Treatment of Exercise-Induced Pulmonary Hemorrhage

A variety of approaches are used to treat or manage exercise-induced pulmonary hemorrhage. The precise etiology of exercise-induced pulmonary hemorrhage is still far from clear and it may well be multifactorial or exacerbated by other coexisting disease processes or by inherited factors. However, to date the number of treatments shown under close scientific scrutiny in properly conducted trials to have any efficacy in terms of reduction of the severity of exercise-induced pulmonary hemorrhage remains small. The goal of abolishing exercise-induced pulmonary hemorrhage in an individual horse asked to exercise intensely is unrealistic. All horses have exercise-induced pulmonary hemorrhage to some extent, even if only detectable on the basis of bronchoalveolar lavage or identification of hemosiderophages in tracheal wash (TW) or bronchoalveolar lavage. However, treatment to reduce a horse consistently experiencing exercise-induced pulmonary hemorrhage at grade 4 or 5 to grade 2 to 3 may be achievable.

Furosemide

The mainstay of treatment for exercise-induced pulmonary hemorrhage for more than 25 years has been furosemide. In North America and some other racing jurisdictions, racing after furosemide treatment is permitted. However, in many other countries, whilst training horses on furosemide is permitted, its use during racing is banned. Now a wealth of evidence exists that furosemide reduces pulmonary vascular pressures both at rest and during exercise when administered in doses ranging from 250 to 500 mg 1 to 4 hours before exercise. Based on postrace surveys at racetracks furosemide does reduce the severity of bleeding (based on the amount of blood in trachea visualised endoscopically), but in a significant proportion of horses no clear reduction in exercise-induced pulmonary hemorrhage occurs. The failure to record reductions in the severity of exercise-induced pulmonary hemorrhage could point to a relative insensitivity of endoscopic grading in relation to the true severity of hemorrhage or to the fact that in some horses, the major underlying and precipitating cause of exercise-induced pulmonary hemorrhage is not related to high pulmonary vascular pressures.

More recently a number of studies have been conducted using red blood cell counts in bronchoalveolar lavage to quantify the severity of exercise-induced pulmonary hemorrhage in treadmill studies on horses treated with and without furosemide. The studies conducted in treadmill exercised horses showed that furosemide given intravenously (250 mg 30 min before or 500 mg given 4 hr before exercise) reduced red blood cell counts recovered in bronchoalveolar lavage fluid, and reduced pulmonary artery pressure to varying degrees. Given by nebulization or at the lower dose (250 mg) 4 hours before exercise, the effects were minimal in comparison. In general, furosemide had its greatest effect on horses that began with the most severe exercise-induced pulmonary hemorrhage. These treadmill-based studies require replication in the field but show a clear link between pulmonary artery pressure, exercise-induced pulmonary hemorrhage, and a dose-related effect of furosemide on the severity of exercise-induced pulmonary hemorrhage.

Other Vasodilators

Inhaled nitric oxide (NO; 80 ppm), a potent smooth muscle dilator, has been shown previously to decrease pulmonary vascular pressures during exercise in the horse. Infusion of nitroglycerine (an NO donor) at a dose of 20 μg/kg/min has been shown to decrease pulmonary vascular pressures at rest but to have no effect on pressures during maximal exercise and both control and treated horses show blood in the trachea after exercise. Oral nitroglycerine administered to horses at a dose of 22.5 mg, however, had no effect of pulmonary vascular pressures. The substrate for nitric oxide synthase (NOS), L-arginine at a dose of 200 mg/kg intravenously also has been reported not to reduce pulmonary vascular pressures during moderate intensity exercise. A more recent study has shown that inhaled NO (80 ppm) produced a small but consistent reduction in pulmonary vascular pressures, but in fact the red blood cell count in bronchoalveolar lavage was doubled with NO inhalation.

Although reduction in pulmonary vascular pressures by circulatory volume reduction with furosemide appears to be effective in reducing the severity of exercise-induced pulmonary hemorrhage, reduction in pressure using vasoactive drugs may increase the severity of exercise-induced pulmonary hemorrhage. This points to the fact that the precapillary arterioles may be constricted to protect the pulmonary capillaries and thus be the cause of the high pulmonary vascular pressures seen in the horse. This would tend to suggest that treatment with vasodilators for exercise-induced pulmonary hemorrhage is contraindicated.

Nasal Strips

On the basis that a large proportion of the resistance to breathing occurs in the upper airways and particularly in the nasal passages, nasal dilator strips recently have been developed for horses (FLAIR, CNS Inc., Minneapolis, Minn.). The soft tissue overlying the nasal incisive notch is supported poorly and can be observed to be drawn inwards during inspiration, narrowing the nasal passages. This would have the effect of increasing inspiratory pleural (hence transmural) pressures, therefore placing greater stress on the blood vessels. Increased inspiratory pressures are a reflection of increased resistance to breathing. In fact, preliminary findings in one study have shown that the FLAIR strip decreases both upper airway resistance and inspiratory tracheal pressure in horses during treadmill exercise. In addition, the FLAIR strip also has been shown to decrease oxygen consumption during exercise, presumably as a result of decreased work of breathing. In essence, these studies demonstrate that nasal dilation devices have the potential to improve racing performance irrespective of exercise-induced pulmonary hemorrhage.

In two recent treadmill studies, the FLAIR strip was shown to reduce the number of red blood cell in bronchoalveolar lavage by an average of 44% and by 74%. In the latter study, the greatest reduction in hemorrhage was seen in those horses exhibiting the higher volumes of bleeding in the control runs (no nasal strip). One recent study failed to demonstrate any change in the incidence of exercise-induced pulmonary hemorrhage scored as blood present or absent in the trachea following exercise. Therefore, the effect on exercise-induced pulmonary hemorrhage remains controversial. It is also important to emphasize that correct placement of a nasal strip is essential. The tendency for many users appears to be to place the strip too high on the nose. For this reason a template is included with the FLAIR strip to facilitate correct placement and should be used.

In the United Kingdom and many other racing jurisdictions the use of nasal strips currently is prohibited during racing but allowed during training. This is in contrast to North America where its use in racing is widespread. The efficacy demonstrated in the recent study (74% reduction in bronchoalveolar lavage red blood cell count) approaches that of furosemide on the same horses (80%). The FLAIR strip and furosemide in combination reduced the average bronchoalveolar lavage red blood cell count by 87%. Thus the use of nasal dilator strips based on these two treadmill studies, although on a limited number of horses, suggests that such devices merit strong consideration to use with or as an alternative to treatment with furosemide.

Upper Airway Resistance

The efficacy of the nasal strip, which reduces upper airway resistance during high-intensity exercise, has stressed the potential importance of respiratory system resistance to exercise-induced pulmonary hemorrhage. Resistance can be increased by a number of phenomena, including laryngeal hemiplegia, dorsal displacement of the soft palate, nasal, pharyngeal or tracheal collapse, guttural pouch disease, head flexion, and pharyngeal inflammation. Thus all these sources should be examined during the investigation of exercise-induced pulmonary hemorrhage in the individual horse.

Miscellaneous Treatments

Phlebotomy has been used as a treatment in hypervolemic Standardbred trotters. A reduction of the total blood volume by 22% (36 ml/kg) decreased the severity of exercise-induced pulmonary hemorrhage but treadmill performance and other indices of function, such as heart rate and oxygen uptake, were affected adversely.

Pentoxifylline, a phosphodiesterase inhibitor, is known to increase the deformability of RBCs, decrease blood viscosity, and potentially may decrease pulmonary vascular pressures during exercise and attenuate exercise-induced pulmonary hemorrhage. Administration of 8.5 mg/kg pentoxifylline intravenously had no effect on pulmonary vascular pressures or the incidence of exercise-induced pulmonary hemorrhage and did not enhance the effect of furosemide when given in combination.

Clenbuterol administered either alone or with furosemide apparently has no effect on pulmonary vascular pressures or pulmonary function in clinically healthy horses during exercise. Its effect on exercise-induced pulmonary hemorrhage has not been investigated. Water restriction is not an uncommon practice in many countries that have racing, in the belief that the dehydration may alter “blood pressure” and thus prevent or reduce the severity of exercise-induced pulmonary hemorrhage. To this author’s knowledge, no information exists in the scientific literature that demonstrates any efficacy of water deprivation against exercise-induced pulmonary hemorrhage. Prolonged water deprivation and dehydration cannot be controlled in the same way as with diuretics such as furosemide, and any benefit from a reduction in severity of exercise-induced pulmonary hemorrhage may be offset by a reduction in performance resulting from prolonged dehydration, electrolyte (Ca+ +, K+) depletion, and acid-base derangement.

Atrial fibrillation appears to increase the severity of exercise-induced pulmonary hemorrhage in a few horses. Atrial fibrillation should therefore be ruled out in cases in which a sudden increase in the severity of exercise-induced pulmonary hemorrhage occurs, possibly associated with loss of performance.