Exercise Induced Pulmonary Hemorrhage
The debate goes on. That brief statement is about the most accurate way to open a discussion on exercise-induced pulmonary hemorrhage (EIPH) in horses. The condition has been a concern for 300 years and, during that time, has been addressed, researched, and argued about by some of the most brilliant scientists in the world. Yet, there is much that remains a mystery, and there is just as much that remains a battleground of disagreement.
The major source of debate concerns the exact cause of EIPH. At this point, the specific cause has not been defined, and there are no bright lights of solution shining at the end of the information tunnel. Likely, there is no single cause, but rather a combination of factors that come into play when a horse's pulmonary system is heavily stressed to the point where capillaries and blood vessels burst.
Many researchers believe that bleeding stems from high cardiac output, which ruptures capillaries and blood vessels. But one venerable researcher who has studied and written many articles on upper airway disease believes that the prime cause of bleeding is upper airway obstruction and disease that cause pulmonary edema.
Then, there are questions concerning the effectiveness of furosemide (Lasix). Does it truly reduce bleeding? Some argue persuasively that it does, while others contend that a number of studies indicate that it has little or no effect on EIPH.
A question also has surfaced concerning the use of phenylbutazone. Does it actually increase pressures that could stimulate bleeding in the lungs? One group of researchers says yes; another group says no.
We will seek to address all of these issues, but first we must set the stage with a description of pulmonary function. For that, we turn to John Pascoe, BVSc, PhD, Diplomate ACVS, of the University of California, Davis. Pascoe, one of the leading researchers on EIPH, was a featured speaker at the 1996 AAEP Convention in Denver last December and had the rapt attention of a large audience as he explained the history and current research involving EIPH.
In his opening remarks at the convention, Pascoe gave this description of the pulmonary system and how its construction relates to EIPH:
"The lung has two distinct vascular supplies--the pulmonary and the bronchial circulations. The pulmonary circulation is a large-volume, low-pressure vascular system with important gas-exchange and metabolic functions.
"In contrast, the bronchial circulation is a small-volume, high-pressure vascular system that supplies nutrition to the structural components of the lung, is involved in the repair of lung tissue, and plays an important role in conditioning respired air.
"Vessels of a range of sizes and wall strengths occur in each circulation, and whereas it is presumed that bleeding is occurring from the capillaries, the possibility that larger vessels are involved has not been ruled out.
"Morphologic and physiologic evidence exists to suggest that both circulations, the pulmonary and the bronchial, contribute to bleeding that occurs in EIPH. The initial site of hemorrhage and the actual cause are not yet known, although it seems likely that events occur first in the pulmonary circulation, with later contributions from the bronchial circulation."
Pascoe's assertion that bleeding originates in the pulmonary circulation is consistent with the views held by many modern researchers, but it wasn't always that way.
Some early observers and researchers who were intrigued with EIPH assumed that epistaxis (bleeding from the nostrils) originated in the nasal cavity, with blood being inspired into the lungs.
Pascoe quoted the following statement, articulating that contention, which was published in 1913: "If the lesion occurs high up in the nasal cavity and close to the pharynx whilst the horse is doing a gallop, not infrequently some of the blood is forced by the inspired air into the glottis, and so gains access to the lungs."
Yet, there were other researchers, reporting even earlier on their theories, who believed that bleeding originated in the lungs and exited through the nostrils, rather than vice versa. For example, a researcher writing in a veterinary textbook in 1883 attributed bleeding to "hyperemia (an excess of blood) condition of the capillary vessels, sometimes attended with an extravasation (a discharge or escape, as of blood, from a vessel into the tissues) from these into the air-sacs and interconnective tissue."
Sounds much like what researchers are saying today.
In 1974, a researcher at Tufts University, W. Robert Cook, MRCVS, FRCVS, PhD, now emeritus professor at the school, compiled evidence that the source of bleeding in equines was most likely the lung. There has been an accumulation of evidence since that time to support the lung-source theory.
Aiding in the substantiation of this view has been the development of the fiberoptiscope, which not only has helped identify hemorrhaging, but has provided shocking evidence that more horses are bleeders than was imagined prior to its diagnostic employment.
Before the advent of endoscopy, it was believed that bleeding was a serious problem, but only in a limited number of horses. Today, we know that almost 100% of racing Thoroughbreds suffer from EIPH when running at speed. We also know that they are not the only ones.
Various percentages have been bandied about concerning the number of horses of other breeds and disciplines which bleed. Included are the following: pony club horses, up to 10%; three-day event horses, 40%; racing Standardbreds, from 25-40%; racing Quarter Horses, 65%; steeplechasers, up to 70%; and polo ponies, 10-15%.
Remember, these are only assumptions. In the majority of horses, the bleeding is not profuse enough for any visible signs, such as blood coming from the nostrils, and many of these horses do not undergo endoscopic examinations.
While Cook was one of the first to provide definitive evidence that bleeding originated in the lungs, he has, today, taken issue with some of the research findings that point to capillary and vessel breakdown due to high pressures as the cause of bleeding. He contends that upper airway obstruction and disease that cause pulmonary edema are the originating causes.
More about his theory later. First, let's take a look at the position taken by Pascoe and many of his colleagues involving cause and source of bleeding.
Capillaries as a Source
Strong evidence that pulmonary circulation is involved in bleeding was produced about four years ago, when a group of researchers published electron micrographs of pulmonary capillaries from the lungs of two horses known to have experienced EIPH. The electron micrographs provided evidence of pulmonary disruption, leakage of erythrocytes into the interstitial spaces (areas between cells) and air spaces, and accumulation of fluid in the interstitial spaces.
There was to be more evidence when labeled microspheres were injected both into the systemic circulation and into the pulmonary circulation of horses exercised on the treadmill. The microspheres were recovered via lavage.
Pascoe had this to say about the findings:
"Recovery in bronchoalveolar lavage fluid of labeled microspheres injected into the pulmonary circulation, but not of those injected into the systemic circulation of treadmill horses, provided direct evidence that vessels in the pulmonary circulation were the source of bleeding in these horses.
"There is no morphometric evidence to suggest that structurally the alveolar capillary membrane is any less robust in horses than in other mammals, so it would appear that stress failure associated with high transmural (extending through or affecting the entire thickness of the wall of an organ) pressure during strenuous exercise is the most probable cause of vascular disruption."
The research also indicated that although bronchial circulation might be involved in EIPH, it does not appear to be the source of the problem.
The next logical question is: Where in the lungs does the bleeding originate? Pascoe had this to say:
"Finally, although one might anticipate that the lesions associated with EIPH would occur in the lower parts of the lungs because intravascular pressures should be highest in these regions, a recent study has provided evidence that there is a preferential redistribution of flow to the dorsocaudal (upper rear portion) regions of the lungs during exercise."
Thus, he concludes, that is the area where capillary and vessel ruptures seem first to occur.
While high cardiac output during strenuous exercise appears implicated in EIPH, there is still debate about specific causes.
Pascoe outlined some of them: "Exercised-induced changes in hemostasis (changes in the rate of blood flow), red cell morphology (a change in shape and structure of red blood cells), blood viscosity, barotrauma (injury caused by pressure), visceral trauma, atrial (heart) fibrillation, airway obstruction associated with recurrent laryngeal neuropathy, lung disease caused by infectious respiratory disease, environmental pollution and inhaled particulates, and mechanical stresses on the lung all have been implicated as causes of EIPH."
There is evidence to support some of these concepts and evidence to refute others, says Pascoe. The logical conclusion is that while there is a no single cause, EIPH might be the result of a combination of the above factors and conditions, along with the high pressures in capillaries and veins during strenuous exercise.
Breeding for Bleeders?
The high prevalence of EIPH in racing Thoroughbreds might be an indication that we have, through selective breeding, developed a horse whose lung capacity is insufficient to answer the demands placed on it when the horse travels at high speed even for a short distance.
In his address to the AAEP attendees, Pascoe summed up his views this way:
"From the available evidence, it seems likely that EIPH occurs as a consequence of the high cardiac outputs necessary to sustain metabolic function in strenuously exercising horses. Selection in horses of phenotypic traits that require high aerobic performance have probably placed the functional requirements of the circulatory system, to sustain a high mass specific blood flow to exercising tissues, in conflict with its structural elements.
"(Researcher J. J.) Jones has suggested that because the selection for maximal respiratory function is weak in most mammalian species, components of the respiratory system may be underdeveloped in relation to other structures and contribute disproportionately to limiting oxygen transport.
"Strong selection for aerobic capacity, combined with other training-induced improvements in cardiovascular function, likely results in a functional demand that exceeds structural capacity. Any pathological process that is superimposed on the system will, in all likelihood, increase the risk of structural failure.
"For example, during exercise, dynamic upper airway obstruction results in large increases in impedance to air flow, such that there is often at least a two-fold increase in inspiratory pressure which, in turn, will be reflected in an increased vascular transmural pressure."
Cook believes that nerve disease to the larynx (recurrent laryngeal neuropathy) is strongly implicated in EIPH.
"Whereas this finding has not been refuted," Pascoe said, "clinical experience and treadmill endoscopy suggest that impaired laryngeal function occurs in a relatively small percentage of horses, and thus it seems unlikely that recurrent laryngeal neuropathy is the initiating cause of EIPH in most horses."
While racing Thoroughbreds top the list when it comes to numbers suffering from EIPH, they are not the only ones with the affliction.
"Short duration, intense bursts of activity, such as a barrel racing and breaking a horse out of the starting gate for half a furlong, can elicit pulmonary hemorrhage," Pascoe said. "Horses have also been reported to bleed during pulling competitions, immediately after pulling back against a steer in roping competitions, and after jumping.
"By contrast, horses used for slower, longer duration activities, such as harness racing and, notably, endurance racing, would appear to have a lower prevalence of EIPH."
Pascoe's position on EIPH represents that taken by the majority of researchers, but there are other viewpoints. An opposing theory is offered by Cook of Tufts University.
His research, Cook says, indicates that horses that bleed are suffering from pulmonary edema, something that many researchers say is not implicated in EIPH. In order to find pulmonary edema in a horse which has succumbed as the result of EIPH, he said, the post mortem examination must be carried out within 30 minutes of death and most are not. Often, he says, post mortems are postponed for several hours after death. After several hours, Cook says, the edema will have dispersed or have been masked by congestive lung changes that occur in all horses after death.
Cook says the condition referred to as EIPH is actually a misnomer. He thinks it should be referred to as asphyxia-induced pulmonary edema (AIPE).
Cook has offered several arguments to substantiate his position.
First of all, he says, the nasal discharge that has been called a hemorrhage is not blood, but is heavily blood-stained pulmonary fluid that does not have the ability to clot.
Second, he says, the post mortem lesions that have been labeled as having been exercise-induced are not specific to exercise alone and also can be found in a horse which has not been recently exercised.
Third, he goes on, the factor common to both nasal discharge and lesions is not exercise, but asphyxia or lack of adequate oxygen supply. Asphyxia is the result of upper airway obstructions that can occur at any point between the nostrils and the windpipe at the level of the first rib. He contends that the same post mortem findings will be present whether the horse with upper airway obstruction was exercising or standing still.
Pulmonary edema, he says, is secondary to upper airway obstruction. Construction of the walls of the air sacs figures into the equation. Cook points out that the walls of the air sacs are extremely thin--15 times thinner than a standard sheet of airmail paper. When there is an upper airway obstruction, he maintains, the walls are exposed to a greater than normal suction pressure, and fluid and red blood cells are sucked out of the lungs into the small airways.
Upper airway obstruction is common in racehorses, Cook states, and can result from a number of factors, ranging from head flexion in response to bit pressure to a variety of conformational defects, such as a narrow throat and larynx and a collapsed windpipe.
Cook also takes issue with the contention that few horses suffer from recurrent laryngeal neuropathy (RLN) which, he contends, also can be a cause of asphyxia and which can result in asphyxia-induced pulmonary edema. He maintains that (RLN) occurs in up to 95% of horses, but in varying degrees. The reason a number of scientists think it exists in only a few horses, he declares, is that they are not looking for it.
And so, the debate goes on.
Compromise or Commonplace?
As mentioned earlier, EIPH is difficult to detect in many horses without an endoscopic examination. The only outward clinical sign is blood from the nostrils when a horse bleeds profusely, and most do not.
There is another issue that begs debate. How much does EIPH compromise a horse's ability to perform?
For the horse which bleeds profusely, the answer is simple. Its ability can be compromised to the point where it must come to a standstill. Some horses, including Kentucky Derby favorite Demons Begone, have been pulled up because blood was pouring from their nostrils. Not so easily assessed is the horse which does not bleed from the nostrils, but demonstrates signs of EIPH when examined endoscopically.
The loss of blood itself is rarely the problem. The problem stems from the interference caused by the fluid in gas exchange within the lungs.
Ongoing bleeding can produce long-range problems. Blood in the horse's airways induces inflammation. With repeated hemorrhaging, the problems increase with interstitial fibrosis and chronic changes occurring within the small airways. Adding to the problem can be the inhalation of dust and other particulates, such as particles of flying dirt while racing, all of which exacerbate small airway disease.
As small airway disease progresses, the lungs become even less capable of withstanding the pressures applied during exercise, and more bleeding can occur.
With further hemorrhage and inflammation, says Pascoe, the lesions expand until confluence over a substantial region of the dorsal aspect of the caudal lung occurs.
"This process," he said, "continues throughout the horse's athletic career and, from pathologic evidence, it seems unlikely that the changes, once established, are reversible."
The damage from bleeding, he said, has been observed in the lungs of horses long after athletic activities have ceased.
A basic problem for any malady is how to prevent it. This presents an even greater problem when one doesn't know exactly what causes the malady.
There have been some therapeutic drugs offered, but most of them have done little to prevent bleeding. The drug of choice that has been around for about a quarter of a century is furosemide, which is sold under the trade name Lasix.
Its efficacy long has been a subject of debate, with some racing jurisdictions making its use illegal. Even the manufacturer of furosemide makes no claims that it can prevent bleeding. One of its stated uses is to reduce edema.
Furosemide and its utilization to prevent bleeding were discussed as part of the overall session on EIPH during the AAEP convention.
A bit of background on furosemide (Lasix) is in order. First, it is a diuretic. It can be administered either intravenously or intramuscularly, but the most rapid effect is from intravenous injection.
It is a drug that works quickly, but for a short period of time, and it has a very high dose-to-response relationship.
The question of how much Lasix to administer has been debated. There is a strong belief among some researchers that the dosage permitted in pre-race injections by most racing jurisdictions is too small to be effective. Researchers at the University of Illinois have studied this matter and have indicated that the more effective dosage is two milligrams per kilogram of body weight. This is a good deal more than what is allowed at present by most racing jurisdictions.
There are some downsides to Lasix. If it is used in excess or for prolonged periods, the result, primarily because of its diuretic quality, can be dehydration, electrolyte imbalance, and reduced plasma volume. It can lower a horse's potassium level, and supplementation might be necessary.
Horses suffering from electrolyte imbalance will show signs of fatigue, lethargy, thirst, drowsiness, restlessness, and might urinate infrequently. Horses which are suffering from any type of kidney disease or urination problems should not be administered Lasix.
One researcher, K. W. Hinchcliff, BVSc, MS, PhD, of The Ohio State University, told the AAEP assemblage that research indicates that the diuretic effect of Lasix has a direct bearing on lowering plasma volume and reducing right atrial and pulmonary pressure. Thus, he said, it might be concluded that Lasix is instrumental in preventing EIPH.
But, does it really prevent bleeding and return a horse to normal performance?
There really is no conclusive evidence that it does either.
There was a study that demonstrated that pre-race administration of Lasix increased the racing time of one group of horses, but several other studies demonstrated that Lasix does not improve racing performance. Some studies also indicated that Lasix can and does have a positive effect in preventing EIPH, while others fail to show beneficial results.
In fact, one study came up with an opposite result. A group of horses which were declared as EIPH-negative were administered Lasix prior to racing. After competing, more than 26% were found to have bled.
Phenylbutazone's Side Effects
There are other facets to the debate on EIPH and Lasix. Hinchcliff, in his report, said that administering phenylbutazone had a deleterious effect on the positive benefits of Lasix. He found, he said, that administering phenylbutazone increased right atrial and pulmonary pressure, the very opposite of what transpired when Lasix was administered. Thus, it could be reasoned, administering phenylbutazone could, at worst, be a causative factor in EIPH, and, at best, mitigate the beneficial effects of Lasix in lowering right atrial and pulmonary pressure if both drugs were administered at the same time.
Thomas E. Goetz, DVM, of the University of Illinois, took issue with Hinchcliff's findings. He said that research conducted at Illinois showed that there was no significant rise in right atrial and pulmonary pressure when phenylbutazone was administered.
In his report, he stated: "The results of these studies demonstrated that the heart rate and right atrial and pulmonary vascular pressures, especially the pulmonary capillary blood pressure, were not significantly affected by the administration of phenylbutazone, either at rest or during high-intensity exercise. Because EIPH probably results from stress failure of pulmonary capillaries, phenylbutazone is therefore unlikely to exacerbate the incidence or severity of EIPH. Veterinarians and trainers can thus be reassured that phenylbutazone does not cause further exaggeration of the already high pulmonary capillary blood pressure that is observed in strenuously exercising Thoroughbred horses."
A colleague of Goetz, Murli Manohar, BVSc, PhD, also at the University of Illinois, addressed the question of whether there were negative results when Lasix and phenylbutazone were administered simultaneously.
Seven healthy, sound, exercise-conditioned Thoroughbreds were used in the study. Three sets of experiments were carried out. In the control study, no medications were administered. In another phase, furosemide only was administered. In the third phase, both furosemide and phenylbutazone were administered.
Experiments were carried out in random order and were separated by at least seven days. In the control study, horses received no medications. In the furosemide-control study, horses received 250 milligrams of furosemide intravenously four hours before exercising. (This is the legal dosage at racing jurisdictions in Illinois.) In the phenylbutazone plus furosemide study, horses received four intravenous injections of phenylbutazone at the rate of 4.4 milligrams per kilogram of body weight at 12-hour intervals. Twenty-four hours after the last phenylbutazone injection, horses received 150 milligrams of furosemide intravenously. This mimicked the prevailing veterinary practice at Illinois racetracks.
Manohar had this to say concerning results: "In the furosemide-control and the phenylbutazone plus furosemide studies, the exercise-induced rise in the mean right atrial as well as pulmonary vascular pressures was significantly attenuated in comparison with the control experiments. However, statistically significant differences were not found between the furosemide-control study and the phenylbutazone plus furosemide study, either at rest or during exertion at maximal heart rate.
"Our data are in agreement with previous observations that exercising horses develop significant right atrial, as well as pulmonary arterial, capillary and venous hypertension, and that intravenous furosemide administration at 250 milligrams four hours pre-exercise is effective in significantly attenuating the exercise-induced pulmonary arterial, capillary and venous hypertension.
Then Manohar added this interesting observation: "In the present study, furosemide pre-medication did not affect the incidence of EIPH, however."
In fact, six of the seven horses in the study bled even though furosemide was administered.
Thus, another puzzling finding. Yes, furosemide did lower blood pressures, but, no, it did not prevent EIPH in this particular group of healthy Thoroughbreds.
And the debate goes on, with there being room for varying views and theories until scientific evidence clears up all aspects of the mystery, something that does not appear to be just over the horizon.
The trainer, owner, and veterinarian are left to grapple with this problem that in its mildest form might not compromise immediate performance, although it certainly can have long-range negative effects. In its most severe form, it can bring death.
While the EIPH mystery remains unsolved at the moment, there are, nevertheless, management procedures that can be implemented to mitigate the negative long-range effects of bleeding and attendant small airway disease.
First of all, it must be recognized that dust and airborne particulates are enemies of the EIPH-positive horse. Dust should be minimized in feed, bedding, and the general atmosphere. Of utmost importance in a stable setting is proper ventilation.
There is little in the way of drug therapy that can be carried for a horse in the wake of a bleeding episode, except to use medication to counteract harmful bacteria after a severe episode in an effort to prevent bacterial pneumonia.
The negative part of this whole discussion is that based on what we know today, it appears that EIPH in some form is unavoidable when we ask horses to perform in strenuous fashion in an athletic endeavor, such as running at speed on a racetrack or speeding around cloverleaf barrels.
The hope is that scientists will find a definitive cause, and that this will be followed by determining appropriate preventative measures.
If, however, we have, indeed, bred and developed horses in which the lungs do not have the capability of functioning at a level consistent with the circulatory system, there will be little that can be done to prevent EIPH other than to wait for the pulmonary system to catch up in the evolutionary process.
About the Author
Les Sellnow is a free-lance writer based near Riverton, Wyo. He specializes in articles on equine research, and operates a ranch where he raises horses and livestock. He has authored several fiction and non-fiction books, including Understanding Equine Lameness and Understanding The Young Horse, published by Eclipse Press and available at www.exclusivelyequine.com or by calling 800/582-5604.
POLL: University Equine Hospitals