Exercise-induced pulmonary hemorrhage

Exercise-Induced Pulmonary Hemorrhage
The Ohio State University, Columbus, Ohio Epidemiology
Exercise-induced pulmonary hemorrhage (EIPH) occurs in horses that race at high speeds, such as Thoroughbred and Standardbred racehorses. The disease is almost unknown in endurance horses ordraft breeds. As a general rule, the more intense the exercise or higher the speed attained, the greaterthe proportion of horses with EIPH.
The prevalence of EIPH varies with the method used to detect it and the frequency with which horses are examined. Almost all Thoroughbred racehorses in active training have hemosiderophages in bron-choalveolar lavage fluid, indicating that all have some degree of EIPH (McKane et al., 1993). Theprevalence of EIPH decreases when diagnosis is based on endoscopic examination of horses after exer-cise or racing.
EIPH is very common in Thoroughbred racehorses with estimates of prevalence, based on a single endoscopic examination of the trachea and bronchi, of 43 to 75% (Pascoe et al., 1981a; Raphel andSoma, 1982; Mason et al., 1983). The prevalence increases with the frequency of examination, with over80% of horses having evidence of EIPH on at least one occasion after three consecutive races (Sweeneyet al., 1990). When examined after each of three races, 87% of Standardbred racehorses have evidenceof EIPH on at least one occasion (Lapointe et al., 1994), suggesting that EIPH is as common inStandardbred racehorses as it is in Thoroughbred racehorses.
History and Presenting Complaint
Poor athletic performance or epistaxis (bleeding from the nostrils) are the most common presenting complaints for horses with EIPH. Epistaxis due to EIPH occurs during or shortly after exercise and is usu-ally first noticed at the end of a race, particularly when the horse is returned to the paddock or winner’scircle and is allowed to lower its head. Failure of racehorses to perform to the expected standard (poor performance) is often attributed to EIPH. Many horses with poor performance have cytologic evidence of EIPH on microscopic examinationof tracheobronchial aspirates or bronchoalveolar lavage fluid or have blood evident on endoscopicexamination of the tracheobronchial tree performed 30 to 90 minutes after strenuous exercise or racing(McKane et al., 1993; Martin et al., 1999). Severe EIPH undoubtedly results in poor performance and, onrare occasions, death of Thoroughbred racehorses (Gunson et al., 1988). We recently completed a study of Thoroughbred horses racing in Melbourne, Australia. The study involved endoscopic examination of 744 horses after racing. There was a clear association between pres-ence and severity of EIPH and performance; horses with any more than a fleck of blood in the airway had poorer performances than unaffected horses. These horses were not racing after administration offurosemide (Lasix, Salix) as use of this drug is not permitted on race day in Australia. However, it isimportant to recognize that EIPH is very common in racehorses and it should be considered the cause ofpoor performance only after other causes have been eliminated. Diagnosis of EIPH
There are a variety of techniques available for determining the presence and severity of EIPH includ- ing direct visualization of the airways through a flexible endoscope or examination of bronchial lavagefluid or tracheal aspirates for evidence of hemorrhage. The utility of these diagnostic tests varies andchoice of examination technique depends on the time between the horse racing and the examination,and the desired sensitivity of the test. For instance, tracheobronchoscopic examination is most appropri-ate if a horse is examined within 1-2 hours of exercise, whereas examination of airway washings is mostappropriate if the examination is days to a week after strenuous exercise. Radiography, pulmonaryscintigraphy, and lung function tests are useful in eliminating other respiratory diseases as a cause ofpoor performance, but are minimally useful in confirming a diagnosis of EIPH or in determining theseverity of hemorrhage.
Observation of blood in the trachea or large bronchi of horses 30-120 minutes after racing or strenu- ous exercise provides a definitive diagnosis of EIPH. The amount of blood in the large airways varies froma few small specks on the airway walls to abundant blood covering the tracheal surface. Blood may alsobe present in the larynx and nasopharynx. If there is a strong suspicion of EIPH and blood is not presenton a single examination conducted soon after exercise, the examination should be repeated 60-90 min-utes later. Some horses with EIPH do not have blood present in the rostral airways immediately afterexercise, but do so when examined 1-2 hours later. Blood is detectable by tracheobronchoscopic exami-nation for 1-3 days in most horses, with some horses having blood detectable for up to 7 days.
A grading system can be used to estimate the severity of EIPH following bronchoscopic examination (Pascoe et al., 1981b; Mason et al., 1983; Pascoe et al., 1985; Lapointe et al., 1994). A commonly usedgrading system has four levels from 0 (no hemorrhage visible) to 3 (streak of blood >5 mm wide). The presence of red cells or macrophages containing either effete red cells or the breakdown prod- ucts of hemoglobin (hemosiderophages) in tracheal or bronchoalveolar lavage fluid provides evidenceof EIPH. Detection of red cells or hemosiderophages in tracheal aspirates or bronchoalveolar lavage fluidis believed to be both sensitive and specific in the diagnosis of EIPH (Fogarty and Buckley, 1991; McKaneet al., 1993). Examination of airway fluids indicates the presence of EIPH in a greater proportion of hors-es than does tracheobronchoscopic examination after strenuous exercise or racing. The greatersensitivity of examination of airway fluid is likely attributable to the ability of this examination to detectthe presence of small amounts of blood or its residual products and the longevity of these products inthe airways. Recent studies have reported on the use of red cell numbers in bronchoalveolar lavage fluidas a quantitative indicator of EIPH (Meyer et al., 1998; Langsetmo et al., 2000; Geor et al., 2001; Kindiget al., 2001). However, this indicator of EIPH severity has not been validated or demonstrated to be morereliable or repeatable than tracheobronchoscopic examination and visual scoring. Pathophysiology and Etiology
Ultimately, the cause of EIPH is rupture of alveolar capillary membranes with subsequent leakage of blood into interstitial and alveolar spaces (West et al., 1993). The source of blood in such instances is thepulmonary circulation. Bleeding from bronchial circulation during exercise has been suggested based onhistologic evidence of bronchial angiogenesis in horses that have experienced previous episodes of EIPH(Pascoe, 1996). Whether there is a contribution of the bronchial circulation to EIPH has not been deter-mined. Hemorrhage into the interstitial space and alveoli, with subsequent rostral movement of bloodinto the airways, results in blood in the trachea and bronchi and, infrequently, epistaxis.
Rupture of alveolar capillaries occurs secondary to an exercise-induced increase in transmural pres- sure (pressure difference between the inside of the capillary and the alveolar lumen). If the transmuralstress exceeds the tensile strength of the capillary wall, the capillary ruptures (West and Mathieu-Costello, 1994). The proximate cause of alveolar capillary rupture is the high transmural pressuregenerated by positive intracapillary pressures (largely attributable to capillary blood pressure) and thelower intraalveolar pressure (generated by the negative pleural pressures associated with inspiration).
During exercise, the absolute magnitudes of both pulmonary capillary pressure and alveolar pressureincrease, with a consequent increase in transmural pressure (West and Mathieu-Costello, 1994;Ducharme et al., 1999). Other theories of the pathogenesis of EIPH include small airway disease, upperairway obstruction, hemostatic abnormalities, changes in blood viscosity and erythrocyte shape,intrathoracic shear forces associated with gait, and bronchial artery angiogenesis (Pascoe, 1996;Schroter et al., 1998). It is likely that the pathogenesis of EIPH involves several processes, including pul-monary hypertension, lower alveolar pressure, and changes in lung structure, that summate to inducestress failure of pulmonary capillaries. Regardless of the cause, rupture of pulmonary capillaries and subsequent hemorrhage into airways and interstitium cause inflammation of both airways and interstitium with subsequent development offibrosis and alteration of tissue compliance. Heterogeneity of compliance within the lungs, and particu-larly at the junction of normal and diseased tissue, results in development of abnormal shear stress withsubsequent tissue damage. These changes are exacerbated by inflammation and obstruction of smallairways with resulting uneven inflation of the lungs (Robinson and Derksen, 1980). The structuralabnormalities, combined with pulmonary hypertension and the large intrathoracic forces associatedwith respiration during strenuous exercise, cause repetitive damage at the boundary of normal and dis-eased tissue with further hemorrhage and inflammation. The process continues for as long as the horseperforms strenuous exercise (Pascoe, 1996).
Treatment and Prognosis
Therapy for EIPH is controversial in that many treatments are used but none are backed by conclusive evidence of efficacy in horses under field conditions (i.e., racing). Therapy for EIPH is usually a combina-tion of attempts to reduce the severity of subsequent hemorrhage and efforts to minimize the effect ofrecent hemorrhage. Treatment of EIPH is problematic for a number of reasons. Firstly, the pathogenesis of EIPH has not been determined, although the available evidence supports a role for stress failure of pulmonary capil-laries secondary to exercise-induced pulmonary hypertension (see below). Secondly, there is a lack of information using large numbers of horses under field conditions that demonstrates an effect of any medication or management practice (with the exception of bedding) onEIPH. There are numerous studies of small numbers of horses (<~40) under experimental conditions,but these studies often lacked the statistical power to detect treatment effects, and the relevance ofstudies conducted on a treadmill to horses racing competitively is questionable. Treatments for EIPH areusually intended to address a specific aspect of the pathogenesis of the disease and will be discussed inthat context.
Prevention of stress failure of the pulmonary capillaries Stress failure of pulmonary capillaries, and subsequent hemorrhage, is believed to occur as a result of the high transmural pressures in pulmonary capillaries that develop in the lungs of horses during stren-uous exercise. Consequently, there is interest in reducing the pressure difference across the pulmonarycapillary membrane in an effort to reduce EIPH. Theoretically, this can be achieved by reducing the pres-sure within the capillary or increasing (making less negative) the pressure within the intrathoracicairways and alveolus.
Furosemide administration as prophylaxis of EIPH is permitted in a number of racing jurisdictions worldwide (Anonymous, 2002). Within the United States and Canada, almost all Thoroughbred,Standardbred, and Quarter Horse racing jurisdictions permit administration of furosemide before racing.
Approximately 85% of all Thoroughbred racehorses in the United States and Canada receive furosemideat some stage in their careers, and on average, 75% of horses in a race receive furosemide (Gross et al.,1999). Although accurate numbers are not available, it appears that a smaller proportion ofStandardbred and Quarter Horse racehorses receive furosemide before racing. Furosemide is adminis-tered to 22-32% of Standardbred racehorses and 19% of racing Quarter Horses in two racingjurisdictions (Sime et al., 1994; Soma et al., 1996; Soma et al., 2000).
The efficacy of furosemide in treatment of EIPH is uncertain. While field studies of large numbers of horses do not demonstrate an effect of furosemide on the prevalence of EIPH (Sweeney et al., 1990;Birks et al., 2002), studies of Thoroughbred horses running on a treadmill provide evidence thatfurosemide reduces the severity of EIPH (Geor et al., 2001; Kindig et al., 2001). Under field conditions,based on tracheobronchoscopic evaluation of the severity of bleeding, furosemide has been reported toreduce or have no influence on the severity of bleeding (Pascoe et al., 1985; Birks et al., 2002). Thisapparent inconsistency may be attributable to measurement of red blood cell counts in bronchoalveolarlavage fluid of horses that have run on a treadmill not being representative of effects of furosemideunder field conditions. The weight of evidence from field studies does not support a role for furosemidein preventing or reducing the severity of EIPH.
Furosemide is associated with superior performance in both Thoroughbred and Standardbred race- horses (Gross et al., 1999; Soma et al., 2000). Thoroughbred horses treated with furosemide were 1.4times as likely to win a race and earn more money, and had a standardized 6-furlong race time 0.56 to1.09 seconds less than untreated horses (Gross et al., 1999). Similarly, furosemide reduced one-mile racetimes of Standardbred pacers by 0.31 to 0.74 seconds (Soma et al., 2000). Nitric oxide is a potent vasodilator in many vascular beds. Administration of nitroglycerin (a nitric oxide donor) reduces pulmonary artery pressure of standing horses but does not affect pulmonaryartery pressure of horses during intense exercise (Manohar and Goetz, 1999). L-arginine is a nitric oxidedonor with no demonstrated efficacy in reducing pulmonary capillary pressure or EIPH in horses.
Sildenafil, a phosphodiesterase inhibitor that accentuates the effect of nitric oxide and is used in thetreatment of erectile dysfunction in men, has been administered to horses in an apparent attempt toreduce EIPH. However, its efficacy in preventing EIPH or reducing pulmonary capillary pressure has notbeen demonstrated.
Recently, the role of the nares in contributing to upper airway resistance, and hence lowering inspira- tory intrapleural pressure during intense exercise, has attracted the attention of some investigators.
Application of nasal dilator bands (Flair® strips) reduces nasal resistance by dilating the nasal valve(Holcombe et al., 2002), and reduces red cell count of bronchoalveolar lavage fluid collected from horsesafter intense exercise on a treadmill (Geor et al., 2001; Kindig et al., 2001). However, the effect of thisintervention in horses racing competitively has not been demonstrated.
The role of small airway inflammation and bronchoconstriction in the pathogenesis of EIPH is unclear. However, horses with EIPH are often treated with drugs intended to decrease lower airwayinflammation and relieve bronchoconstriction. Beta-adrenergic bronchodilatory drugs such as clen-buterol and albuterol are effective in inducing bronchodilation in horses with bronchoconstriction, buttheir efficacy in preventing EIPH is either unknown or, in very small studies, is not evident. Clenbuteroldoes not alter the hemodynamic responses of horses to exertion or attenuate exercise-induced arterialhypoxemia in normal horses (Slocombe et al., 1992; Manohar et al., 2000). Ipratropium, a parasympa-tholytic drug administered by inhalation, showed promised in a very small study (2 horses) ofpreventing EIPH (Sweeney et al., 1984). Corticosteroids, including dexamethasone, fluticasone, andbeclomethasone administered by inhalation, parenterally, or enterally, reduce airway inflammation andobstruction, but have no demonstrated efficacy in preventing EIPH. Cromolyn sodium (sodium cromo-glycate) has no efficacy in preventing EIPH (Hillidge et al., 1987).
Reducing Inflammation
Hemorrhage into interstitial tissues induces inflammation with subsequent development of fibrosis and bronchial artery angiogenesis (O’Callaghan et al., 1987; McKane and Slocombe, 1999; McKane andSlocombe, 2002). The role of these changes in perpetuating EIPH in horses is unclear but likely is of some importance. Treatments to reduce inflammation and promote healing with minimal fibrosis have beenproposed. Rest is an obvious recommendation and many racing jurisdictions have rules regardingenforced rest for horses with epistaxis. While the recommendation for rest is intuitive, there is no infor-mation that rest reduces the severity or incidence of EIPH in horses with prior evidence of this disorder.
Similarly, corticosteroids are often administered, either by inhalation, enterally or parenterally, in an attempt to reduce pulmonary inflammation and minimize fibrosis. Again, the efficacy of this interven-tion in preventing or minimizing severity of EIPH has not been documented.
Excessive Bleeding
These is no evidence that horses with EIPH have defective coagulation or increased fibrinolysis (Bayly et al., 1983; Johnstone et al., 1991). Regardless, aminocaproic acid, a potent inhibitor of fibrin degrada-tion, has been administered to horses to prevent EIPH. The efficacy of aminocaproic acid in preventingEIPH has not been demonstrated. Similarly, estrogens are given to horses with the expectation ofimproving hemostasis although effect of estrogens on coagulation in any species is unclear. There is noevidence that estrogens prevent EIPH in horses.
Vitamin K is administered to horses with EIPH presumably with the expectation that it will decrease coagulation times. However, as EIPH is not associated with prolonged bleeding times, it is unlikely thatthis intervention will affect the prevalence or severity of EIPH. Aspirin inhibits platelet aggregation in horses and increases bleeding time (Kopp et al., 1985).
Seemingly paradoxically, aspirin is sometimes administered to horses with EIPH because of concernsthat increased platelet aggregation contributes to EIPH (Mahony et al., 1992). There is no evidence thataspirin exacerbates or prevents EIPH. Capillary fragility increases the risk of hemorrhage in many species. Various bioflavinoids have been suggested to increase capillary integrity and prevent bleeding. However, hesperidin and citrus bioflavi-noids have no efficacy in prevention of EIPH in horses (Sweeney and Soma, 1984). Similarly, vitamin C isadministered to horses with EIPH without scientific evidence of any beneficial effect.
Overview of Treatment
Selection of therapy for horses with EIPH is problematic. Given that most horses have some degree of pulmonary hemorrhage during most bouts of intense exercise, the decision must be made not only as tothe type of treatment and its timing but also which horses to treat. Moreover, the apparent progressivenature of the disease with continued work highlights the importance of early and effective prophylaxisand emphasizes the need for studying factors, such as air quality and respiratory infections, that incitethe disorder. The currently favored treatment for EIPH is administration of furosemide before intense exercise. Its use is permitted in racehorses in a number of countries. Increasingly persuasive laboratory evidence ofan effect of furosemide to reduce red cell count in bronchoalveolar lavage fluid collected from horsessoon after intense exercise supports the contention that furosemide is effective in reducing the severityof EIPH in racehorses. However, it should be borne in mind that neither the relationship between severi-ty of EIPH and red cell count in bronchoalveolar lavage fluid nor the efficacy of furosemide in reducingseverity of EIPH in racehorses in the field have been demonstrated. In fact, there is strong evidence thatfurosemide does not reduce the prevalence of EIPH and other evidence that it does not reduce the sever-ity of EIPH under field conditions. The association between furosemide administration and superiorperformance in Standardbred and Thoroughbred racehorses should be considered when recommendinguse of this drug. Rest is an obvious recommendation for horses with EIPH, but the hemorrhage is likely to recur when the horse is next strenuously exercised. The duration of rest and the optimal exercise program to returnhorses to racing after EIPH is unknown, although some jurisdictions require exercise no more intensethan trotting for 2 months. Firm recommendations cannot be made on duration of rest because of a lackof objective information.
Although a role for lower airway disease (either infectious or allergic) in the genesis of EIPH has not been demonstrated, control of infectious diseases and minimization of noninfectious lower airwayinflammation appears prudent.
Prognosis
The prognosis for racing for horses with clinically significant EIPH is guarded because of the progres- sive nature of the disease. Horses that have experienced severe EIPH on one occasion are likely to do soagain regardless of treatment. However, the risk of horses experiencing a repeated bout of severe hem-orrhage and the effect of EIPH on career longevity are unknown.
Further Reading
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Uboh. 2002. EIPH: Postrace endoscopic evaluation of Standardbreds amd Thoroughbreds. Equine Vet. J. Suppl. 34:375-378.
Ducharme, N.G., R.P. Hackett, R.D. Gleed, D.M. Ainsworth, H.N. Erb, L.M. Mitchell, and L.V. Soderholm. 1999. Pulmonary capillary pressure in horses undergoing alteration of pleural pressure by imposition of various airway resistive loads. Equine Vet.
Fogarty, U., and T. Buckley. 1991. Bronchoalveolar lavage findings in horses with exercise intolerance. Equine Vet. J. 23: Geor, R.J., L. Ommundson, G. Fenton, and J.D. Pagan. 2001. Effects of an external nasal strip and frusemide on pulmonary haemorrhage in Thoroughbreds following high-intensity exercise. Equine Vet. J. 33: 577-584.
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