed in the caudodorsal region of the caudal lung lobes. In collapsed lungs, these regions were blue to blue-gray. On inflation, they changed to dispersed regions of bronze-brown discoloration. These stained regions of the lung inflated and deflated slowly, suggesting that regional airflow was altered. Subpleural bronchial arteries were more prominent than in normal lungs, and the greatest density of vessels was associated with the discolored regions of lung. 18 The distribution of the pulmonary and bronchial arterial circulations and their association with a stained area of lung was determined by first injecting red latex into the bronchial arteries and then injecting blue latex into the pulmonary arteries. Systematic examination of transverse lung slices showed that rust-colored subpleural staining extended into the parenchyma; this was preferentially distributed to the dorsal bronchopulmonary segments of the lung. Also, the vessels in these stained areas were full of red latex, suggesting that these regions receive their vascular supply almost exclusively from the bronchial arterial circulation. 19 The airways within and subtending these stained areas often were abnormal and had thickening of the airway walls with either partial or complete luminal obstruction with exudate. 20 Additional supportive evidence for bronchial artery neovascularization was obtained from computed tomography and microradiography. Intense bronchial arterial neovascularization was identified within and immediately adjacent to stained areas and was focused around diseased small airways.
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Microscopic findings included bronchiolitis and increased fibrous connective tissue in interlobular septa in deeper parts of the pleura and around diseased airways and some vessels. 20 Large accumulations of macrophages and giant cells containing iron pigments were found in alveoli, airways, connective tissue around air spaces, and vessels. 20 Bronchiolitis was observed in lung regions without hemosiderophages; however, the converse was not true. Focal accumulations of eosinophils were seen in some regions with hemosiderophages but generally were located in regions distant from the hemosiderophages. 20
PATHOGENESIS
Despite the extensive epidemiologic and pathologic studies of EIPH conducted in the 1970s and 1980s, the pathogenesis of EIPH still is unknown. In 1974 Cook5 proposed that bronchiolitis or chronic lung disease was the underlying lesion of EIPH. Using the presence of mucus or mucopurulent material in the trachea to indicate .chronic lung disease, three studies found no association between EIPH and this pulmonary disease. 2· 13· 35 In 1982 O'Callaghan and Goulden16 proposed that the location of the lesion of EIPH suggests a possible parasitic pathogenesis. Alternatively, hematogenous invasion of other small particles, such as thrombi or bacteria, may cause EIPH because of their predilection for lodging in the caudal segment of the diaphragmatic lobe. Masses of veterinarians have suggested that coagulation defects are responsible for EIPH; Cook5 and Johnson et al12 eliminated coagulation deficits as an causative factor of EIPH. Pulmonary vascular hypertension as a cause of EIPH is unlikely, because massive pulmonary edema would occur with subsequent dyspnea before capillary pressure could increase enough to rupture a vessel. 30 In 1970 Rooney32 suggested that asphyxia resulting from breath holding or partial airway obstruction distends air spaces and compromises blood flow through pulmonary vessels, resulting in venous obstruction. In 1979 Robinson30 discounted this suggestion for several reasons. Clarke4 postulates that mechanical stresses during strenuous exercise may cause EIPH. Robinson and Dersken31 hypothesize that pulmonary hemorrhage results from accentuated distending forces on areas of the lungs that do not synchronize with ventilation in the rest of the lung because of subclinical airway obstruction. They suggested that the poor collateral ventilation of horses may allow extreme fluctuation of alveolar pressure in an asynchronous region, producing a parenchymal tear or capillary rupture. This theory is based on the property of interdependence of lung lobes. Cook6 proposes that EIPH is a clinical sign of recurrent laryngeal neuropathy. In their most recent work, O'Callaghan and colleagues21 suggest that small airway disease is the key feature of EIPH, and maximal exercise is required to provoke the intense hemorrhagic response. Underlying small airway disease and the
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resulting partial airway obstruction increase the susceptibility of affected small airways and dependent air exchange areas to extreme hypoxia during strenuous exercise. 21 Because of gravitational effects on vertical air-exchange characteristics, partially obstructed airways in the dorsal lung are most susceptible to impaired exchange. The intense bronchial vascular response may result from both inflammation and exacerbation by the combinations of reflex shunt development to offset local tissue hypoxia. Over time there appears to be a breakdown of the precapillary control mechanisms under the effect of superior systemic pressures and flow. Local hemorrhage is believed to be from the bronchial rather than the pulmonary arteries. O'Callaghan et al21 report that susceptibility to hemorrhage can be increased by local release of heparin by macrophages or mast cells, an essential factor in angiogenesis. When combined with high systemic pressures during exercise, this could facilitate vessel fragility. Once the bronchial arteries break, left-to-right shunting is established through the control of local alveolar perfusion, and the perfusion deficits noted on scintigraphic examination become evident. 21 Recent work by Derksen and colleagues (Derksen FJ, personal communication) has demonstrated that lung injury and exercise can cause EIPH. In horses with ovalbumin-induced allergic lung disease, exercise allowed hemorrhage, which previously had not been present in large airways, to be seen on endoscopic examination. Their observations raise the possibility that in naturally occurring EIPH, hemorrhagic lung lesions are present before exercise and that exercise only serves to move blood into the large airway. Continued research ultimately will determine the pathogenesis of EIPH and lead to better preventive or therapeutic measures for the condition.
TREATMENT
Although many therapeutic regimens have been advocated to prevent EIPH in performance horses, most remedies have no proven efficacy. Until the cause of EIPH is understood, it is difficult to rationalize the use of most medications. This section discusses current thoughts on selective therapeutic regimens including management changes, furosemide, bronchodilators, hesperidin and citrus bioflavonoid, estrogens, and water vapor therapy. There is no consensus regarding the appropriate stable management of horses with EIPH. Efforts to improve the stabling environment and reduce airborne irritants possibly may be beneficial, but they are difficult to implement. The association of small airway disease and EIPH may be significant, and environmental changes to decrease the inhalation of irritants and allergens may improve respiratory function . Prolonged rest periods may be beneficial, but most horses bleed after return to the previous level
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of training or racing. Prerace management factors may have some benefit in controlling EIPH. The most common management technique is drawing; that is, feed and water are removed before breezing or racing. 1 Hay is withdrawn from the horse for 6 to 24 hours before race time. Water is withdrawn 3 to 12 hours before racing. Some trainers allow horses free access to both hay and water up to race time on the belief that psychologic factors may be as important as physiologic ones. 1 Management of horses after episodes of EIPH usually is not required. In most horses, hemorrhage ceases within hours after racing. Although massive episodes of pulmonary hemorrhage may result in fatalities, the frequency of this occurrence is low. 9 If massive nonfatal pulmonary hemorrhage occurs, prophylactic treatment with broad-spectrum antimicrobial drugs is indicated to prevent secondary bacterial infection. Such horses should be rested for several weeks to months. Furosemide is the most popular drug used in the treatment of EIPH. Most states regulate the use of furosemide and allow it to be administered only from 120 to 240 minutes before racing. In some states, the dose of furosemide is restricted to less than 250 mg intravenously; many states have no dosage restriction. When furosemide's use is unrestricted by law, the drug usually is administered at a dosage of approximately 150 to 300 mg intravenously 90 to 120 minutes before racing. In refractory cases of EIPH, some practitioners administer 350 to 500 mg furosemide divided into two doses, one at 5 or 6 hours and the other at the permitted time before racing. The origin of furosemide as a treatment for EIPH is unknown, but it is presumed that its use was based on the assumption that EIPH is preceded by pulmonary edema. Although pulmonary edema as an underlying cause of EIPH is possible, there is no evidence that exercising horses experience pulmonary edema. The efficacy of furosemide in prevention of EIPH has been reported. 7• 8 • 23• 24 • 37 • 38 • 41 In 1981 Pascoe et al 24 reported that of 56 furosemide~treated horses, 30 (53.6%) showed evidence of EIPH after racing. Pascoe states "Assuming that these horses were legitimately treated because of prior episodes of EIPH, the results create doubts about the efficacy of furosemide treatment for the prevention of EIPH. It is not known, however, whether furosemide reduced the amount of hemorrhage these horses may have otherwise experienced. "24 A subsequent study showed that of 61 horses with a history of EIPH treated with furosemide before racing, 34 (55. 7%) continued to bleed. 37 Both of these studies determined the presence or absence of blood in the tracheobronchial tree but did not grade the amount of blood seen. In another study, 38 three horses were repeatedly given furosemide at varying doses ranging from 350 to 600 mg before breezing; no change was noted in the EIPH incidence or degree. 38 In 1985 Pascoe et al25 reported that although furosemide did not stop EIPH, it did reduce the EIPH score in 28 (64%) of 44 horses. In that study, of 15 horses studied
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CORINNE RAPHEL SWEENEY
after racing, 53% of them continued to be EIPH-positive. Of 38 bleeders examined after breezing, 47% of them were noted to bleed. This study indicates that although furosemide does not decrease the incidence of EIPH, it may decrease the degree of bleeding. However, this conclusion should be viewed cautiously because of the subjectivity of the nature of the EIPH scoring system. Additionally, the anatomic relationship between the site of bleeding and the site of observation in the trachea, the efficiency of mucociliary clearance, the volume of blood, the rate of bleeding, and the time between exercise and observation all may influence the EIPH score. 25 Despite these inherent weaknesses, a scoring method was used because it seemed reproducible and was the only method available for evaluating responses of EIPH-positive horses to therapy. 25 A recent study by Erickson et aF reports that "furosemide did not prevent horses from hemorrhaging while exercising on the treadmill." These same researchers report that "furosemide failed to prevent horses from hemorrhaging during exercise in this study, nor did it appear to reduce the amount of hemorrhage. "8 In summary, several reports confirm that furosemide does not prevent EIPH in racehorses. There is evidence for and against the assertion that furosemide may reduce the amount of bleeding in horses with EIPH. This assertion has not been proved and needs further study. A preliminary study38 of the use of parasympatholytic bronchodilators showed a decrease in the prevalence of EIPH; however, subsequent investigations by the same and other15 investigators failed to document this improvement. Because of restrictive racing medication rules, many horse trainers have sought feed supplements that might have therapeutic value in the treatment of EIPH. A group of flavonoids that strengthens capillaries has been demonstrated in citrus and paprika. These flavonoids are thought to be essential for normal capillary integrity and to act synergistically with ascorbic acid. Citrus bioflavonoids used in conjunction with ascorbic acid reportedly enhance the efficacy of other therapeutic agents in controlling infection, stress, and nutritional deficiencies in humans. Although anecdotal reports suggest that bioflavonoids are helpful in preventing EIPH, controlled studies using a dose of 20 g/d for 90 days did not alter the prevalence of EIPH. 37 Conjugated estrogens are permitted for the treatment of EIPH in some racing jurisdictions. These substances reduce capillary bleeding and accelerate blood clotting in laboratory animals. As previously mentioned, no coagulation defects have been noted with EIPH; therefore, no rationale exists for therapy with conjugated estrogens. Commonly used preparations are potassium estrone sulfate or a mixture of sodium estrone sulfate and equilin sulfate. Conjugated estrogens can be used concurrently with furosemide. Numerous coagulants and anticoagulants have been used in the treatment of EIPH. Because no coagulation defect has been demonstrated, these treatments are unwarranted.
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Water vapor therapy is probably the oldest known respiratory therapy. Despite the long history of its use in humans, there is no clear evidence of any beneficial effects. Controlled studies using endoscopy have shown that water vapor-saturated air therapy does not change the bleeding status of horses. 39
REFERENCES 1. Arthur RM: Respiratory problems in the racehorse. Vet Clin North Am Equine Practice 6:179, 1990 2. Burrell MH: Endoscopic and virological observations on respiratory disease in a group of young Thoroughbred horses in training. Equine Vet J 17:99, 1985 3. Choy TH: cited in Cook WR: Epistaxis in the racehorse. Equine Vet J 6:45, 1972 4 . Clarke AF: Review of exercise induced pulmonary hemorrhage and its possible relationship with mechanical stress. Equine Vet J 17:166, 1985 5. Cook WR: Epistaxis in the racehorse. Equine Vet J 6:45, 1974 6. Cook WR, Williams RM, Kirkerhead CA, et al: Upper airway obstruction (partial asphyxia) as the possible cause of exercise-induced pulmonary hemorrhage in the horse: An hypothesis. J Eq Vet Sci 8:11, 1988 7. Erickson BK, Erickson HH, Coffman JR: Exercise-induced pulmonary hemorrhage during high intensity exercise: Potential causes and the role of furoserriide. Proceedings, AAEP 35:375, 1989 8. Erickson BK: Does the research support using furosemide? The Equine Athelete 11:35, 1989 9. Gunson DE, Sweeney CR, Soma LR: Sudden death attributable to exercise-induced pulmonary hemorrhage in racehorses: New cases (1981-1983). J Am Vet Med Assoc 193:102, 1988 10. Hilledge CJ, Lane TJ, Johnson EL, et al: Preliminary investigations of exercise-induced pulmonary hemorrhage in racing Quarter Horse. Equine Veterinary Science 4:21, 1984 11. Hilledge CJ, Lane TJ, Whitlock TW: Exercise-induced pulmonary hemor,rhage in the racing Appaloosa horse. Equine Veterinary Science 5:351, 1984 12. Johnson JH, Garner HE, Hutcheson DP, et al: Epistaxis. Proceedings AAEP 19:115, 1973 13. MacNamara B, Bauer S, Iafe J: Endoscopic evaluation of exercise-induced pulmonary hemorrhage and chronic obstructive pulmonary disease in association with poor performance in racing Standardbreds. J Am Vet Med Assoc 196:443, 1990 14. Mason DK, Collins EA, Watkins KL: Exercise-induced pulmonary haemorrhage in horses. In Snow DH, Persson SGB, Rose RJ (eds): Equine Exercise Physiology. Cambridge, Granta Editions, 1983, p 57 15. McDonnell W, Viel L, Tesarowski D , et al: Clenbuterol treatment for exercise-induced pulmonary hemorrhage (EIPH) in horses. Proceedings Veterinary Respiratory Symposium 8:94, 1989 16. O'Callaghan MW, Goulden BE: Radiographic changes in the lungs of horses with exerciseinduced epistaxis. NZ Vet J 30:117, 1982 17. O'Callaghan MW, Pascoe JR, Tyler MS: Exercise-induced pulmonary hemorrhage in the horse: Results of a detailed clinical, post mortem and imaging study. I. Clinical profile of horses. Equine Vet J 19:384, 1987 18. O'Callaghan MW, Pascoe JR, Tyler MS, et al: Exercise-induced pulmonary hemorrhage in the horse: Results of a detailed clinical, postmortem and imaging study. II. Gross lung pathology. Equine Vet 9:389, 1987 19. O'Callaghan MW, Pascoe JR, Tyler MS, et al: Exercise-induced pulmonary hemorrhage in the horse: Results of a detailed clinical, postmortem and imaging study. III. Subgross findings in lungs, subjected to later perfusion of the bronchial and pulmonary arteries. Equine Vet J 19:394, 1987 20. O'Callaghan MW, Pascoe JR, Tyler MS, et al: Exercise-induced pulmonary hemorrhage in the horse: Results of a detailed clinical, postmortem and imaging study. V. Microscopic observations. Equine Vet J 19:411, 1987
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21. O'Callaghan M: Recent progress on the pathogenesis and diagnosis of exercise-induced pulmonary hemorrhage in horses. Proceedings American College of Veterinary Internal Medicine 6:625, 1988 22. O'Callaghan M: New clues about EIPH. The Equine Athelete 1:1, 1988 23. Pascoe JR, Wheat JD: Historical background, prevalence, clinical findings and diagnosis of exercise-induced pulmonary hemorrhage (EIPH) on the racing horse. Proceedings AAEP 26:417, 1980 24. Pascoe JR, Ferraro CL, Cannon JH, et al: Exercise-induced pulmonary haemorrhage in racing Thoroughbreds: A preliminary study. Am J Vet Res 24:703, 1981 25. Pascoe JR, McCabe AE, Franti CE, et al: Efficacy of furosemide in the treatment of exercise-induced pulmonary hemorrhage in Thoroughbred racehorses. Am J Vet Res 46:2000, 1985 26. Pfaff G : Epistaxis in racehorses: Incidence in South Africa. J S Afr Vet Med Assoc 21:74, 1950 27. Pfaff G: The incidence of epistaxis in racehorses in South Africa. J S Afr Vet Med Assoc 47:215, 1976 28. Raphel CF, Soma RS: Exercise-induced pulmonary haemorrhage in Thoroughbreds after racing and breezing. Am J Vet Res 43:1123, 1982 29. Robertson JB: Biological search on racehorse breeding VI: The hereditary of blood vessel breaking in the Thoroughbred. The Bloodstock Breeder's Review 1:265, 1913 30. Robinson NE: Functional abnormalities caused by upper airway obstruction and heaves. Their relationship to the aetiology of epistaxis. Vet Clin North Am Large Anim Pract 1:17, 1979 31. Robinson NE, Derksen FJ: Small airway obstruction as a cause of exercise associated pulmonary haemorrhage: An hypothesis. Proceedings AAEP 26:421, 1980 32. Rooney JR: Technique and interpretation; Autopsy of the horse. Baltimore, William & Wilkins, 1970, p 117 33. Roszel JF, Freeman KP, Slusher SH, et al: Siderophage in pulmonary cytology specimens from racing and non-racing horses. Proceedings AAEP 33:321, 1987 34. Soma LR, Laster L, Oppenlander F , et al: Effects of furosemide on the racing times of horses with exercise-induced pulmonary hemorrhage. Am J Vet Res 46:763, 1985 35. Speirs VC, Van Veenendaal JD, Harrison IW, et al: Pulmonary haemorrhage in Standardbred horses after racing. Aust Vet J 59:38, 1982 36. Sweeney CR, Soma LR: Exercise-induced pulmonary haemorrhage in horses after different competitive exercises. Proceedings First International Conference Equine Exercise Physiology, September 1982:51, 1983 37. Sweeney CR, Soma LR: Exercise-induced pulmonary haemorrhage in Thoroughbred horses: Response to furosemide ofhesperidin-citrus bioflavinoids. J Am Vet Med Assoc 185:195, 1984 38. Sweeney CR, Soma LR, Bucan CA, et al: Exercise-induced pulmonary hemorrhage in exercising Thoroughbreds: Preliminary results with pre-exercise medication. Cornell Vet 74:263, 1984 39. Sweeney CR, Hall J, Fisher J, et al: Efficacy of water-vapor saturated air in the treatment of EIPH in Thoroughbred racehorses. Am J Vet Res 49:1705, 1988 40. Sweeney CR: Tracheal mucus transport rates in healthy horses. Am J Vet Res 50:2135, 1989 41. Sweeney CR, Soma LR, Maxson AD, et al: Effects of furosemide on the racing times of Thoroughbreds. Am J Vet Res 51:772, 1990 42. Voynick B, Sweeney CR: Exercise-induced pulmonary hemorrhage in Philippine racehorses and polo ponies. J Am Vet Med Assoc 188:301, 1985 43. Whitwell JE, Greet TRC: Collection and evaluation of tracheobronchial washes in the horse. Equine Vet J 16:499, 1984
Address reprint requests to Corinne Raphel Sweeney, DVM University of Pennsylvania School of Veterinary Medicine 382 West Street Road Kennett Square, PA 19348
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Exercise-Induced Pulmonary Hemorrhage Corinne Raphel Sweeney, DVM*
In 1980, Pascoe and colleagues 23 stunned the racing industry with the results from their postrace endoscopic examination of racehorses. Forty percent of the Thoroughbreds and 27% of the Standardbreds examined after racing were identified with exercise-induced pulmonary hemorrhage (EIPH). Before Pascoe's report, bleeding was though( to occur in fewer than 3% of racing horses on the basis of studies noting the incidence of epistaxis in horses in Great Britain, 29 South Africa, 26• 27 Australia, 5 and Singapore. 3 Since this initial endoscopic study, many studies have been conducted around the world to attempt to gain a better understanding of the causes, pathogenesis, and treatment of this widespread condition. Although this article reviews many aspects of EIPH, it may fail to acknowledge every investigator who has contributed to the body of knowledge about EIPH.
PREVALENCE Table 1 is taken from racing records and shows the prevalence of bleeding among racehorses. These figures are based on observation of blood at the nostrils at the completion of a race. Endoscopic surveys indicate that the prevalence of EIPH is significantly higher than indicated in studies that base the diagnosis on epistaxis (Table 2). The figures in Table 2 were derived from endoscopic examinations on Thoroughbreds, 23• 28• 42 Standardbreds, 23 polo ponies, 42 Quarter Horses, 10 Appaloosas, 11 and mixedbreed horses 36 within 2 hours of completing exercise. These results indicate that although pulmonary hemorrhage is experienced by a large number of exercising horses, epistaxis is a relatively infrequent manifestation of this *Diplomate, American College of Veterinary Internal Medicine; Assistant Professor of Medicine, University of Pennsylvania School of Vete rinary Medicine, Kennett Square, Pennsylvania Veterinary Clinics of North America: Equine Practice-Vol. 7, No. 1, April 1991
93
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CORINNE RAPHEL SWEENEY
Table 1. Reported Prevalence of Bleeding in Thoroughbred Horses Based on Observation of Blood at One or Both Nostrils PREVALENCE OF EPISTAXIS YEAR
COUNTRY
(%)
REFERENCE
1913 1950 1973 1973 1973 1976
United Kingdom South Africa Australia Singapore South Africa South Africa
0.25 1.2 0.8 2.5 2.5 2.4
Robertson Pfaff 1990 Cook 1974 Choy Cook 1974 Pfaff 1976
phenomenon. It is well accepted that EIPH is a problem of exercising horses and not any specific breed of horses or type of activity. Results of cytologic examination of tracheobronchial aspirates suggest that most Thoroughbred horses in race training bleed after exercise. 43 Repeated endoscopic examination of horses after exercise reveals a higher incidence of EIPH than is indicated by a single examination alone. In a group of 51 horses examined on three or more occasions, Mason et al14 found that 82% had EIPH at least once. Burrell2 found that 18 of 19 (95%) horses examined two or more times bled on at least one occasion. In an effort to determine the prevalence and repeatability of EIPH in horses, the author endoscopically examined 42 horses after breezing. Horses were examined 4 to 12 times. The overall prevalence of EIPH in Thoroughbreds in this training center was 62%. Of the horses initially found to be bleeders, approximately one-third were positive for EIPH on all subsequent endoscopic examinations after breezing; one-third were EIPH-posiTable 2. Incidence of Exercise-Induced Pulmonary Hemorrhage (EIPH) in Horses After Different Types of Exercise EXERCISE
BREED*
NO.
NO. WITH
%WITH
NO. WITH
%WITH
EXAMINED
EIPH
EIPH
EPISTAXIS
EPISTAXIS
Racing
TB
llBO
497
42
15
3
Racing Racing Racing Racing Breezing Pacing
TB TB
191
75
QH
231
144 16 144 49 62 66
62 52 45 26
13 0 12 2 1 9
9 0 8 4 2 14
Steeplechase Flat turf racing Timber races Endurance
TB TB
31 14
21 2
68 14
3 0
14 0
TB Mixed
3 10
2 0
67 0
2 0
100 0
Polo Cross-country
TBtrB-X Mixed
27 45
3 6
11
13
0 1
0 17
App TB STDBD
25 94
139 249
64
REFERENCE
Pascoe and Wheat Raphel Voynick Hilledge et aJI0 Hilledge et al 11 Raphel Pascoe and Wheat Raphel Raphel Raphel Sweeney and Soma 1983 Voynick Voynick
event
*TB = Thoroughbred, TB-X Quarter Horse, App = Appaloosa
=
Thoroughbred cross, STDBD
=
Standardbred, QH
EXERCISE-INDUCED P ULMONARY HEMORRHAGE
95
tive 50% to 75% of the time; and one-third were EIPH-positive 25% of the time or less. Following the results of the postexercise endoscopic examination of this group of bleeders over several months, it was apparent that the EIPH score frequently changes by one grade (either an increase or decrease). Obviously, horses that were categorized as grade -1 could fluctuate between grade O (EIPH-negative) and grade 1 (EIPH-positive).24 Although there are differences of opinion on the effects of age on the incidence of EIPH, most studies report a trend of increasing incidence of EIPH with increasing age. This age association may reflect the chronicity and possible progression of an underlying lung condition.
EIPH AND PERFORMANCE
If performance is based solely on the finishing position in a race, there is no clear association of EIPH and impaired performance. 23• 24• 28• 3.5, 36 Although it is widely accepted that EIPH is deleterious to racing performance, studies to determine the effect of EIPH on performance and ability have not been done. One study34 in which each horse's racing times were standardized for distance and adjusted for track variance reported the poorest performance (based on racing times) in that race in which EIPH was recognized. Because results of an endoscopic examination were unavailable for previous races, it still is not possible to determine the actual effects of EIPH on the performance of horses in this study.34 Although methods are available to compare an individual horse's performance between races, repeated endoscopic examinations to determine the onset of EIPH and an acceptable method of determining the presence of EIPH are necessary.
CLINICAL SIGNS Other than endoscopic observation of blood in the airways, a clearly definable set of clinical signs on which to base a diagnosis of EIPH has not been documented. Most clinical signs are nonspecific. Ascribing a pattern of clinical signs is complicated further by the variable response of individual horses to the presence of blood in the airway and the lack of knowledge concerning the lesion, if any, that predisposes to EIPH. Exercise intolerance frequently is believed to be a clinical sign associated with EIPH, however, it is difficult to determine how frequently exercise intolerance is a result of EIPH. For example, when a horse's training or racing performance is considered unacceptable, routine diagnostic evaluation often includes a postexercise endoscopic examination. If a horse that previously was considered to be a nonbleeder is found to have blood in the trachea, it usually is assumed that the exercise intolerance is a result of the EIPH. However,
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CORI NN E RAPHEL SWEENEY
research studies of horses with satisfactory exercise performance often found blood in the trachea during endoscopic examination after breezing or racing. These findings suggest that the presence of EIPH is not always associated with the trainer's perception of poor performance.
DIAGNOSIS
The ability to diagnose EIPH is dependent on the definition of the condition. If EIPH is defined as the presence of blood in the tracheobronchial tree of a horse, then confirmation of EIPH requires direct observation of blood in these airways after exercise. If the diagnosis of EIPH is more liberal and includes the acceptance of hemosiderophages in respiratory secretions, then diagnosis of EIPH can be made by identification of such cells in tracheobronchial aspirates or bronchoalveolar lavage fluid. Roszel et al33 caution against presuming that siderophages are diagnostic of hemorrhage. Although the heme from hemoglobin in the presence of hemorrhage is a common source for iron in siderocytes, it may originate from plasma in the absence of hemorrhage. Alveolar macrophage filled with macropolysaccharides can bind with plasma iron to form an iron pigment resembling hemosiderin, which stains positively with Perl's Prussian blue. Although Perl's Prussian blue often is considered a stain for hemosiderin, it is a stain for inorganic iron and does not discriminate between its sources. Roszel33 believes that this process may occur with cardiac-related pulmonary chronic passive congestion, in which large numbers of cells with pigment may be present in the tissue. Mucus, which is reported in the trachea of some horses after exercise, also may be the source of mucopolysaccharides for alveolar cell engulfment. 33 In the author's experience, tracheobronchial aspirates and bronchoalveolar fluid (BAL) aspirates from horses with excessive mucus in the respiratory tract (horses with chronic obstructive pulmonary disease [COPD]) do not have hemosiderophages. Cardiac-related pulmonary chronic passive congestion has not been determined to occur in most bleeders. Thus, the author believes that the presence of hemosiderophages in a tracheobronchial aspirate or BAL sample, although not specific, is an acceptable means to diagnose EIPH. Lung lavages from the caudodorsal lung field of horses shortly after breezing demonstrate large numbers of red blood cells and hemosiderophages. Similar samples from nonexercising horses do not have the same findings. These findings are circumstantial evidence that the presence of hemosiderophages is directly correlated with the occurrence of EIPH. The presence of blood at the nares is strongly suggestive of EIPH, whereas failure to identify blood on endoscopic examination immediately after exercise does not rule out EIPH. Because the severity of the lung hemorrhage may vary, the time between bleeding and the observation of
EXERCISE-INDUCED PULMONARY HEMORRHAGE
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blood in the trachea also varies. Some horses have blood at the nares and in the trachea at the completion of their exercise, but most horses require between 30 and 120 minutes after completion of the exercise before blood is apparent in the trachea. Considering that the tracheal mucus transport rate in the horse is approximately 1. 9 cm/min, 40 and blood in the trachea can be seen "in streams" as if being transported on a mucus elevator, this time differential is not unexpected. Horses with severe pulmonary hemorrhage have been observed to have streams of old discolored blood in the trachea up to 4 days after exercise. Most typical bleeders have blood apparent in the trachea 60 minutes after exercise. If no blood is present in the trachea and EIPH is highly suspected, a repeat endoscopic examination 60 to 90 minutes later is recommended.
RADIOGRAPHY
Radiographic examination of the thorax of bleeders indicates that despite serious and widespread lung involvement, EIPH lesions are responsible for only a vaguely discernible increase in interstitial density. 21 The predominant radiographic location is in the dorsocaudal lung field . As most bleeders have no radiographically discernible lesions several days after bleeding, an increase in soft tissue density noted in the dorsocaudal lung field at this time is suggestive of a severe episode of EIPH. Resolutions of these radiodensities can be rapid, suggesting that these changes are the result of hemorrhage rather than pneumonia, lung consolidation, or lung abscesses. Radiography is not an effective method to diagnose EIPH.
SCINTIGRAPHY
Scintigraphic imaging of ventilation and perfusion function in horses with EIPH demonstrates consistent patterns of reduced pulmonary perfusion in the caudodorsal lung fields. 21 These areas of relative perfusion deficit are confined to the dorsocaudal lung field and demonstrate a horizontal ventral margin with the normally perfused and ventilated lung below. The use of scintigraphic imaging has been reported to detect approximately 95% of horses with EIPH compared with 10% of bleeders detected by standard radiographic evaluation. 22 In addition, nuclear imaging can detect EIPH at an earlier stage of the disease, because it detects functional changes in the lung as opposed to structural changes. 22 O'Callaghan and Goulden 16 were the first to record a distinctive area of change in the peripheral extremity of the caudal lobe of the lungs associated with EIPH. An apparent progression in the radiologic changes associated with EIPH was described. An alveolar interstitial pattern progressed to superimposition of coarse bronchial densities with peribronchial cuffing and hazy, indistinct internal
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CORINNE llAPHEL SWEENEY
margins indicative of mucosal edema and inflammation. Ultimately, a chronic bronchointerstitial pattern was observed. Clarke 4 reported that histologic evidence of EIPH could be found without radiologic changes in the excised lung. The size and extent of lesions, the presence of lung tissue above the relatively dense ventral processes of the thoracic vertebra, and the density of the thoracic wall may all contribute to the failure to observe a radiologically distinct change.
PATHOLOGY
In 1974, Cook5 described a necropsy of a racehorse examined 1 month after its last episode of EIPH. Chronic bronchitis and pulmonary emphysema in the cranial third of both lungs were noted. The site of hemorrhage was described. Death after pulmonary hemorrhage is an uncommon occurrence. 5 • 9• 35 Most bleeders survive; therefore, postmortem findings associated with an episode of EIPH rarely are available. In an effort to address many of the questions associated with the pathophysiology of EIPH, a correlated clinical and pathologic study of 26 Thoroughbred racehorses with histories of EIPH was conducted in Hong Kong. 17 The mean time interval from last recorded bleeding episode to necropsy was 156 ± 141 days, range 12 to 513 days. 17 Necropsy revealed that the lungs had bilateral, symmetric, subpleural staining of the parenchyma that was preferentially distributed in the caudodorsal region of the caudal lung lobes. In collapsed lungs, these regions were blue to blue-gray. On inflation, they changed to dispersed regions of bronze-brown discoloration. These stained regions of the lung inflated and deflated slowly, suggesting that regional airflow was altered. Subpleural bronchial arteries were more prominent than in normal lungs, and the greatest density of vessels was associated with the discolored regions of lung. 18 The distribution of the pulmonary and bronchial arterial circulations and their association with a stained area of lung was determined by first injecting red latex into the bronchial arteries and then injecting blue latex into the pulmonary arteries. Systematic examination of transverse lung slices showed that rust-colored subpleural staining extended into the parenchyma; this was preferentially distributed to the dorsal bronchopulmonary segments of the lung. Also, the vessels in these stained areas were full of red latex, suggesting that these regions receive their vascular supply almost exclusively from the bronchial arterial circulation. 19 The airways within and subtending these stained areas often were abnormal and had thickening of the airway walls with either partial or complete luminal obstruction with exudate. 20 Additional supportive evidence for bronchial artery neovascularization was obtained from computed tomography and microradiography. Intense bronchial arterial neovascularization was identified within and immediately adjacent to stained areas and was focused around diseased small airways.
EXERCISE-INDUCED PULMONARY HEMORRHAGE
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Microscopic findings included bronchiolitis and increased fibrous connective tissue in interlobular septa in deeper parts of the pleura and around diseased airways and some vessels. 20 Large accumulations of macrophages and giant cells containing iron pigments were found in alveoli, airways, connective tissue around air spaces, and vessels. 20 Bronchiolitis was observed in lung regions without hemosiderophages; however, the converse was not true. Focal accumulations of eosinophils were seen in some regions with hemosiderophages but generally were located in regions distant from the hemosiderophages. 20
PATHOGENESIS
Despite the extensive epidemiologic and pathologic studies of EIPH conducted in the 1970s and 1980s, the pathogenesis of EIPH still is unknown. In 1974 Cook5 proposed that bronchiolitis or chronic lung disease was the underlying lesion of EIPH. Using the presence of mucus or mucopurulent material in the trachea to indicate .chronic lung disease, three studies found no association between EIPH and this pulmonary disease. 2· 13· 35 In 1982 O'Callaghan and Goulden16 proposed that the location of the lesion of EIPH suggests a possible parasitic pathogenesis. Alternatively, hematogenous invasion of other small particles, such as thrombi or bacteria, may cause EIPH because of their predilection for lodging in the caudal segment of the diaphragmatic lobe. Masses of veterinarians have suggested that coagulation defects are responsible for EIPH; Cook5 and Johnson et al12 eliminated coagulation deficits as an causative factor of EIPH. Pulmonary vascular hypertension as a cause of EIPH is unlikely, because massive pulmonary edema would occur with subsequent dyspnea before capillary pressure could increase enough to rupture a vessel. 30 In 1970 Rooney32 suggested that asphyxia resulting from breath holding or partial airway obstruction distends air spaces and compromises blood flow through pulmonary vessels, resulting in venous obstruction. In 1979 Robinson30 discounted this suggestion for several reasons. Clarke4 postulates that mechanical stresses during strenuous exercise may cause EIPH. Robinson and Dersken31 hypothesize that pulmonary hemorrhage results from accentuated distending forces on areas of the lungs that do not synchronize with ventilation in the rest of the lung because of subclinical airway obstruction. They suggested that the poor collateral ventilation of horses may allow extreme fluctuation of alveolar pressure in an asynchronous region, producing a parenchymal tear or capillary rupture. This theory is based on the property of interdependence of lung lobes. Cook6 proposes that EIPH is a clinical sign of recurrent laryngeal neuropathy. In their most recent work, O'Callaghan and colleagues21 suggest that small airway disease is the key feature of EIPH, and maximal exercise is required to provoke the intense hemorrhagic response. Underlying small airway disease and the
100
CORINNE RAPHEL SWEENEY
resulting partial airway obstruction increase the susceptibility of affected small airways and dependent air exchange areas to extreme hypoxia during strenuous exercise. 21 Because of gravitational effects on vertical air-exchange characteristics, partially obstructed airways in the dorsal lung are most susceptible to impaired exchange. The intense bronchial vascular response may result from both inflammation and exacerbation by the combinations of reflex shunt development to offset local tissue hypoxia. Over time there appears to be a breakdown of the precapillary control mechanisms under the effect of superior systemic pressures and flow. Local hemorrhage is believed to be from the bronchial rather than the pulmonary arteries. O'Callaghan et al21 report that susceptibility to hemorrhage can be increased by local release of heparin by macrophages or mast cells, an essential factor in angiogenesis. When combined with high systemic pressures during exercise, this could facilitate vessel fragility. Once the bronchial arteries break, left-to-right shunting is established through the control of local alveolar perfusion, and the perfusion deficits noted on scintigraphic examination become evident. 21 Recent work by Derksen and colleagues (Derksen FJ, personal communication) has demonstrated that lung injury and exercise can cause EIPH. In horses with ovalbumin-induced allergic lung disease, exercise allowed hemorrhage, which previously had not been present in large airways, to be seen on endoscopic examination. Their observations raise the possibility that in naturally occurring EIPH, hemorrhagic lung lesions are present before exercise and that exercise only serves to move blood into the large airway. Continued research ultimately will determine the pathogenesis of EIPH and lead to better preventive or therapeutic measures for the condition.
TREATMENT
Although many therapeutic regimens have been advocated to prevent EIPH in performance horses, most remedies have no proven efficacy. Until the cause of EIPH is understood, it is difficult to rationalize the use of most medications. This section discusses current thoughts on selective therapeutic regimens including management changes, furosemide, bronchodilators, hesperidin and citrus bioflavonoid, estrogens, and water vapor therapy. There is no consensus regarding the appropriate stable management of horses with EIPH. Efforts to improve the stabling environment and reduce airborne irritants possibly may be beneficial, but they are difficult to implement. The association of small airway disease and EIPH may be significant, and environmental changes to decrease the inhalation of irritants and allergens may improve respiratory function . Prolonged rest periods may be beneficial, but most horses bleed after return to the previous level
EXERCISE-INDUCED PULMONARY HEMORRHAGE
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of training or racing. Prerace management factors may have some benefit in controlling EIPH. The most common management technique is drawing; that is, feed and water are removed before breezing or racing. 1 Hay is withdrawn from the horse for 6 to 24 hours before race time. Water is withdrawn 3 to 12 hours before racing. Some trainers allow horses free access to both hay and water up to race time on the belief that psychologic factors may be as important as physiologic ones. 1 Management of horses after episodes of EIPH usually is not required. In most horses, hemorrhage ceases within hours after racing. Although massive episodes of pulmonary hemorrhage may result in fatalities, the frequency of this occurrence is low. 9 If massive nonfatal pulmonary hemorrhage occurs, prophylactic treatment with broad-spectrum antimicrobial drugs is indicated to prevent secondary bacterial infection. Such horses should be rested for several weeks to months. Furosemide is the most popular drug used in the treatment of EIPH. Most states regulate the use of furosemide and allow it to be administered only from 120 to 240 minutes before racing. In some states, the dose of furosemide is restricted to less than 250 mg intravenously; many states have no dosage restriction. When furosemide's use is unrestricted by law, the drug usually is administered at a dosage of approximately 150 to 300 mg intravenously 90 to 120 minutes before racing. In refractory cases of EIPH, some practitioners administer 350 to 500 mg furosemide divided into two doses, one at 5 or 6 hours and the other at the permitted time before racing. The origin of furosemide as a treatment for EIPH is unknown, but it is presumed that its use was based on the assumption that EIPH is preceded by pulmonary edema. Although pulmonary edema as an underlying cause of EIPH is possible, there is no evidence that exercising horses experience pulmonary edema. The efficacy of furosemide in prevention of EIPH has been reported. 7• 8 • 23• 24 • 37 • 38 • 41 In 1981 Pascoe et al 24 reported that of 56 furosemide~treated horses, 30 (53.6%) showed evidence of EIPH after racing. Pascoe states "Assuming that these horses were legitimately treated because of prior episodes of EIPH, the results create doubts about the efficacy of furosemide treatment for the prevention of EIPH. It is not known, however, whether furosemide reduced the amount of hemorrhage these horses may have otherwise experienced. "24 A subsequent study showed that of 61 horses with a history of EIPH treated with furosemide before racing, 34 (55. 7%) continued to bleed. 37 Both of these studies determined the presence or absence of blood in the tracheobronchial tree but did not grade the amount of blood seen. In another study, 38 three horses were repeatedly given furosemide at varying doses ranging from 350 to 600 mg before breezing; no change was noted in the EIPH incidence or degree. 38 In 1985 Pascoe et al25 reported that although furosemide did not stop EIPH, it did reduce the EIPH score in 28 (64%) of 44 horses. In that study, of 15 horses studied
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CORINNE RAPHEL SWEENEY
after racing, 53% of them continued to be EIPH-positive. Of 38 bleeders examined after breezing, 47% of them were noted to bleed. This study indicates that although furosemide does not decrease the incidence of EIPH, it may decrease the degree of bleeding. However, this conclusion should be viewed cautiously because of the subjectivity of the nature of the EIPH scoring system. Additionally, the anatomic relationship between the site of bleeding and the site of observation in the trachea, the efficiency of mucociliary clearance, the volume of blood, the rate of bleeding, and the time between exercise and observation all may influence the EIPH score. 25 Despite these inherent weaknesses, a scoring method was used because it seemed reproducible and was the only method available for evaluating responses of EIPH-positive horses to therapy. 25 A recent study by Erickson et aF reports that "furosemide did not prevent horses from hemorrhaging while exercising on the treadmill." These same researchers report that "furosemide failed to prevent horses from hemorrhaging during exercise in this study, nor did it appear to reduce the amount of hemorrhage. "8 In summary, several reports confirm that furosemide does not prevent EIPH in racehorses. There is evidence for and against the assertion that furosemide may reduce the amount of bleeding in horses with EIPH. This assertion has not been proved and needs further study. A preliminary study38 of the use of parasympatholytic bronchodilators showed a decrease in the prevalence of EIPH; however, subsequent investigations by the same and other15 investigators failed to document this improvement. Because of restrictive racing medication rules, many horse trainers have sought feed supplements that might have therapeutic value in the treatment of EIPH. A group of flavonoids that strengthens capillaries has been demonstrated in citrus and paprika. These flavonoids are thought to be essential for normal capillary integrity and to act synergistically with ascorbic acid. Citrus bioflavonoids used in conjunction with ascorbic acid reportedly enhance the efficacy of other therapeutic agents in controlling infection, stress, and nutritional deficiencies in humans. Although anecdotal reports suggest that bioflavonoids are helpful in preventing EIPH, controlled studies using a dose of 20 g/d for 90 days did not alter the prevalence of EIPH. 37 Conjugated estrogens are permitted for the treatment of EIPH in some racing jurisdictions. These substances reduce capillary bleeding and accelerate blood clotting in laboratory animals. As previously mentioned, no coagulation defects have been noted with EIPH; therefore, no rationale exists for therapy with conjugated estrogens. Commonly used preparations are potassium estrone sulfate or a mixture of sodium estrone sulfate and equilin sulfate. Conjugated estrogens can be used concurrently with furosemide. Numerous coagulants and anticoagulants have been used in the treatment of EIPH. Because no coagulation defect has been demonstrated, these treatments are unwarranted.
EXERCISE-INDUCED PULMONARY HEMORRHAGE
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Water vapor therapy is probably the oldest known respiratory therapy. Despite the long history of its use in humans, there is no clear evidence of any beneficial effects. Controlled studies using endoscopy have shown that water vapor-saturated air therapy does not change the bleeding status of horses. 39
REFERENCES 1. Arthur RM: Respiratory problems in the racehorse. Vet Clin North Am Equine Practice 6:179, 1990 2. Burrell MH: Endoscopic and virological observations on respiratory disease in a group of young Thoroughbred horses in training. Equine Vet J 17:99, 1985 3. Choy TH: cited in Cook WR: Epistaxis in the racehorse. Equine Vet J 6:45, 1972 4 . Clarke AF: Review of exercise induced pulmonary hemorrhage and its possible relationship with mechanical stress. Equine Vet J 17:166, 1985 5. Cook WR: Epistaxis in the racehorse. Equine Vet J 6:45, 1974 6. Cook WR, Williams RM, Kirkerhead CA, et al: Upper airway obstruction (partial asphyxia) as the possible cause of exercise-induced pulmonary hemorrhage in the horse: An hypothesis. J Eq Vet Sci 8:11, 1988 7. Erickson BK, Erickson HH, Coffman JR: Exercise-induced pulmonary hemorrhage during high intensity exercise: Potential causes and the role of furoserriide. Proceedings, AAEP 35:375, 1989 8. Erickson BK: Does the research support using furosemide? The Equine Athelete 11:35, 1989 9. Gunson DE, Sweeney CR, Soma LR: Sudden death attributable to exercise-induced pulmonary hemorrhage in racehorses: New cases (1981-1983). J Am Vet Med Assoc 193:102, 1988 10. Hilledge CJ, Lane TJ, Johnson EL, et al: Preliminary investigations of exercise-induced pulmonary hemorrhage in racing Quarter Horse. Equine Veterinary Science 4:21, 1984 11. Hilledge CJ, Lane TJ, Whitlock TW: Exercise-induced pulmonary hemor,rhage in the racing Appaloosa horse. Equine Veterinary Science 5:351, 1984 12. Johnson JH, Garner HE, Hutcheson DP, et al: Epistaxis. Proceedings AAEP 19:115, 1973 13. MacNamara B, Bauer S, Iafe J: Endoscopic evaluation of exercise-induced pulmonary hemorrhage and chronic obstructive pulmonary disease in association with poor performance in racing Standardbreds. J Am Vet Med Assoc 196:443, 1990 14. Mason DK, Collins EA, Watkins KL: Exercise-induced pulmonary haemorrhage in horses. In Snow DH, Persson SGB, Rose RJ (eds): Equine Exercise Physiology. Cambridge, Granta Editions, 1983, p 57 15. McDonnell W, Viel L, Tesarowski D , et al: Clenbuterol treatment for exercise-induced pulmonary hemorrhage (EIPH) in horses. Proceedings Veterinary Respiratory Symposium 8:94, 1989 16. O'Callaghan MW, Goulden BE: Radiographic changes in the lungs of horses with exerciseinduced epistaxis. NZ Vet J 30:117, 1982 17. O'Callaghan MW, Pascoe JR, Tyler MS: Exercise-induced pulmonary hemorrhage in the horse: Results of a detailed clinical, post mortem and imaging study. I. Clinical profile of horses. Equine Vet J 19:384, 1987 18. O'Callaghan MW, Pascoe JR, Tyler MS, et al: Exercise-induced pulmonary hemorrhage in the horse: Results of a detailed clinical, postmortem and imaging study. II. Gross lung pathology. Equine Vet 9:389, 1987 19. O'Callaghan MW, Pascoe JR, Tyler MS, et al: Exercise-induced pulmonary hemorrhage in the horse: Results of a detailed clinical, postmortem and imaging study. III. Subgross findings in lungs, subjected to later perfusion of the bronchial and pulmonary arteries. Equine Vet J 19:394, 1987 20. O'Callaghan MW, Pascoe JR, Tyler MS, et al: Exercise-induced pulmonary hemorrhage in the horse: Results of a detailed clinical, postmortem and imaging study. V. Microscopic observations. Equine Vet J 19:411, 1987
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21. O'Callaghan M: Recent progress on the pathogenesis and diagnosis of exercise-induced pulmonary hemorrhage in horses. Proceedings American College of Veterinary Internal Medicine 6:625, 1988 22. O'Callaghan M: New clues about EIPH. The Equine Athelete 1:1, 1988 23. Pascoe JR, Wheat JD: Historical background, prevalence, clinical findings and diagnosis of exercise-induced pulmonary hemorrhage (EIPH) on the racing horse. Proceedings AAEP 26:417, 1980 24. Pascoe JR, Ferraro CL, Cannon JH, et al: Exercise-induced pulmonary haemorrhage in racing Thoroughbreds: A preliminary study. Am J Vet Res 24:703, 1981 25. Pascoe JR, McCabe AE, Franti CE, et al: Efficacy of furosemide in the treatment of exercise-induced pulmonary hemorrhage in Thoroughbred racehorses. Am J Vet Res 46:2000, 1985 26. Pfaff G : Epistaxis in racehorses: Incidence in South Africa. J S Afr Vet Med Assoc 21:74, 1950 27. Pfaff G: The incidence of epistaxis in racehorses in South Africa. J S Afr Vet Med Assoc 47:215, 1976 28. Raphel CF, Soma RS: Exercise-induced pulmonary haemorrhage in Thoroughbreds after racing and breezing. Am J Vet Res 43:1123, 1982 29. Robertson JB: Biological search on racehorse breeding VI: The hereditary of blood vessel breaking in the Thoroughbred. The Bloodstock Breeder's Review 1:265, 1913 30. Robinson NE: Functional abnormalities caused by upper airway obstruction and heaves. Their relationship to the aetiology of epistaxis. Vet Clin North Am Large Anim Pract 1:17, 1979 31. Robinson NE, Derksen FJ: Small airway obstruction as a cause of exercise associated pulmonary haemorrhage: An hypothesis. Proceedings AAEP 26:421, 1980 32. Rooney JR: Technique and interpretation; Autopsy of the horse. Baltimore, William & Wilkins, 1970, p 117 33. Roszel JF, Freeman KP, Slusher SH, et al: Siderophage in pulmonary cytology specimens from racing and non-racing horses. Proceedings AAEP 33:321, 1987 34. Soma LR, Laster L, Oppenlander F , et al: Effects of furosemide on the racing times of horses with exercise-induced pulmonary hemorrhage. Am J Vet Res 46:763, 1985 35. Speirs VC, Van Veenendaal JD, Harrison IW, et al: Pulmonary haemorrhage in Standardbred horses after racing. Aust Vet J 59:38, 1982 36. Sweeney CR, Soma LR: Exercise-induced pulmonary haemorrhage in horses after different competitive exercises. Proceedings First International Conference Equine Exercise Physiology, September 1982:51, 1983 37. Sweeney CR, Soma LR: Exercise-induced pulmonary haemorrhage in Thoroughbred horses: Response to furosemide ofhesperidin-citrus bioflavinoids. J Am Vet Med Assoc 185:195, 1984 38. Sweeney CR, Soma LR, Bucan CA, et al: Exercise-induced pulmonary hemorrhage in exercising Thoroughbreds: Preliminary results with pre-exercise medication. Cornell Vet 74:263, 1984 39. Sweeney CR, Hall J, Fisher J, et al: Efficacy of water-vapor saturated air in the treatment of EIPH in Thoroughbred racehorses. Am J Vet Res 49:1705, 1988 40. Sweeney CR: Tracheal mucus transport rates in healthy horses. Am J Vet Res 50:2135, 1989 41. Sweeney CR, Soma LR, Maxson AD, et al: Effects of furosemide on the racing times of Thoroughbreds. Am J Vet Res 51:772, 1990 42. Voynick B, Sweeney CR: Exercise-induced pulmonary hemorrhage in Philippine racehorses and polo ponies. J Am Vet Med Assoc 188:301, 1985 43. Whitwell JE, Greet TRC: Collection and evaluation of tracheobronchial washes in the horse. Equine Vet J 16:499, 1984
Address reprint requests to Corinne Raphel Sweeney, DVM University of Pennsylvania School of Veterinary Medicine 382 West Street Road Kennett Square, PA 19348
