Exercise-induced pulmonary hemorrhage

Exercise induced pulmonary hemorrhage (EIPH), also known as "bleeding" or a "bleeding attack", refers to the presence of blood in the airways of the lung in association with exercise. EIPH is common in horses undertaking intense exercise, but it has also been reported in human athletes, racing camels and racing greyhounds. Horses that experience EIPH may also be referred to as "bleeders" or as having "broken a blood vessel". In the majority of cases EIPH is not apparent unless an endoscopic examination of the airways is performed following exercise. However, a small proportion of horses may show bleeding at the nostrils after exercise, which is known as epistaxis.

In horses

EIPH has been reported to occur in a variety of race horse breeds including racing Thoroughbreds (both flat racing and steeplechasing or jump racing), American Quarter Horses (incidence of 50–75%), Standardbreds (incidence of 40–60%), Arabians, and Appaloosas. EIPH has also been reported in eventers, jumpers, polo ponies, endurance horses, draft horses that pull competitively,[1] and horses taking part in Western speed events such as reining, cutting and barrel racing. EIPH is now considered to be an inevitable consequence of moderate to intense exercise in horses and other athletic animals. The lowest intensities of exercise which have been reported to cause EIPH are intense trotting (40–60% maximal oxygen uptake)[2] and cantering at speeds of 16–19 miles per hour (26–31 km/h).[3]

It occurs less frequently in stallions than mares or geldings,[4] and it is associated with airway inflammation and with increasing age.[5]

The affliction occurs when blood enters the air passages of a horse's lung, due to fractured lung capillaries. Blood is sometimes evident discharging from a horse's nostrils (epistaxis), however, epitaxis usually only occurs in .25–13% of bleeders.[1][6] If a horse does not exhibit epistaxis but is suspected to have EIPH, an endoscopic exam is performed soon after the horse is exercised.

EIPH often occurs in horses that race at high speeds. The number of horses with EIPH increases in proportion to speed and intensity. It is rare in endurance horses or draft breeds.(Hinchcliff & 2007 95)[7] Sudden death in horse athletes can be caused by exercise-induced pulmonary hemorrhage (EIPH).[8]

Prevalence

Based on surveys of horses examined endoscopically following racing, around 43 to 75% of horses have been reported to have blood in the trachea and bronchi following a single post-race examination.[9] One of the more recent and larger studies found an overall prevalence of just under 60%.[10] The time at which the examination is carried out can determine whether or not blood is seen. The usual time for examination is 30–40 minutes following exercise. If examination is carried out too soon after exercise then blood may not have progressed from the dorso-caudal (top and back) of the lung into the trachea. If the examination is carried out too long after exercise then any blood may have moved up the trachea and been swallowed and therefore not be visible at the time of examination. In one study (Birks et al. 2002), when horses were endoscoped on at least three separate occasions following racing, all horses had blood in the trachea on at least one occasion.

Epistaxis (blood coming from one or both nostrils) is much less common. In a survey of over 220,000 horse starts in UK Flat and National Hunt (jump) racing, 185 cases of epistaxis were identified giving a frequency of 0.83/1000 starts. Similar frequencies have been reported for epistaxis in Japan (1.5 per 1000 starts) and South Africa (1.65 per 1000 starts). However a study of racehorses in Korea reported a much higher frequency (8.4 per 1000 starts).[11]

It is believed that nearly all horses experience EIPH to varying degrees when exposed to both sub-maximal as well as strenuous exercise,[12] and it has the potential to decrease lung function over time.

Clinical signs

Poor athletic performance, dull hair coat, frequent swallowing and coughing in the immediate post-exercise recovery period, and poor appetite post-performance may be suggestive of EIPH. But, a definitive diagnosis can only be made by endoscopic examination of the trachea. In the case where no blood is visible in the trachea, EIPH in the small airways may still be present and can be confirmed by a bronchoalveolar lavage. Impaired arterial blood gas (oxygen) tensions during intense exercise, increased blood lactate, and rarely death have been noted (likely due to ruptured chordae tendinae or a different mechanism of lung hemorrhage). Epistaxis is diagnosed when blood is visible at either or both nostrils during or following exercise. To confirm whether the blood is coming from the upper or lower airway requires further examination by endoscopy, although in some cases it is not possible to determine the location. IN the majority of epistaxis cases, the blood originates from the lung. Epistaxis during or following exercise can less commonly occur as a result of upper airway hemorrhage, for example following head trauma, subepiglottic cysts, atrial fibrillation, or gutteral pouch mycoses.

Diagnosis

Post mortem

Lungs of horses that have experienced repeated episodes of EIPH show a characteristic blue-gray-brown staining when examined post mortem. The staining is due to the presence of hemosiderin. The staining is usually most intense in the dorso-caudal region of the left and right diaphragmatic lobes which often progresses cranioventral with repetitive damage. There are often distinct borders between healthy lung tissue and those parts of the lungs that have been affected by EIPH. Other histopathologic findings include fibrosis, bronchial artery neovascularization, venous remodeling, bronchiolitis, hemosiderin accumulation, increased tissue cellularity (i.e. hemosiderophages), multifocal areas of inflammation, and increased thickness of vascular and airway walls.

Etiology

A variety of different causes of EIPH have been proposed with the primary mechanism being high pulmonary vascular pressures summating with concurrently negative airway pressures which causes extreme stress across the pulmonary capillary membrane (the fragile membrane separating blood in the pulmonary capillaries from the air-filled alveoli) and consequent hemorrhage into the air spaces of the lung. Other contributing factors include upper airway obstruction, increased blood viscosity, abnormalities of cardiac origin (small cross-sectional area of atrioventricular valves, stiff valves, slow left ventricular relaxation time, right tricuspid valve regurgitation), preferential distribution of blood flow to the dorsocaudal lung regions, mechanical trauma, lower airway obstruction, inflammation, abnormalities of blood coagulation, inhomogeneity of ventilation and locomotory trauma. EIPH begins in the dorso-caudal region of the lung and progresses in a cranioventral direction over time.

High pulmonary blood pressures

The most widely accepted theory at present is that high transmural pressures lead to pulmonary capillary stress failure. Others hypothesize that there are contributions from the bronchial circulation as well. Pulmonary capillary transmural pressure is determined by pulmonary capillary pressure and airway pressure. The horse has very high pulmonary vascular pressures during intense exercise; commonly exceeding 100mmHg in the pulmonary artery during intense exercise. During expiration the high positive pressures in the pulmonary blood vessels pushing out are opposed by high positive airway pressures pushing back and this does not place undue stress on the thin blood vessel walls. During inspiration the high positive pressures in the pulmonary blood vessels pushing out are met by negative pressures distending the blood vessel and placing increased stress on the walls. Studies in vitro have demonstrated that significant disruption of the pulmonary capillaries occurs at pressures of approximately 80 mmHg. In vivo it has also been shown that significant EIPH occurs above a mean pulmonary artery pressure of around 80–95 mmHg.[14] On the basis of this theory, any factor or disease that would increase pulmonary vascular pressures (e.g. hypervolaemia) or increase the magnitude of the negative pressures in the lung during inspiration (e.g. dynamic upper airway obstruction) would be expected to increase the severity of EIPH. But neither experimentally induced laryngeal hemiplegia nor dorsal displacement of the soft palate increased pulmonary capillary transmural pressure.[15] Furthermore, the magnitude of exercise-induced pulmonary arterial, capillary and venous hypertension is reportedly similar in horses either with or without EIPH.

Locomotory associated trauma

Another factor believed to contribute to the etiology of EIPH includes locomotory forces. The theory is based on the fact that during galloping, the absence of any bone attachment of the forelegs to the spine in the horse causes the shoulder to compress the cranial rib cage (Schroter et al. 1998). The compression of the chest initiates a pressure wave of compression and expansion which spreads outwards. However, due to the shape of the lung and reflections off the chest wall, the wave of expansion and compression becomes focussed and amplified in the dorso-caudal lung (Schroter et al. 1999). The alternate expansion and compression at the microscopic level in adjacent areas of lung tissue creates shear stress and capillary disruption. The theory predicts that hemorrhage would be more severe on hard track surfaces, but it does not explain why EIPH can occur in horses during swimming exercise.

Veno-occlusive remodelling

A new proposal as to how high pulmonary venous pressures lead to the capillary rupture and the tissue changes observed has recently been proposed.[16] Regional veno-occlusive remodeling, especially within the caudodorsal lung fields, contributes to the pathogenesis of EIPH, with the venous remodeling leading to regional vascular congestion and hemorrhage, hemosiderin accumulation, fibrosis, and bronchial angiogenesis.

EIPH is most likely a multi-factorial condition involving airway, vascular, inflammatory, blood, cardiac, locomotory, and remodelling components.

Risk factors

While all horses undertaking intense exercise experience some degree of EIPH, some horses consistently experience greater haemorrhage and other horses experience isolated episodes of increased EIPH. In the case of horses that consistently demonstrate greater severity of EIPH this is most likely due to congenital factors, such as very high pulmonary vascular pressures. In horses that experience isolated episodes of increased severity of EIPH, possible contributing factors may include, amongst others, pulmonary infection or atrial fibrillation, inflammation, longer distances, longer duration of exercise, hard surfaces, steeplechasing/hurdling, increased length of career, breed (i.e. Thoroughbred greater than Standardbred), age, (related to time in training/racing), genetics, and cold temperatures.

Effects on performance

Epistaxis has been shown to have a marked negative effect on performance and shorten a horse's racing career.[17] However the effects of endoscopically diagnosed EIPH on performance have been less clear, with conflicting studies reporting a negative,[18] none,[19] and in some cases a positive effect on performance.[20] While single bouts of EIPH may not even be apparent to the rider, owner or trainer of a horse unless an endoscopic examination is undertaken, the effect on performance within a single race appears to be significant but relatively subtle.[10] In a 2005 study, horses finishing races with grade 4 EIPH were on average 6 metres behind those finishing with grade 0.[10] However, the effect of repeated bouts of EIPH that occur with daily training may lead to more significant changes and a greater degree of tissue damage over time[16] with consequent loss of lung function.

Management and treatment

There is no single treatment that has been shown to completely eliminate EIPH. The pathogenesis of EIPH is multifactorial and therefore, the most successful treatment may be that of pharmacological agents and non-pharmacological agents that attack the different known etiologies of EIPH (i.e. vascular, extravascular/airways, inflammation, etc.). Routes of drug administration include parenteral injection (i.e. IV or IM) and inhalation.

The only vascular agent that has shown scientific evidence of efficacy and is the most widely studied pharmaceutical in both controlled laboratory and field trials is Lasix/furosemide. It has been reported that up to 85% of Thoroughbred racehorses in the United States have been administered furosemide at least once during their racing career.[9] Furosemide decreases pulmonary arterial pressure via its diuretic effects, bronchodilates, and redistributes blood flow during exercise. It reduces EIPH ranging from 90% at sub-maximal exercise and about 50% at maximal exercise intensities. However, the downside of this therapy includes the creation of electrolyte imbalances and reduced effectiveness over time. In addition, the use of Lasix in competing horses prohibited in some countries, its race day use is controversial in the United States, and it is regarded as a banned substance by the International Olympic Committee. The United States and Canada are the only countries in the world permitting Lasix use during racing. Other vascular agents such as nitric oxide (NO), n-nitro-l-arginine methyl ester (L-Name), nitroglycerin, NO + phosphodiesterase inhibitors (i.e. Sildenafil), and endothelin receptor antagonists have demonstrated no effect and in some cases worsening of hemorrhage due to the protective effects at the arteriolar level of the pulmonary vasculature.

Scientifically controlled treadmill and track studies have consistently and repeatedly demonstrated that the non-pharmacological FLAIR® Equine Nasal Strip prophylactically reduces EIPH at all exercise intensities and levels of competition by 30–50%, but varies depending on the severity of EIPH in an individual horse, the length of the exercise bout, and the intensity of exercise. At all levels of exercise, wearing the nasal strip affords the greatest reduction in EIPH to the worst "bleeders", with reductions ranging from 20–79%. Whereas the effectiveness of Lasix diminishes as exercise intensity or duration increases (decreasing from 90–50%), the nasal strip attenuates EIPH more effectively (increasing from 33–50%) by minimizing the continued increase in resistance to breathing and work of breathing as exercise intensity increases. In addition, in one study of over 400 horses, those horses wearing the nasal strip were able to race back 6 days sooner than when not wearing the Strip. It appears that a synergistic benefit exists when the nasal strip is combined with Lasix. The scientifically proven mechanism of action of the FLAIR® Strip during exercise involves the spring-like action that mechanically supports and maintains the size of the nasal passage at the nasal valve, which is the narrowest part of the upper airway. This is key in exercising horses since the resistance to breathing doubles during intense exercise or long-duration endurance exercise, with >50% of the total resistance originating at the nasal passages. Clinical studies have proven that decreases in resistance to breathing and thus the work of breathing muscles results in a reduction in the contribution of airway forces across the pulmonary capillary membrane that consequently results in less performance impairment and lung damage caused by EIPH. This may increase the longevity of a horse's career due to less bleeding cumulatively during the training and performance life of the horse. All disciplines (i.e. barrel racing, eventing, track racing, rodeo, endurance, etc.) can benefit from use of the Strip. The Strip is approved in all 50 states for racing and by most US and international sport horse and regulatory bodies throughout the world including FEI.

Bronchodilatory agents (i.e. clenbuterol, albuterol, etc.) have not shown effectiveness in reducing EIPH, as in normal conditions bronchodilatation is maximized in the exercising horse. However, there were some anecdotal and preliminary research reports indicating possible benefits of Ipratropium in reducing EIPH. In addition, research has indicated long-term deleterious cardiac effects resulting from chronic use of bronchodilators in horses.

Anticoagulatory agents (i.e. herbal formulations (i.e. Kentucky Red), aspirin, Premarin, Amicar, and vitamin K) have not proven to be effective in reducing EIPH as coagulation dysfunction has not been documented as an etiology of EIPH, and again in some cases these pharmaceuticals worsen the level of hemorrhage.

There have been two anti-inflammatory agents that have shown promise in preliminary reports from controlled laboratory studies with regards to reducing EIPH and include omega-3 fatty acids (DHA and EPA) and concentrated equine serum. Omega-3 fatty acids significantly reduced EIPH presumably via an anti-inflammatory effect of controlling inflammation through increased functionality of the WBCs in removing the blood from the lungs. The serum therapy reduced EIPH by 53% through a combined mechanism of a 30% reduction in inflammation and an increased functionality of the WBCs with regards to more efficiently removing the RBCs in the lungs. Other anti-inflammatory agents (hesperidin-citrus bioflavinoids, vitamin C, NSAIDs such as phenylbutazone (bute), corticosteroids, heated water vapor therapy, and cromoglycates (i.e. cromolyn sodium and nedocromil) have been looked at but demonstrate no beneficial effects in reducing EIPH severity, and bute has been shown to partially reverse the beneficial effects of Lasix.

Other pharmaceutical and non-pharmacological treatments that have been tried, but shown no scientific efficacy include leukocyte elastase protease inhibitors, the EIPH Patch, hyperbaric oxygen therapy, pentoxyfylline, guanabenz, clonidine, snake venom, and enalapril. Horses that undergo surgical correction for upper airway dysfunction are rested, and are under environmentally controlled environments with reduced dust may see some benefit.

References

  1. 1 2 Riegal
  2. ↑ Epp et al. 2006 EVJ
  3. ↑ Oikawa (1999)
  4. ↑ Hillidge (1986)
  5. ↑ Newton (2005)
  6. ↑ Merck
  7. ↑ Hinchcliff, Kenneth W. "Exercise-Induced Pulmonary Hemorrhage". Pulmonary Hemorrhage (PDF). Versailles, Kentucky: Kentucky Equine Research, Inc. Archived from the original (PDF) on 2010-01-07.
  8. ↑ Ho, Clara (13 July 2013). "Chuckwagon horse died from burst lung artery, say Stampede officials". Calgary Herald.
  9. 1 2 Hinchcliff, Kenneth (2009). "Exercise-Induced Pulmonary Hemorrhage" (PDF). Advances in Equine Nutrition. 4: 367–374 – via Google Scholar.
  10. 1 2 3 Hinchcliff et al. 2005
  11. ↑ Kim et al. 1998
  12. ↑ "AAEP CAUTIONS CAREFUL EVALUATION OF NEW FUROSEMIDE STUDY" (Press release). American Association of Equine Practitioners. 2 September 1999. Retrieved 24 August 2010.
  13. ↑ Votion et al 1998
  14. ↑ Meyer et al, 1998; Langsetmo et al 2000
  15. ↑ Jackson et al 1997; Hackett et al 1997
  16. 1 2 Derksen et al. 2009
  17. ↑ e.g. Newton et al. (2005)
  18. ↑ Mason et al. (1983); Hillidge et al. (1985); Kim et al. (1988); MacNamara et al. (1990); Hinchcliff et al. (2005)
  19. ↑ Pascoe et al. (1981); Raphel and Soma (1982); Speirs et al. (1982); Roberts et al. (1993); Lapointe et al. (1994); Doucet and Viel (2002); Birks et al. (2002)
  20. ↑ Rohrbach (1990); Saulez (2007)

Sources

Additional reading

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