Furosemide facts and fiction

"There is terror in numbers," writes Darrell Huff in his mathematical primer How to Lie with Statistics. Published in 1954, this best-selling book rapidly changed the way people viewed numbers and data in research and how that data could be used to influence ideas and opinions. More than 50 years later, Huff's hypothesis still holds true: Data can be interpreted, slanted and presented to support virtually any agenda. He went on to explain that "the secret language of statistics, so appealing in a fast-minded culture, is employed to sensationalize, inflate, confuse and oversimplify."

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The current debate in the horse racing world over the use or abuse of the diuretic furosemide contains many of these elements—sensationalism by the press and various animal welfare groups, inflated claims by both sides and oversimplification of the science involved. Furosemide proponents think that the drug helps treat an important condition found in almost all athletic horses and that its use is both ethical and humane. Critics maintain that it is an unnecessary performance-enhancing drug that's rarely used in the racing world outside of North America and that its continued use is ultimately weakening racehorse genetics.

Both camps can cite scholarly studies, field research projects and statistics to bolster their arguments, but all this science has not produced much common ground. There are, however, some indisputable facts regarding furosemide and exercise-induced pulmonary hemorrhage (EIPH), the disease that furosemide is used to treat in racehorses. Any attempts to clarify this contentious debate should start there.

Agreeing on etiology

While it is often linked with racehorses, EIPH is a condition that can affect all categories of performance horses, including three-day eventers, polo ponies and draft horses. EIPH results from rupture of pulmonary capillaries and subsequent leakage of blood into the airway. The site of initial bleeding is in the dorsocaudal lung. The reason for this is not fully understood.

The most commonly accepted theory to explain the occurrence of EIPH relates to the dramatic increase in blood pressure that normally occurs in the lungs of a maximally exercising horse. Increased blood pressure is caused by an increase in cardiac output. As a horse exercises, there is an increased oxygen demand by the body, and the normal equine heart is capable of tremendous increases in output to meet this demand. The huge difference between high blood pressure inside the capillaries and low pressure outside the vessels in the lungs causes capillaries to burst.

"To some extent, EIPH is an inevitable consequence (some might say physiological consequence) of the extremely high cardiac output required by racehorses," says Cate Steel, BVSc, FACVS, in Racing Victoria magazine.

Some theories suggest that there are other contributing factors, including any problems that restrict airflow (upper airway obstruction "roaring" and allergic, bacterial or viral airway disease), changes in blood viscosity, mechanical concussion and shear forces in the chest associated with running and bronchial artery angiogenesis. With each bleeding bout, the horse experiences inflammation of the airways and subsequent fibrosis. This pattern of inflammation and less than functional repair is repeated with each bleeding episode, leading to repetitive damage.

Pinning down prevalence

The true prevalence of EIPH stirs debate. Horses with EIPH are called "bleeders" because the classic clinical sign of this condition is poor performance and bleeding from the nostrils after exercise. Most bleeders (about 95 percent), however, do not show blood at their nostrils, even when they are bleeding deep in their lungs.1

The best and most accurate method of diagnosing a bleeder is with a tracheobronchial examination via fiberoptic scope. Although EIPH has been described in horses for hundreds of years, the horses that were known to suffer from this condition were those that bled, sometimes copiously and dramatically, from the nose. Horses that showed no external bleeding were considered free from EIPH and to be normal.

The development of the fiberoptic endoscope and the small flexible versions that followed in the 1970s helped us understand where the blood was coming from and exactly how many horses were affected. However, many countries did not and still do not have ready access to such equipment. Some trainers and owners forego these exams even when appropriate equipment is available, so the actual incidence of EIPH varies depending on how studies have been conducted. Some countries and breeders report a low incidence of EIPH, but these claims are rarely substantiated with well-controlled studies using endoscopic examination.

Much EIPH research, even some done very recently, suffers because of a lack of uniform agreement as to what constitutes a bleeder. Is it only a horse that visibly bleeds? Is it a horse that is assigned one of the four grades of abnormal bleeding in the trachea as seen with a scope? How and when should these individuals be examined? Within an hour after racing or sooner? After one race or after several? The decision about how and when to examine possible bleeders plays a large role in the statistical outcome. The results of any investigation cannot be relied on if the methodology is inconsistent.

However, it has been shown conclusively in the United States that between 43 and 75 percent of racehorses exhibit signs of EIPH based on a single endoscopic examination.2 In 1990, veterinary researchers at the University of Pennsylvania's New Bolton Center at the School of Veterinary Medicine showed that the prevalence of EIPH increases with the frequency of examination.3 More than 80 percent of horses showed evidence of EIPH on at least one occasion when examined after three consecutive races. Ken Hinchcliff, BVSc, MSc, PhD, repeated this work in 2005 in Australia and reported that 55 percent of horses examined showed some evidence of EIPH and that if horses were scoped after three successive strenuous workouts, nearly 100 percent would show some bleeding by the third endoscopic exam.4

Prevalence statistics reported from other countries by the International Federation of Horseracing Authorities all show relatively similar rates for the incidence of epistaxis in horses after racing, with Japan reporting 1.5 cases per 1,000 starts, the U.K. showing 0.83 per 1,000 starts, South Africa reporting 1.65 per 1,000 starts and Korea reporting a high of 4.4 per 1,000 starts.

Opponents of the use of furosemide to pretreat racehorses point out that this drug is used for this purpose only in the United States and Canada and that the rest of the world does not race on it. Furosemide is not needed, goes the argument, because EIPH is not seen in as high prevalence in other countries. Science does not support this view, and since many other countries only identify bleeders visually, the number of endoscopic-confirmed EIPH cases would likely be much greater. The simple scientific fact is that EIPH occurs with similar frequency in racehorses and equine athletes in almost all parts of the world.5

Administering a competitive edge

Hinchcliff was also the lead researcher on a groundbreaking study released in 2009 looking at the effects of furosemide.6 In this uniformly accepted, well-designed study, 155 South African racehorses from 40 different stables were raced in a controlled environment. The distance, track surface, jockey influences and as many other factors as possible were kept the same. Horses were raced once after being given furosemide, and then, one week later, the same horses were raced after receiving a placebo of saline solution.

After the race (roughly 42 minutes later), the horses were returned to the parade ring and untacked, and a tracheobronchoscopic examination was performed. Hinchcliff was able to show that 57 percent of the horses running after furosemide administration demonstrated EIPH, while 79 percent of the same horses showed evidence of bleeding after saline treatment. The degree of severity of cases of EIPH was substantially reduced with furosemide treatment as well. No cases of severe (grade three or four) bleeding were noted with furosemide treatment, and all horses were judged to be grade two or less (the levels thought to have minimal to no effect on performance). This study finally confirmed what many other studies and countless horsemen believed: Furosemide reduces the severity and influences of EIPH in performance horses.

"There is ample scientific evidence that furosemide decreases the severity of EIPH in horses," says Warwick Bayly, BVSc, MS, PhD, DACVIM, of the College of Veterinary Medicine at Washington State University. "In the long term, reducing the severity of EIPH bouts is beneficial to lung health, as the presence of blood in the lungs has been shown to induce permanent changes in their tissue structure."

In support of veterinary treatment in the best interest of the horse, the American Association of Equine Practitioners (AAEP) maintains that "horses that experience EIPH should receive appropriate veterinary care; furosemide is currently the most effective therapeutic medication available for the treatment of EIPH; and increased scientific research regarding EIPH will provide improved treatment options and the greatest benefit to the health and welfare of the horse."7

Furosemide is a loop diuretic and causes increased excretion of water in the urine. One consequence of increased water loss is decreased blood pressure, which helps reduce bleeding associated with EIPH. Exactly how much water loss do we see after furosemide administration? Many values have been tossed around in this diuretic debate—from 20 pounds to 100 pounds. Hinchcliff's study definitively showed that furosemide use was associated with 27.9 pounds of water loss compared with 11.9 pounds lost when racing after receiving saline solution.6 So horses lost an additional 16 pounds when treated with furosemide, which can give them a competitive advantage.

Another study by Hinchcliff's group specifically looked at the issue of furosemide and its effect on racing performance in horses in the United States and Canada.8 This study looked at the race records of more than 22,000 horses. They learned that 74.2 percent of these athletes competed on furosemide, and those that did "raced faster, earned more money, and were more likely to win or finish in the top three positions than horses that did not." This study estimated that in a 6-furlong race, a horse on furosemide would have a 3 to 5.5 length advantage. It is not known if the "winning edge" was due to a disproportionate loss of weight or an increase in air flow because of the absence of blood in the airways. Either way, this and other similar studies led to the third unchallenged scientific fact in this debate—furosemide use is strongly associated with improved performance in racehorses.

Rehashing the genetics debate

Some veterinarians, researchers, trainers and owners have stated that furosemide is not performance-"enhancing" but rather performance-"restoring." This drug does not make horses run any faster than they normally could, they argue. But it allows horses to perform at their normal physiological level, free from the effects of blood in their airways. If it is all about a level playing field, then furosemide just returns horses to normal, they contend.

Furosemide opponents counter that the field was never supposed to be level in the first place. Genetically superior horses that do not bleed and do not need furosemide should have an advantage over lesser-quality horses.

Genetics have been dragged into this debate in other ways as well. Critics of the use of furosemide to prevent or treat EIPH in racehorses think that its use is weakening the thoroughbred breed, since horses that race on furosemide and win then move to the breeding shed. There they possibly pass this propensity for EIPH and a need for drug treatment on to future generations of racehorses.

Whether EIPH is a genetic condition is a contested point with insufficient science to prove it either way. Researchers in South Africa conducted a retrospective pedigree and race-run data project looking at the genetic analysis of EIPH in Southern African thoroughbreds.5 They concluded that "epistaxis as associated with EIPH in the Southern African Thoroughbred has a strong genetic basis." They also recommended emphatically that "affected stallions and those racing while being treated with furosemide should be barred from breeding and not be considered as future sires."

Scientists, veterinarians and horsemen have not uniformly accepted this paper. Some question the methodology of this type of study and comment that such a broad and hardline conclusion based on only this one study is unwise. Rick Arthur, DVM, a member of the AAEP's racing panel, simply says, "There is legitimate suspicion that EIPH has a hereditary component, but nothing has been proven."

Genetically speaking, students of horseracing can point to Bartlett's Childers (Eclipse's great grandsire and a known bleeder), to Hero (one of the original three thoroughbred foundation sires and a known bleeder) and even to Northern Dancer (not an overt bleeder but one of the first horses to be treated with furosemide and one of the most prolific stallions in memory). If there was a hereditary component to EIPH and if these three prominent stallions carried and transmitted these genes, then EIPH cases should be increasing rapidly. While the prevalence of epistaxis has increased slightly over time, the rate does not approach what would be expected if so many prominent stallions were in fact passing on this condition. As Arthur explained, the best we have is a "legitimate suspicion," and the more correct conclusion is that more research and studies should be done focusing on this question.

Many in the horse industry suggest that perhaps the debate should be widened as well. Why single out furosemide, they say, when any number of orthopedic procedures done to straighten foals' legs or to correct various conformational defects (many with more proven genetic tendencies than EIPH) are not being discussed? Shouldn't these procedures—which are done worldwide—be considered when discussing the "weakening of the breed"? Focusing on furosemide, some say, seems to be a singular witch-hunt that avoids the larger issues of what is best for the horse and for the industry.

The United States Trotting Association (USTA) recently reviewed furosemide use and issued a position statement that covers the known information about EIPH and furosemide and addresses positions critical of its use. "Given the stress experienced by equine athletes during competition, EIPH is expected to occur in excess of 90 percent of all racehorses," the USTA said in a press release. "The use of furosemide has for quite some time been an accepted therapeutic resource for the horse industry in combating the effects of EIPH." These USTA comments nicely summarize what we know—horses bleed, furosemide works. Beyond this point, the debate continues. And science alone may not be enough to stem the controversy.

Dr. Kenneth Marcella is an equline practitioner in Canton, Ga.

References

1. Goldberg R. Lasix: Demystifying the drug, methods of training without it. Racing Daily Forum 2011. Available at: http://www.drf.com/news/lasix-demystifying-drug-methods-training-without-it

2. Pascoe JR, Ferraro GL, Cannon JH, et al. Exercise-induced pulmonary hemorrhage in racing thoroughbreds: a preliminary study. Am J Vet Res 1981;42(5):703-707.

3. Sweeney CR, Soma LR, Mason AD, et al. Effects of furosemide on the racing times of Thoroughbreds. Am J Vet Res 1990;51(5):772-778.

4. Hinchcliff KW, Jackson MA, Morley PS, et al. Association between exercise-induced pulmonary hemorrhage and performance in Thoroughbred racehorses. J Am Vet Med Assoc 2005;227(5)768-774.

5. Weideman H, Schoeman SJ, Jordaan GF. A genetic analysis of epistaxis as associated with EIPH in the Southern African Thoroughbred. S African J Anim Sci 2004;34(4)265-273.

6. Hinchcliff KW, Morley PS, Guthrie AJ. Efficacy of furosemide for prevention of exercise-induced pulmonary hemorrhage in Thoroughbred racehorses. J Am Vet Med Assoc 2009;235(1):76-82.

7. AAEP cautions careful evaluation of new furosemide study. AAEP Press Release, Sept. 2, 1999.

8. Gross DK, Morley PS, Hinchcliff KW, et al. Effect of furosemide on performance of Thoroughbreds racing in the United States and Canada. J Am Vet Med Assoc 1999;215(5):670-675.