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Exercise-Induced Pulmonary Hemorrhage
C H A P T E R
58
Exercise-Induced Pulmonary Hemorrhage ALICE STACK
PREVALENCE
Exercise-induced pulmonary hemorrhage (EIPH) is a common condition of intensely exercising horses and occurs in up to 75% of horses that race. However, studies have indicated that when horses are evaluated by means of tracheobronchoscopy after each of three races, blood is observed in the large airways of all horses (100%) on at least one of these evaluations. Although the condition is most commonly identified in racing Thoroughbreds, and to a similar extent in Standardbreds, EIPH has also been described in other breeds, such as racing Quarter Horses and polo ponies.
EFFECT ON PERFORMANCE
Exercise-induced pulmonary hemorrhage has a negative effect on racehorse performance. In a study performed in Australia in which 744 Thoroughbred racehorses were evaluated by endoscopy after racing, it was determined that horses with either mild EIPH or no evidence of blood in the large airways were four times as likely to win and almost twice as likely to place in the top three as horses with moderate or severe EIPH.
RISK FACTORS
Exercise-induced pulmonary hemorrhage affects most, if not all, intensely exercising horses to some degree. Besides exercise, other risk factors for EIPH have not been consistently identified. In the largest study evaluating risk factors for EIPH, horses with more than 50 lifetime starts are 1.8 times as likely to have any evidence of EIPH as those with 40 starts or less. Age and sex are not associated with EIPH risk, whereas ambient temperatures less than 68° F (20° C) and a longer time between race finish and examination (up to 60 minutes) are associated with an increased risk for EIPH being diagnosed with endoscopy. Risk factors for postrace epistaxis, which is probably a manifestation of severe EIPH, and EIPH that is diagnosed only endoscopically are not identical. Rather, epistaxis is observed more commonly in older racing animals than in 2-year-olds, in mares more than in stallions, and after shorter, faster races (<1 mile or 1600 meters) than after longer ones.
PATHOPHYSIOLOGY Pathogenesis of EIPH
To discuss therapeutic approaches to this condition, both the pathology and how it relates to the proposed theories of pathogenesis must first be described in some detail. Although extensive descriptions of the clinical and pathologic features of EIPH exist in the literature, critical information detailing exact mechanisms of the condition is still lacking. The first, and until recently the most comprehensive, review of EIPH pathology was performed more than 20 years ago. Specifically, grossly evident pleural discoloration (blueblack) of the caudodorsal lung regions was seen, and on
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histologic evaluation, extensive hemosiderosis, angiogenesis, pleural and septal fibrosis, and bronchiolitis (small airway inflammatory disease) were consistent findings. Authors of that study proposed that bronchiolitis played a causative role in EIPH. However, several lines of evidence exist that do not support this relationship. First, in more recent studies, bronchiolitis was not found in association with the other histopathologic features of EIPH. Second, in an epidemiologic study performed in the United Kingdom, some association between inflammatory airway disease and EIPH was detected in Thoroughbreds in training. However, this association cannot be interpreted as a cause-and-effect relationship because both conditions have a high prevalence in that study population. Finally, if airway inflammation was a significant contributing factor, routine treatments for inflammatory airway disease, such as systemic or nebulized corticosteroids and nonsteroidal antiinflammatory drugs, with or without antimicrobial therapy, would be expected to control EIPH. Although the latter treatments have never been formally investigated, in a clinical setting at least, such therapeutic regimens are not perceived to affect EIPH incidence or severity. A breakthrough study in 1993 demonstrated that pulmonary capillary rupture or disruption was commonly detected in lung tissue that had evidence of extravasation of red blood cells. These extravascular red cells were found both in the pulmonary interstitium and in surrounding alveolar airspaces. This work strongly implicated the pulmonary circulation as the source of hemorrhage in EIPH, and on the basis of these data, it was proposed that so-called stress failure of pulmonary capillaries secondary to transient but significant pulmonary circulation hypertension during exercise resulted in capillary disruption. This concept was strongly corroborated by studies that evaluated the magnitude of blood pressures in the horse’s pulmonary circulation during exercise. Pulmonary arterial pressures of approximately 100 mm Hg are reported, and from these measurements, pulmonary capillary pressures from 72.5 to 83.3 mm Hg can be calculated. Pressures of these magnitudes are unparalleled in any other mammalian species that has been investigated. This information, when considered in the context of a study that described the breaking strength of the horse’s pulmonary capillaries (75 mm Hg), makes pulmonary capillary stress failure a plausible theory of pathogenesis for EIPH. However, this theory does not account for the pathology seen in the lungs of horses with EIPH.
Pathology More recent descriptions of the pathologic features of EIPH have identified a novel lesion in the lungs of horses affected by EIPH—that of venous remodeling. This lesion affects small pulmonary veins (a caliber range of 100 to 200 µm outer diameter) and is characterized mainly by accumulation
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of adventitial collagen and, in some vessels, smooth muscle hyperplasia. In the most severely affected vessels, the lumen is significantly obstructed. Increases in pressure and shearing stresses, such as would be associated with high-flow states, are known stimuli of vascular remodeling in other species. Because, during exercise, pulmonary blood flow and vascular pressures increase dramatically, these stimuli are likely causes of pulmonary vein remodeling. Venous remodeling and resultant luminal occlusion, loss of vessel compliance, or both will have a profound effect on pressures in upstream vessels, in this instance the pulmonary capillaries. Indeed, in cases of complete occlusion of pulmonary veins, pulmonary capillary pressures during exercise would equal pulmonary arterial pressures (96.5 mm Hg) and result in a greater likelihood of capillary wall rupture. Interstitial hemorrhage and hemosiderosis contribute to the fibrotic processes that constitute a significant lesion in affected tissues. This relationship between venous remodeling and EIPH is supported by the observation that venous remodeling, hemosiderosis, and fibrosis are co-localized in affected lung regions. During training and racing, each exercise bout raises pulmonary vascular pressure, and these repeated high-pressure events likely result in venous remodeling, bleeding, and fibrosis. It is not surprising therefore that higher numbers of lifetime race starts are associated with increased risk for EIPH. Lesions of EIPH are found predominantly in the caudodorsal region of the lungs. Interestingly, blood flow is also preferentially distributed to the caudodorsal areas at rest and during exercise. It is likely that increased pressures and flow in this region account for the characteristic distribution of EIPH pathology. A competing theory of pathogenesis to explain this unique distribution of EIPH lesions in the caudodorsal lung emerged in the 1990s and will be mentioned here for the sake of completeness. This theory attributes the caudodorsal lesions to the transmission of concussive forces from the thoracic limb to the lung tissue through the thoracic wall, or locomotory impact-induced trauma, which in turn results in shearing injury of the caudodorsal lung regions. This is similar to the contrecoup explanation of the distribution of intracranial hemorrhage after impact on the front of the cranium. At present, this theory is a modeling concept, does not account for the specific pathologic features of the disease such as venous remodeling, and lacks supporting data.
CLINICAL SIGNS
Horses with EIPH do not typically manifest signs of systemic disease, and on physical examination, the only detectable abnormality may be epistaxis. Because epistaxis is observed in about 0.15% of horses that race, and it is known through use of other diagnostic techniques that most horses experience some degree of EIPH, absence of epistaxis does not rule out EIPH.
58 Exercise-Induced Pulmonary Hemorrhage
Diagnosis of EIPH in the horse is performed relative easily with one or a combination of the following techniques: observation, tracheobronchoscopy, and bronchoalveolar lavage.
Observation Observation of epistaxis after exercise is an infrequent event, and although epistaxis is likely a manifestation of severe EIPH, absence of epistaxis does not rule out severe EIPH. Although EIPH is the most likely cause of postexertional respiratory tract bleeding, other conditions are also possible (see Chapter 57 for a comprehensive review).
Tracheobronchoscopy This simple diagnostic technique should be performed within 60 to 90 minutes of finishing exercise because earlier or later evaluations may result in false-negative diagnoses. Endoscopy readily confirms the lungs as the source of the bleeding (versus pharyngeal or nasal structures). A five-point grading system, which has an established repeatability, is commonly used to describe tracheobronchoscopic findings (Table 58-1). It is not known how much bleeding has to occur before blood becomes visible in the large airways, and on the basis of bronchoalveolar lavage (BAL) data (see below), it is considered highly likely that horses bleed to some degree even when the trachea and large airways are free of blood on endoscopic examination.
Bronchoalveolar Lavage Bronchoalveolar lavage is a commonly used technique that enables characterization of the cytologic population of a horse’s respiratory tract, specifically that of the smaller airways, including small bronchi, bronchioles, and alveoli. This technique is useful in cases in which postexercise endoscopy cannot be performed or when there has been a considerable time period between the episode of intense exercise and evaluation. A diagnosis of EIPH based on the finding
TA B L E 5 8 - 1
Tracheobronchoscopic Grading of Exercise-Induced Pulmonary Hemorrhage
Grade
Endoscopic Findings
0
No blood in the pharynx, larynx, trachea, or mainstem bronchi 1 or more flecks of blood or 1-2 short (<0.25% of the length of the trachea), narrow (<10% of the tracheal surface area) streams of blood in the trachea or mainstem bronchi visible from the tracheal bifurcation 1 long stream of blood (>50% of the length of the trachea) or >2 short streams of blood occupying <33% of the tracheal circumference Multiple, distinct streams of blood covering >33% of the tracheal circumference, with no blood pooling at the thoracic inlet Multiple, coalescing streams of blood covering >90% of the tracheal surface, with blood pooling at the thoracic inlet
1
2
DIAGNOSIS
The clinical evaluation of any horse with suspected EIPH, regardless of the breed, should involve careful cardiac auscultation. The rationale for this is that horses with atrial fibrillation have higher-than-normal pulmonary artery pressures during exercise and, with the reduced passive ventricular filling phase seen at high heart rates, pulmonary venous congestion and capillary rupture are likely to result. Epistaxis has been reported in association with atrial fibrillation in light-horse breeds. In draft horses with atrial fibrillation, severe EIPH is a common observation, in the author’s clinical experience.
253
3
4
Data from Hinchcliff KW, Jackson MA, Brown JA, et al. Tracheobronchoscopic assessment of exercise-induced pulmonary hemorrhage in horses. Am J Vet Res 2005;66:596-598.
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of red blood cells and red cell breakdown products (hemosiderophages) in BAL fluid can be made for weeks to months after an intense exercise bout. The technique is highly sensitive. On the basis of BAL fluid cytology, the prevalence of EIPH approaches 100% in racing horses. Bronchoalveolar lavage can identify horses with EIPH even if the bleeding is of a low grade. Low-grade EIPH has not been associated with poor racing performance. Therefore a diagnosis of EIPH based on BAL cytology should be interpreted with caution, and not necessarily cited as a reason for poor performance. The author recommends the following BAL technique, based on recent literature on the subject (see Suggested Readings). Intravenous sedation (with an α2-adrenergic receptor agonist, with or without butorphanol tartrate) is strongly recommended for safe completion of the procedure, and a twitch may also be used. Either a silicone BAL tube with an inflatable cuff on the distal end and a two-way proximal fitting for aspiration and irrigation1 or a 3-meter endoscope with an irrigation channel can be used to perform the BAL. Although samples retrieved by BAL should not be submitted for bacterial or fungal culture (because of probable contamination when the instrument is passed through the nasal passages), it is still advisable to autoclave or sterilize the outer surface and channels of the tube or endoscope before use in a horse. It is likely that the horse will cough (often violently) throughout the procedure, and having 20 mL of warmed 1% lidocaine solution on hand for infusion in the nasopharynx and large airways is recommended. The tube or endoscope is passed through the ventral meatus to the pharynx. If the endoscope is being used, the larynx is viewed, and at a moment of inspiration when the arytenoids are abducted, the endoscope is quickly advanced into the trachea. With a BAL tube this step is performed blindly but is nevertheless easily achievable. To make passage into the trachea easier, the horse’s head and neck can be straightened. Correct positioning of the instrument in the trachea is confirmed by aspirating air (easily) and by the absence of the tube in the visible and palpable portion of the esophagus on the left side of the neck. Coughing is normal at this time, and lidocaine should be infused slowly and steadily as the instrument is advanced toward the carina. The instrument should be passed until it cannot be advanced further with gentle pressure. If a BAL tube is being used, the balloon may be inflated at this time with a volume recommended by the manufacturer. If an endoscope is being used, it must be held carefully in this position throughout the procedure to ensure that the seal or “wedge” is not lost. After coughing has ceased, lavage fluid is instilled. Three hundred to 500 mL of warmed physiologic saline solution or phosphate buffered saline should be used for lavage. Half of the total volume is infused gently (from either filled 60-mL syringes or a fluid bag and pressure bulb), followed by 60 mL of air, and then gentle suction (using syringes) is applied to a stopcock attached to the irrigation channel to retrieve this fluid. After all available fluid has been retrieved (expect to retrieve <50% of the volume instilled), the second infusion can be performed and retrieved in the same manner without repositioning the tube or endoscope unless there is a failure to maintain the wedge in that site and fluid is not retrievable with gentle suction. Fluid that has been in the small airways and alveoli is easily identifiable by the presence of foam in the retrieved sample. The fluid
1
BAL 240 or BAL 300 (outer diameter 10 mm and 240 or 300 cm in length, respectively). SurgiVet, Smiths Medical, Dublin, OH.
may appear pink–tinged from the presence of red blood cells. This may be a result of EIPH after a recent exercise bout or a result of trauma from suctioning or passage of the tube or endoscope during the BAL procedure; unfortunately, there is no way to visually differentiate between these causes. After all fluid is retrieved, the samples should be pooled. If there will be a delay before submission, refrigeration is recommended. The sample may be submitted as BAL fluid (transported on ice), or as pre-prepared slides. Contacting your laboratory before submission is recommended. Preparation of slides requires centrifugation (at <300 g), resuspension of the cell pellet, and gentle smearing of 250 µL on a slide. For in-house evaluation, staining slides with Diff-Quik will enable generation of a differential cell count. For more specific staining techniques, consultation of a standard clinical pathology text is recommended. It is recommended that horses not have induced exercise for 72 hours after a BAL. Multiple publications use BAL cytology (red blood cell count and presence of hemosiderin-containing macrophages) as a means of quantifying EIPH severity, in particular in the context of evaluating drug efficacy. However, interpreting BAL cytology data should be undertaken cautiously for the following reasons. During a BAL, one region of one lung is sampled (usually the right caudal lobe because of where the instrument tends to wedge), thereby limiting the area of respiratory tract being evaluated. There is no evidence that EIPH occurs to a greater degree in one lung than the other, but the severity of EIPH after each exercise bout may not be identical across all lung regions. Further, mucociliary transportation can move red blood cells and hemosiderophages to regions distant from the source of bleeding. Finally, because clearance of red blood cells by hemosiderophages can take months, a cumulative effect of multiple exercise bouts can also be expected. All of these factors render interpretation of BAL cytology data from one region of one lung, at least in the context of EIPH, a difficult task.
Sudden Death Sudden death during or immediately after intense exercise is an uncommon occurrence, and postmortem examination is usually needed to determine a cause of death. Several papers report that sudden death can be caused by severe pulmonary hemorrhage. In a recent multicenter study of 268 sudden racehorse deaths, a definitive diagnosis was reported in only 53% of cases. Although evidence of acute pulmonary hemorrhage was detected in 70% of necropsies, it was considered to be severe enough to cause death in only 18%. It is not known whether mechanisms that lead to death caused by pulmonary hemorrhage are the same as those at play in less severe EIPH.
TREATMENT
Pharmacotherapeutic Agents Despite the fact that exercise-associated epistaxis has been described in racing horses since the early eighteenth century, interventions that completely prevent or treat EIPH do not currently exist. Because the diagnostic techniques available to both practitioners and those in a research environment are only semiquantitative and subjective in nature, and because affected horses do not bleed to the same extent every time that they race, determination of treatment efficacy is fraught with the possibility of error in interpretation. Well-designed, blinded studies of large numbers of animals are necessary to make informed decisions about EIPH therapy.
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Furosemide The single pharmacologic agent with proven efficacy in reducing EIPH severity is the diuretic furosemide. Furosemide (4-chloro-2[(furylmethyl)amino]-5-sulfamoylbenzoic acid) is a high-ceiling or loop diuretic that is licensed in the United States for use in horses for the treatment of edema (e.g., pulmonary congestion, ascites) associated with cardiac insufficiency and acute noninflammatory tissue edema at a dose range of 250 to 500 mg/horse once or twice daily (http:// www.accessdata.fda.gov/scripts/animaldrugsatfda/details .cfm?dn=034-478). Furosemide is also routinely used in management of acute anuric renal failure and, most commonly, as a preventive for EIPH in strenuously exercising horses. Furosemide is secreted into the proximal renal tubule, and the drug’s primary site of action is the thick ascending loop of Henle, where it acts on the Na-K-2Cl luminal ion cotransporter. This inhibits the transport of chloride and sodium from the tubular lumen, which in turn reduces the surrounding interstitial tonicity and prevents water reabsorption by this mechanism. The pharmacokinetics of furosemide are well established, and using a three-compartment model, α-, β-, and γ-phase half-lives of 5.6, 22.3, and 158.6 minutes, respectively, are reported for 0.5 mg/kg dosing. These times do not change significantly for 1 mg/kg dosing, so within the dose range used in racehorses (0.5 to 1 mg/kg), furosemide pharmacokinetics are dose independent. Furosemide causes rapid and significant urine loss, a 2% to 4% loss in body weight, and, at only 30 minutes after administration, a 13% reduction in plasma volume. The reduction in plasma volume is maintained at 4 hours after administration if water or intravenous fluids are not provided to the horse. Furthermore, under similar circumstances, furosemide significantly reduces pulmonary artery pressure and pulmonary arterial wedge pressures both at rest and during exercise, and this effect is also maintained at 4 hours after administration. Repeated administration of the drug and administration at a time interval of less than 4 hours before exercise does not further decrease exercise-associated pulmonary hypertension. The duration of effect on these variables beyond 4 hours has not been reported. The prolonged effect of furosemide on hemodynamic variables is considered advantageous because prerace administration of the drug is performed exactly 4 hours before racing. Racing regulators stipulate this timing, as the effect of furosemide administered at 4 hours before racing on the accuracy of postrace urine sample drug testing is well established. This regulation also permits uniform conditions for all horses that are given the drug. In North America, more than 90% of racehorses are treated with furosemide before racing. Use of furosemide for EIPH prevention in racing horses long predates the publication of convincing proof of its efficacy. In 2009, a double-blind crossover trial with simulated races (for purse money) 1 week apart was performed to determine whether furosemide could affect postrace tracheobronchoscopic findings. Horses treated with saline were more likely to have moderate or severe EIPH than horses treated with furosemide (odds ratio, 6.9 to 11), and in 67.5% of horses, EIPH score was reduced after furosemide treatment. It is also well established that administration of furosemide is associated with superior performance in racehorses. At present, however, it is not known whether the effect of furosemide on racehorse performance is a result of its effect on EIPH, a condition that is known to negatively affect performance. It is difficult to separate this effect from the furosemide-associated loss in body weight that occurs
58 Exercise-Induced Pulmonary Hemorrhage
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concurrently, and although investigations into this relationship have been performed, the contribution that body weight reduction makes to performance improvement has not been conclusively quantified. Regardless of how furosemide improves racehorse performance, the fact that the drug ameliorates EIPH, at least in part, is well established. Working on the assumption that stress failure of capillaries is the most likely pathogenic mechanism at play in EIPH, plasma volume reduction and mitigation of pulmonary capillary pressures of approximately 10 mm Hg after furosemide administration, resulting in reduced capillary transmural pressures and wall disruption, is the most likely explanation for the reported efficacy of the drug. Reports of the effect of furosemide on cardiac output are inconsistent; however, the preponderance of evidence suggests that cardiac output during exercise is unaffected by furosemide. It is known, however, that furosemide affects pulmonary blood flow during exercise and causes a more uniform distribution of blood flow across the lung. This effectively spares the caudal lung regions from high flow states and may go some way toward explaining furosemide’s protective effects in EIPH. There is some evidence that regional differences in vascular reactivity in the horse lung exist, but the effect of furosemide on pulmonary vasculature has not yet been investigated. It is, however, accepted that furosemide has profound vasoactive effects (specifically vasodilatory effects) in other species, and it is possible that the hemodynamic effects of furosemide in the exercising horse are not solely ascribable to plasma volume reduction. Further to previous discussion about the effect of pulmonary venous remodeling and altered venous compliance on upstream capillary pressures, it also follows that venodilation (furosemide-mediated) would have the converse effect (i.e., a protective effect) on capillaries. Besides furosemide, other so-called adjunct bleeder medications are in use, and the quest for new, effective therapies is ongoing. No other pharmacologic agents are licensed for this purpose in horses, and very few agents are permitted by racing regulatory bodies. They will be discussed briefly here for completeness.
Nitric Oxide The role of nitric oxide (NO) in regulation of the pulmonary vasculature is well established, and for this reason, attempts to modify NO release have been made in attempts to treat EIPH in horses. Administration of NG-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, caused an increase in right atrial, pulmonary artery, and capillary pressures at rest, compared with control horses, presumably by inhibition of NO-mediated vasodilation, but this difference between L-NAME–treated and control animals was not detectable during strenuous exercise. This work, along with a study revealing that administration of an NO donor, glyceryl trinitrate, to horses caused a dose-related reduction in the same parameters, implicate NO as having a key role in control of basal pulmonary vascular tone in the horse, at least at rest. Several attempts to use NO-mediated reductions in pulmonary artery pressure as a preventive measure have been made and have failed to demonstrate protective results. In fact, in a 2001 study, NO inhalation was associated with increased severity of EIPH, compared with control horses. These data support the concept that arterial and precapillary smooth muscle tone is in fact protective to the downstream capillary bed. When this tone is reduced by use
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of NO, vessels dilate so that more of the arterial pressure is transmitted to the capillaries, which makes them more likely to rupture.
clenbuterol has not had a beneficial effect in the treatment of EIPH.
Sildenafil
Although inoculation of blood into the airways results in increased numbers of macrophages in BAL fluid, the role of inflammation in naturally occurring EIPH is not well established. The use of corticosteroids to treat interstitial fibrosis as a component of EIPH lung pathology has not been formally tested at present, and given that corticosteroid use in the horse is associated with significant side effects, the use of this category of drugs for this purpose cannot be recommended.
Sildenafil citrate is a phosphodiesterase-5 inhibitor that mediates reductions in both systemic and pulmonary vascular pressures through its effects on cyclic guanosine monophosphate degradation and resultant vasodilation. An effect of the drug on pulmonary pressures has only been reported in subjects in hypoxic environments. When administered to horses 1 hour before a strenuous exercise test, treatment did not cause any significant alterations in pulmonary arterial pressure, other physiologic parameters, or pulmonary hemorrhage.
Carbazochrome Carbazochrome sodium sulfonate hydrate (also known as Kentucky Red) has been used as a “capillary stabilizer” in conditions such as Dengue fever in human patients, and some experimental evidence suggests this agent can atten uate pulmonary vascular hyperpermeability. No evidence exists that this agent has a protective effect supplemental to that of furosemide in exercising horses. The only study that has been performed to date was inadequately powered to detect a difference between treatment groups.
Aminocaproic Acid Aminocaproic acid is an inhibitor of fibrinolysis that is widely used in human medicine for prevention of excessive postoperative hemorrhage and in racehorses to reduce EIPH severity. Because no evidence exists that horses are coagulopathic during exercise, and there are data suggesting physical disruption of pulmonary capillaries, the rationale for the use of this agent is unclear. In a limited trial, this drug did not reduce EIPH severity, but the study was underpowered, and an absence of effect cannot be interpreted as failure of drug efficacy.
Pentoxifylline Pentoxifylline is a methylated xanthine derivative and a phosphodiesterase inhibitor that is in common use in human medicine for its known actions of inhibiting platelet aggre gation, increasing erythrocyte flexibility or deformability, and reducing blood viscosity. For these reasons, it has been adopted for use in other species, including the horse. Furosemide has been associated with in vitro alterations in erythrocyte plasticity and blood viscosity, and the use of pentoxifylline in the exercising horse was proposed to counter these effects. In a crossover study, six horses were treated with no drugs (control) or with furosemide and pentoxifylline (treatment) before exercise on a high-speed treadmill. It was found that all horses in the treatment group experienced EIPH despite the expected mitigation of pulmonary arterial pressures that is associated with furosemide administration, and it was concluded that pentoxifylline did not “recover” red cell deformability to a degree that prevented EIPH.
Clenbuterol
Clenbuterol, a β2-adrenergic receptor agonist commonly used as a bronchodilator, does not reduce exercise-associated hypertension in horses and does not improve the effect of furosemide on these parameters. Unsurprisingly, therefore,
Corticosteroids
Platelet-Rich Plasma Recent anecdotal reports on the use of platelet-rich plasma to treat EIPH exist but are based on nonblinded evaluations of individual animals. At this time, no data exist to support the use of this treatment for EIPH.
Nonpharmacotherapeutic Agents Nasal Strip
It is possible to reduce airway resistance by application of a commercially available adhesive strip2 across the nose that acts to dilate the nasal valve. The theory behind its effect on EIPH is that reduction in airway resistance at a point of natural anatomic constriction will result in significant pressure reductions throughout the respiratory network. Because the transmural capillary pressure responsible for capillary rupture is made up of the combined effect of intravascular pressures (positive) and airway pressures (negative), reduction of airway pressure will decrease the magnitude of transmural pressures. It follows that reduction in capillary transmural pressure will result in less capillary rupture, and therefore in less severe bleeding. Conflicting data exist on the topic, but it appears that although application of nasal strips has some beneficial effect, when used in conjunction with furosemide, nasal strips do not offer benefit in excess of that associated with furosemide administration alone. Addressing other causes of partial upper respiratory obstruction, such as recurrent laryngeal neuropathy and dorsal displacement of the soft palate, as a component of EIPH management is logical given the effects of obstruction on airway pressures. At this time, however, a direct link between resolution of these conditions and EIPH mitigation has not been demonstrated.
Rest Rest periods after a documented episode of epistaxis or bleeding may be stipulated by certain racing jurisdictions. At this time, it is not known whether rest will improve the likelihood of horses experiencing fewer or less severe bleeding episodes.
Suggested Readings Derksen F, Williams K, Stack A. Exercise-induced pulmonary hemorrhage in horses: the role of pulmonary veins. Compend Contin Educ Vet 2011;33:E1-6. Hinchcliff KW. Exercise-induced pulmonary hemorrhage. In: McGorum BC, Dixon PM, Robinson NE, Schumacher J, eds. Equine Respiratory Medicine and Surgery. Philadelphia: WB Saunders, 2007:617-629. 2
Flair equine nasal strips, Flair LLC, Delano, MN.
58
Exercise-Induced Pulmonary Hemorrhage ALICE STACK
PREVALENCE
Exercise-induced pulmonary hemorrhage (EIPH) is a common condition of intensely exercising horses and occurs in up to 75% of horses that race. However, studies have indicated that when horses are evaluated by means of tracheobronchoscopy after each of three races, blood is observed in the large airways of all horses (100%) on at least one of these evaluations. Although the condition is most commonly identified in racing Thoroughbreds, and to a similar extent in Standardbreds, EIPH has also been described in other breeds, such as racing Quarter Horses and polo ponies.
EFFECT ON PERFORMANCE
Exercise-induced pulmonary hemorrhage has a negative effect on racehorse performance. In a study performed in Australia in which 744 Thoroughbred racehorses were evaluated by endoscopy after racing, it was determined that horses with either mild EIPH or no evidence of blood in the large airways were four times as likely to win and almost twice as likely to place in the top three as horses with moderate or severe EIPH.
RISK FACTORS
Exercise-induced pulmonary hemorrhage affects most, if not all, intensely exercising horses to some degree. Besides exercise, other risk factors for EIPH have not been consistently identified. In the largest study evaluating risk factors for EIPH, horses with more than 50 lifetime starts are 1.8 times as likely to have any evidence of EIPH as those with 40 starts or less. Age and sex are not associated with EIPH risk, whereas ambient temperatures less than 68° F (20° C) and a longer time between race finish and examination (up to 60 minutes) are associated with an increased risk for EIPH being diagnosed with endoscopy. Risk factors for postrace epistaxis, which is probably a manifestation of severe EIPH, and EIPH that is diagnosed only endoscopically are not identical. Rather, epistaxis is observed more commonly in older racing animals than in 2-year-olds, in mares more than in stallions, and after shorter, faster races (<1 mile or 1600 meters) than after longer ones.
PATHOPHYSIOLOGY Pathogenesis of EIPH
To discuss therapeutic approaches to this condition, both the pathology and how it relates to the proposed theories of pathogenesis must first be described in some detail. Although extensive descriptions of the clinical and pathologic features of EIPH exist in the literature, critical information detailing exact mechanisms of the condition is still lacking. The first, and until recently the most comprehensive, review of EIPH pathology was performed more than 20 years ago. Specifically, grossly evident pleural discoloration (blueblack) of the caudodorsal lung regions was seen, and on
252
histologic evaluation, extensive hemosiderosis, angiogenesis, pleural and septal fibrosis, and bronchiolitis (small airway inflammatory disease) were consistent findings. Authors of that study proposed that bronchiolitis played a causative role in EIPH. However, several lines of evidence exist that do not support this relationship. First, in more recent studies, bronchiolitis was not found in association with the other histopathologic features of EIPH. Second, in an epidemiologic study performed in the United Kingdom, some association between inflammatory airway disease and EIPH was detected in Thoroughbreds in training. However, this association cannot be interpreted as a cause-and-effect relationship because both conditions have a high prevalence in that study population. Finally, if airway inflammation was a significant contributing factor, routine treatments for inflammatory airway disease, such as systemic or nebulized corticosteroids and nonsteroidal antiinflammatory drugs, with or without antimicrobial therapy, would be expected to control EIPH. Although the latter treatments have never been formally investigated, in a clinical setting at least, such therapeutic regimens are not perceived to affect EIPH incidence or severity. A breakthrough study in 1993 demonstrated that pulmonary capillary rupture or disruption was commonly detected in lung tissue that had evidence of extravasation of red blood cells. These extravascular red cells were found both in the pulmonary interstitium and in surrounding alveolar airspaces. This work strongly implicated the pulmonary circulation as the source of hemorrhage in EIPH, and on the basis of these data, it was proposed that so-called stress failure of pulmonary capillaries secondary to transient but significant pulmonary circulation hypertension during exercise resulted in capillary disruption. This concept was strongly corroborated by studies that evaluated the magnitude of blood pressures in the horse’s pulmonary circulation during exercise. Pulmonary arterial pressures of approximately 100 mm Hg are reported, and from these measurements, pulmonary capillary pressures from 72.5 to 83.3 mm Hg can be calculated. Pressures of these magnitudes are unparalleled in any other mammalian species that has been investigated. This information, when considered in the context of a study that described the breaking strength of the horse’s pulmonary capillaries (75 mm Hg), makes pulmonary capillary stress failure a plausible theory of pathogenesis for EIPH. However, this theory does not account for the pathology seen in the lungs of horses with EIPH.
Pathology More recent descriptions of the pathologic features of EIPH have identified a novel lesion in the lungs of horses affected by EIPH—that of venous remodeling. This lesion affects small pulmonary veins (a caliber range of 100 to 200 µm outer diameter) and is characterized mainly by accumulation
CHAPTER
of adventitial collagen and, in some vessels, smooth muscle hyperplasia. In the most severely affected vessels, the lumen is significantly obstructed. Increases in pressure and shearing stresses, such as would be associated with high-flow states, are known stimuli of vascular remodeling in other species. Because, during exercise, pulmonary blood flow and vascular pressures increase dramatically, these stimuli are likely causes of pulmonary vein remodeling. Venous remodeling and resultant luminal occlusion, loss of vessel compliance, or both will have a profound effect on pressures in upstream vessels, in this instance the pulmonary capillaries. Indeed, in cases of complete occlusion of pulmonary veins, pulmonary capillary pressures during exercise would equal pulmonary arterial pressures (96.5 mm Hg) and result in a greater likelihood of capillary wall rupture. Interstitial hemorrhage and hemosiderosis contribute to the fibrotic processes that constitute a significant lesion in affected tissues. This relationship between venous remodeling and EIPH is supported by the observation that venous remodeling, hemosiderosis, and fibrosis are co-localized in affected lung regions. During training and racing, each exercise bout raises pulmonary vascular pressure, and these repeated high-pressure events likely result in venous remodeling, bleeding, and fibrosis. It is not surprising therefore that higher numbers of lifetime race starts are associated with increased risk for EIPH. Lesions of EIPH are found predominantly in the caudodorsal region of the lungs. Interestingly, blood flow is also preferentially distributed to the caudodorsal areas at rest and during exercise. It is likely that increased pressures and flow in this region account for the characteristic distribution of EIPH pathology. A competing theory of pathogenesis to explain this unique distribution of EIPH lesions in the caudodorsal lung emerged in the 1990s and will be mentioned here for the sake of completeness. This theory attributes the caudodorsal lesions to the transmission of concussive forces from the thoracic limb to the lung tissue through the thoracic wall, or locomotory impact-induced trauma, which in turn results in shearing injury of the caudodorsal lung regions. This is similar to the contrecoup explanation of the distribution of intracranial hemorrhage after impact on the front of the cranium. At present, this theory is a modeling concept, does not account for the specific pathologic features of the disease such as venous remodeling, and lacks supporting data.
CLINICAL SIGNS
Horses with EIPH do not typically manifest signs of systemic disease, and on physical examination, the only detectable abnormality may be epistaxis. Because epistaxis is observed in about 0.15% of horses that race, and it is known through use of other diagnostic techniques that most horses experience some degree of EIPH, absence of epistaxis does not rule out EIPH.
58 Exercise-Induced Pulmonary Hemorrhage
Diagnosis of EIPH in the horse is performed relative easily with one or a combination of the following techniques: observation, tracheobronchoscopy, and bronchoalveolar lavage.
Observation Observation of epistaxis after exercise is an infrequent event, and although epistaxis is likely a manifestation of severe EIPH, absence of epistaxis does not rule out severe EIPH. Although EIPH is the most likely cause of postexertional respiratory tract bleeding, other conditions are also possible (see Chapter 57 for a comprehensive review).
Tracheobronchoscopy This simple diagnostic technique should be performed within 60 to 90 minutes of finishing exercise because earlier or later evaluations may result in false-negative diagnoses. Endoscopy readily confirms the lungs as the source of the bleeding (versus pharyngeal or nasal structures). A five-point grading system, which has an established repeatability, is commonly used to describe tracheobronchoscopic findings (Table 58-1). It is not known how much bleeding has to occur before blood becomes visible in the large airways, and on the basis of bronchoalveolar lavage (BAL) data (see below), it is considered highly likely that horses bleed to some degree even when the trachea and large airways are free of blood on endoscopic examination.
Bronchoalveolar Lavage Bronchoalveolar lavage is a commonly used technique that enables characterization of the cytologic population of a horse’s respiratory tract, specifically that of the smaller airways, including small bronchi, bronchioles, and alveoli. This technique is useful in cases in which postexercise endoscopy cannot be performed or when there has been a considerable time period between the episode of intense exercise and evaluation. A diagnosis of EIPH based on the finding
TA B L E 5 8 - 1
Tracheobronchoscopic Grading of Exercise-Induced Pulmonary Hemorrhage
Grade
Endoscopic Findings
0
No blood in the pharynx, larynx, trachea, or mainstem bronchi 1 or more flecks of blood or 1-2 short (<0.25% of the length of the trachea), narrow (<10% of the tracheal surface area) streams of blood in the trachea or mainstem bronchi visible from the tracheal bifurcation 1 long stream of blood (>50% of the length of the trachea) or >2 short streams of blood occupying <33% of the tracheal circumference Multiple, distinct streams of blood covering >33% of the tracheal circumference, with no blood pooling at the thoracic inlet Multiple, coalescing streams of blood covering >90% of the tracheal surface, with blood pooling at the thoracic inlet
1
2
DIAGNOSIS
The clinical evaluation of any horse with suspected EIPH, regardless of the breed, should involve careful cardiac auscultation. The rationale for this is that horses with atrial fibrillation have higher-than-normal pulmonary artery pressures during exercise and, with the reduced passive ventricular filling phase seen at high heart rates, pulmonary venous congestion and capillary rupture are likely to result. Epistaxis has been reported in association with atrial fibrillation in light-horse breeds. In draft horses with atrial fibrillation, severe EIPH is a common observation, in the author’s clinical experience.
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3
4
Data from Hinchcliff KW, Jackson MA, Brown JA, et al. Tracheobronchoscopic assessment of exercise-induced pulmonary hemorrhage in horses. Am J Vet Res 2005;66:596-598.
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of red blood cells and red cell breakdown products (hemosiderophages) in BAL fluid can be made for weeks to months after an intense exercise bout. The technique is highly sensitive. On the basis of BAL fluid cytology, the prevalence of EIPH approaches 100% in racing horses. Bronchoalveolar lavage can identify horses with EIPH even if the bleeding is of a low grade. Low-grade EIPH has not been associated with poor racing performance. Therefore a diagnosis of EIPH based on BAL cytology should be interpreted with caution, and not necessarily cited as a reason for poor performance. The author recommends the following BAL technique, based on recent literature on the subject (see Suggested Readings). Intravenous sedation (with an α2-adrenergic receptor agonist, with or without butorphanol tartrate) is strongly recommended for safe completion of the procedure, and a twitch may also be used. Either a silicone BAL tube with an inflatable cuff on the distal end and a two-way proximal fitting for aspiration and irrigation1 or a 3-meter endoscope with an irrigation channel can be used to perform the BAL. Although samples retrieved by BAL should not be submitted for bacterial or fungal culture (because of probable contamination when the instrument is passed through the nasal passages), it is still advisable to autoclave or sterilize the outer surface and channels of the tube or endoscope before use in a horse. It is likely that the horse will cough (often violently) throughout the procedure, and having 20 mL of warmed 1% lidocaine solution on hand for infusion in the nasopharynx and large airways is recommended. The tube or endoscope is passed through the ventral meatus to the pharynx. If the endoscope is being used, the larynx is viewed, and at a moment of inspiration when the arytenoids are abducted, the endoscope is quickly advanced into the trachea. With a BAL tube this step is performed blindly but is nevertheless easily achievable. To make passage into the trachea easier, the horse’s head and neck can be straightened. Correct positioning of the instrument in the trachea is confirmed by aspirating air (easily) and by the absence of the tube in the visible and palpable portion of the esophagus on the left side of the neck. Coughing is normal at this time, and lidocaine should be infused slowly and steadily as the instrument is advanced toward the carina. The instrument should be passed until it cannot be advanced further with gentle pressure. If a BAL tube is being used, the balloon may be inflated at this time with a volume recommended by the manufacturer. If an endoscope is being used, it must be held carefully in this position throughout the procedure to ensure that the seal or “wedge” is not lost. After coughing has ceased, lavage fluid is instilled. Three hundred to 500 mL of warmed physiologic saline solution or phosphate buffered saline should be used for lavage. Half of the total volume is infused gently (from either filled 60-mL syringes or a fluid bag and pressure bulb), followed by 60 mL of air, and then gentle suction (using syringes) is applied to a stopcock attached to the irrigation channel to retrieve this fluid. After all available fluid has been retrieved (expect to retrieve <50% of the volume instilled), the second infusion can be performed and retrieved in the same manner without repositioning the tube or endoscope unless there is a failure to maintain the wedge in that site and fluid is not retrievable with gentle suction. Fluid that has been in the small airways and alveoli is easily identifiable by the presence of foam in the retrieved sample. The fluid
1
BAL 240 or BAL 300 (outer diameter 10 mm and 240 or 300 cm in length, respectively). SurgiVet, Smiths Medical, Dublin, OH.
may appear pink–tinged from the presence of red blood cells. This may be a result of EIPH after a recent exercise bout or a result of trauma from suctioning or passage of the tube or endoscope during the BAL procedure; unfortunately, there is no way to visually differentiate between these causes. After all fluid is retrieved, the samples should be pooled. If there will be a delay before submission, refrigeration is recommended. The sample may be submitted as BAL fluid (transported on ice), or as pre-prepared slides. Contacting your laboratory before submission is recommended. Preparation of slides requires centrifugation (at <300 g), resuspension of the cell pellet, and gentle smearing of 250 µL on a slide. For in-house evaluation, staining slides with Diff-Quik will enable generation of a differential cell count. For more specific staining techniques, consultation of a standard clinical pathology text is recommended. It is recommended that horses not have induced exercise for 72 hours after a BAL. Multiple publications use BAL cytology (red blood cell count and presence of hemosiderin-containing macrophages) as a means of quantifying EIPH severity, in particular in the context of evaluating drug efficacy. However, interpreting BAL cytology data should be undertaken cautiously for the following reasons. During a BAL, one region of one lung is sampled (usually the right caudal lobe because of where the instrument tends to wedge), thereby limiting the area of respiratory tract being evaluated. There is no evidence that EIPH occurs to a greater degree in one lung than the other, but the severity of EIPH after each exercise bout may not be identical across all lung regions. Further, mucociliary transportation can move red blood cells and hemosiderophages to regions distant from the source of bleeding. Finally, because clearance of red blood cells by hemosiderophages can take months, a cumulative effect of multiple exercise bouts can also be expected. All of these factors render interpretation of BAL cytology data from one region of one lung, at least in the context of EIPH, a difficult task.
Sudden Death Sudden death during or immediately after intense exercise is an uncommon occurrence, and postmortem examination is usually needed to determine a cause of death. Several papers report that sudden death can be caused by severe pulmonary hemorrhage. In a recent multicenter study of 268 sudden racehorse deaths, a definitive diagnosis was reported in only 53% of cases. Although evidence of acute pulmonary hemorrhage was detected in 70% of necropsies, it was considered to be severe enough to cause death in only 18%. It is not known whether mechanisms that lead to death caused by pulmonary hemorrhage are the same as those at play in less severe EIPH.
TREATMENT
Pharmacotherapeutic Agents Despite the fact that exercise-associated epistaxis has been described in racing horses since the early eighteenth century, interventions that completely prevent or treat EIPH do not currently exist. Because the diagnostic techniques available to both practitioners and those in a research environment are only semiquantitative and subjective in nature, and because affected horses do not bleed to the same extent every time that they race, determination of treatment efficacy is fraught with the possibility of error in interpretation. Well-designed, blinded studies of large numbers of animals are necessary to make informed decisions about EIPH therapy.
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Furosemide The single pharmacologic agent with proven efficacy in reducing EIPH severity is the diuretic furosemide. Furosemide (4-chloro-2[(furylmethyl)amino]-5-sulfamoylbenzoic acid) is a high-ceiling or loop diuretic that is licensed in the United States for use in horses for the treatment of edema (e.g., pulmonary congestion, ascites) associated with cardiac insufficiency and acute noninflammatory tissue edema at a dose range of 250 to 500 mg/horse once or twice daily (http:// www.accessdata.fda.gov/scripts/animaldrugsatfda/details .cfm?dn=034-478). Furosemide is also routinely used in management of acute anuric renal failure and, most commonly, as a preventive for EIPH in strenuously exercising horses. Furosemide is secreted into the proximal renal tubule, and the drug’s primary site of action is the thick ascending loop of Henle, where it acts on the Na-K-2Cl luminal ion cotransporter. This inhibits the transport of chloride and sodium from the tubular lumen, which in turn reduces the surrounding interstitial tonicity and prevents water reabsorption by this mechanism. The pharmacokinetics of furosemide are well established, and using a three-compartment model, α-, β-, and γ-phase half-lives of 5.6, 22.3, and 158.6 minutes, respectively, are reported for 0.5 mg/kg dosing. These times do not change significantly for 1 mg/kg dosing, so within the dose range used in racehorses (0.5 to 1 mg/kg), furosemide pharmacokinetics are dose independent. Furosemide causes rapid and significant urine loss, a 2% to 4% loss in body weight, and, at only 30 minutes after administration, a 13% reduction in plasma volume. The reduction in plasma volume is maintained at 4 hours after administration if water or intravenous fluids are not provided to the horse. Furthermore, under similar circumstances, furosemide significantly reduces pulmonary artery pressure and pulmonary arterial wedge pressures both at rest and during exercise, and this effect is also maintained at 4 hours after administration. Repeated administration of the drug and administration at a time interval of less than 4 hours before exercise does not further decrease exercise-associated pulmonary hypertension. The duration of effect on these variables beyond 4 hours has not been reported. The prolonged effect of furosemide on hemodynamic variables is considered advantageous because prerace administration of the drug is performed exactly 4 hours before racing. Racing regulators stipulate this timing, as the effect of furosemide administered at 4 hours before racing on the accuracy of postrace urine sample drug testing is well established. This regulation also permits uniform conditions for all horses that are given the drug. In North America, more than 90% of racehorses are treated with furosemide before racing. Use of furosemide for EIPH prevention in racing horses long predates the publication of convincing proof of its efficacy. In 2009, a double-blind crossover trial with simulated races (for purse money) 1 week apart was performed to determine whether furosemide could affect postrace tracheobronchoscopic findings. Horses treated with saline were more likely to have moderate or severe EIPH than horses treated with furosemide (odds ratio, 6.9 to 11), and in 67.5% of horses, EIPH score was reduced after furosemide treatment. It is also well established that administration of furosemide is associated with superior performance in racehorses. At present, however, it is not known whether the effect of furosemide on racehorse performance is a result of its effect on EIPH, a condition that is known to negatively affect performance. It is difficult to separate this effect from the furosemide-associated loss in body weight that occurs
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concurrently, and although investigations into this relationship have been performed, the contribution that body weight reduction makes to performance improvement has not been conclusively quantified. Regardless of how furosemide improves racehorse performance, the fact that the drug ameliorates EIPH, at least in part, is well established. Working on the assumption that stress failure of capillaries is the most likely pathogenic mechanism at play in EIPH, plasma volume reduction and mitigation of pulmonary capillary pressures of approximately 10 mm Hg after furosemide administration, resulting in reduced capillary transmural pressures and wall disruption, is the most likely explanation for the reported efficacy of the drug. Reports of the effect of furosemide on cardiac output are inconsistent; however, the preponderance of evidence suggests that cardiac output during exercise is unaffected by furosemide. It is known, however, that furosemide affects pulmonary blood flow during exercise and causes a more uniform distribution of blood flow across the lung. This effectively spares the caudal lung regions from high flow states and may go some way toward explaining furosemide’s protective effects in EIPH. There is some evidence that regional differences in vascular reactivity in the horse lung exist, but the effect of furosemide on pulmonary vasculature has not yet been investigated. It is, however, accepted that furosemide has profound vasoactive effects (specifically vasodilatory effects) in other species, and it is possible that the hemodynamic effects of furosemide in the exercising horse are not solely ascribable to plasma volume reduction. Further to previous discussion about the effect of pulmonary venous remodeling and altered venous compliance on upstream capillary pressures, it also follows that venodilation (furosemide-mediated) would have the converse effect (i.e., a protective effect) on capillaries. Besides furosemide, other so-called adjunct bleeder medications are in use, and the quest for new, effective therapies is ongoing. No other pharmacologic agents are licensed for this purpose in horses, and very few agents are permitted by racing regulatory bodies. They will be discussed briefly here for completeness.
Nitric Oxide The role of nitric oxide (NO) in regulation of the pulmonary vasculature is well established, and for this reason, attempts to modify NO release have been made in attempts to treat EIPH in horses. Administration of NG-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, caused an increase in right atrial, pulmonary artery, and capillary pressures at rest, compared with control horses, presumably by inhibition of NO-mediated vasodilation, but this difference between L-NAME–treated and control animals was not detectable during strenuous exercise. This work, along with a study revealing that administration of an NO donor, glyceryl trinitrate, to horses caused a dose-related reduction in the same parameters, implicate NO as having a key role in control of basal pulmonary vascular tone in the horse, at least at rest. Several attempts to use NO-mediated reductions in pulmonary artery pressure as a preventive measure have been made and have failed to demonstrate protective results. In fact, in a 2001 study, NO inhalation was associated with increased severity of EIPH, compared with control horses. These data support the concept that arterial and precapillary smooth muscle tone is in fact protective to the downstream capillary bed. When this tone is reduced by use
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of NO, vessels dilate so that more of the arterial pressure is transmitted to the capillaries, which makes them more likely to rupture.
clenbuterol has not had a beneficial effect in the treatment of EIPH.
Sildenafil
Although inoculation of blood into the airways results in increased numbers of macrophages in BAL fluid, the role of inflammation in naturally occurring EIPH is not well established. The use of corticosteroids to treat interstitial fibrosis as a component of EIPH lung pathology has not been formally tested at present, and given that corticosteroid use in the horse is associated with significant side effects, the use of this category of drugs for this purpose cannot be recommended.
Sildenafil citrate is a phosphodiesterase-5 inhibitor that mediates reductions in both systemic and pulmonary vascular pressures through its effects on cyclic guanosine monophosphate degradation and resultant vasodilation. An effect of the drug on pulmonary pressures has only been reported in subjects in hypoxic environments. When administered to horses 1 hour before a strenuous exercise test, treatment did not cause any significant alterations in pulmonary arterial pressure, other physiologic parameters, or pulmonary hemorrhage.
Carbazochrome Carbazochrome sodium sulfonate hydrate (also known as Kentucky Red) has been used as a “capillary stabilizer” in conditions such as Dengue fever in human patients, and some experimental evidence suggests this agent can atten uate pulmonary vascular hyperpermeability. No evidence exists that this agent has a protective effect supplemental to that of furosemide in exercising horses. The only study that has been performed to date was inadequately powered to detect a difference between treatment groups.
Aminocaproic Acid Aminocaproic acid is an inhibitor of fibrinolysis that is widely used in human medicine for prevention of excessive postoperative hemorrhage and in racehorses to reduce EIPH severity. Because no evidence exists that horses are coagulopathic during exercise, and there are data suggesting physical disruption of pulmonary capillaries, the rationale for the use of this agent is unclear. In a limited trial, this drug did not reduce EIPH severity, but the study was underpowered, and an absence of effect cannot be interpreted as failure of drug efficacy.
Pentoxifylline Pentoxifylline is a methylated xanthine derivative and a phosphodiesterase inhibitor that is in common use in human medicine for its known actions of inhibiting platelet aggre gation, increasing erythrocyte flexibility or deformability, and reducing blood viscosity. For these reasons, it has been adopted for use in other species, including the horse. Furosemide has been associated with in vitro alterations in erythrocyte plasticity and blood viscosity, and the use of pentoxifylline in the exercising horse was proposed to counter these effects. In a crossover study, six horses were treated with no drugs (control) or with furosemide and pentoxifylline (treatment) before exercise on a high-speed treadmill. It was found that all horses in the treatment group experienced EIPH despite the expected mitigation of pulmonary arterial pressures that is associated with furosemide administration, and it was concluded that pentoxifylline did not “recover” red cell deformability to a degree that prevented EIPH.
Clenbuterol
Clenbuterol, a β2-adrenergic receptor agonist commonly used as a bronchodilator, does not reduce exercise-associated hypertension in horses and does not improve the effect of furosemide on these parameters. Unsurprisingly, therefore,
Corticosteroids
Platelet-Rich Plasma Recent anecdotal reports on the use of platelet-rich plasma to treat EIPH exist but are based on nonblinded evaluations of individual animals. At this time, no data exist to support the use of this treatment for EIPH.
Nonpharmacotherapeutic Agents Nasal Strip
It is possible to reduce airway resistance by application of a commercially available adhesive strip2 across the nose that acts to dilate the nasal valve. The theory behind its effect on EIPH is that reduction in airway resistance at a point of natural anatomic constriction will result in significant pressure reductions throughout the respiratory network. Because the transmural capillary pressure responsible for capillary rupture is made up of the combined effect of intravascular pressures (positive) and airway pressures (negative), reduction of airway pressure will decrease the magnitude of transmural pressures. It follows that reduction in capillary transmural pressure will result in less capillary rupture, and therefore in less severe bleeding. Conflicting data exist on the topic, but it appears that although application of nasal strips has some beneficial effect, when used in conjunction with furosemide, nasal strips do not offer benefit in excess of that associated with furosemide administration alone. Addressing other causes of partial upper respiratory obstruction, such as recurrent laryngeal neuropathy and dorsal displacement of the soft palate, as a component of EIPH management is logical given the effects of obstruction on airway pressures. At this time, however, a direct link between resolution of these conditions and EIPH mitigation has not been demonstrated.
Rest Rest periods after a documented episode of epistaxis or bleeding may be stipulated by certain racing jurisdictions. At this time, it is not known whether rest will improve the likelihood of horses experiencing fewer or less severe bleeding episodes.
Suggested Readings Derksen F, Williams K, Stack A. Exercise-induced pulmonary hemorrhage in horses: the role of pulmonary veins. Compend Contin Educ Vet 2011;33:E1-6. Hinchcliff KW. Exercise-induced pulmonary hemorrhage. In: McGorum BC, Dixon PM, Robinson NE, Schumacher J, eds. Equine Respiratory Medicine and Surgery. Philadelphia: WB Saunders, 2007:617-629. 2
Flair equine nasal strips, Flair LLC, Delano, MN.