Thursday, January 01, 1998

Tying Up

To update the address of Dr. Stephanie Valberg, She is at the Univeristy of Minnesota College of Vet Med. She has done the most in depth biochemical analysis of the causes of tying up to date and has some very interesting data regarding the possible genetic nature of the syndrome in Thoroughbreds and Quarter Horses. Her email address is for those with questions or wish to discuss a case. She is actively looking for horses with both acute and chronic tying up syndromes to further study the mechanisms involved. I believe that her contributions to diagnosis and treatment have already made substantial impact on the way the tying up is managed in athletic horses.

Regards, Sam Jones

Here is a basic review of rhabdomyolysis (tying up; azoturia, Monday morning disease, set fast, etc.):

Exertional rhabdomyolysis means that the muscle fibers themselves are separating, or "dissolving" in a way. There are several muscle diseases that show similar signs, but there are 2 basic types of exertional rhabdomyolysis. 1) acute; and 2) recurrent

The primary difference is that the acute form shows up suddenly after exercise with no previous history of this problem, and may leave the horse mildly affected to recumbant. The recurrent form may occur repeatedly over a lifetime in mild or moderate form and results in general poor performance. Signs for both can include a short and stiffened gait. elevated respiration, profuse sweating, rapid heart rate, increased temp., and in some endurance horses severe dehydration , synchronous diaphragmatic flutter (thumps), and collapse.

Diagnosis is based on history, enzyme levels in the blood, and sometimes evaluation of urine, which may appear brown in severe cases from leakage of muscle proteins. Treatment tries to alleviate pain, correct electrolyte problems, and protect the kidneys.

The acute form cause may be just that the exercise is too strenuous for the horse at that time. Outbreaks of repiratory disease may also trigger the acute form (influenza and herpes virus 1). The exact metabolic problem is unknown, but may involve electrolyte imbalance, or problems with the muscle membrane.

The recurrent form is more mysterious, but usually occurs after exercise as well. Diet and exercise protocols are the most likely predisposing causes. High soluble carbohydrate diets (grains) and a day of stall rest after heavy work have been shown to trigger attacks. Vit. E /Selenium deficiency can cause the acute form, but many horses with the recurrent form do not show this, and there is no evidence to suggest extra protection from feeeding high levels of Vit. E. Feeding too much Selenium is potentially toxic to horses and SHOULD NOT be attempted. Other predisposing factors for the recurrent form may be hypothyroidism, metabolic enzyme disorders, or electrolyte regulation problems.

There is current and active research going on at this time at several places, including UPenn`s New Bolton Center (Dr. Jill Beech), and the Swedish Univ. of Ag. Science (Dr. Stephanie Valberg). Hopefully, we will be able to understand much more in the future. Hope it helps!!!! Cheers...

Lynn Taylor, MS, PhD
Otterbein College
Westerville, Ohio

Blood Selenium is a good test in horses, and more accurate than SERUM Selenium. The whole blood (cells and water) has to be analyzed to be accurate.

Equine Blood:
Se deficiency: .096-.160 ppm wet wt
Adequate: .170-.250 ppm
Toxic: 1.1-6.3 ppm
newborns are 50% of adult value for adequate

0.3 mg of Se per kg of diet dry matter from either sodium selenate or sodium selenite is adequate for horses per day

Lynn E. Taylor, MS, PhD
Assistant Professor
Dept. of Equine Science
Otterbein College
Westerville, Oh 43081

I went to my Veterinary Notes for Horse Owners by Captain M. Horace Hayes for the true definition and explanation of tying up. This is what I found:

Azoturia (Typing Up, Setfast, Exertional Rhabdomyolysis)
Clinical Signs
Azoturia is a relatively poorly understood disease, resulting in a variable degree of muscle stiffness and pain, which occurs under a number of different circumstances. Traditionally the problem occurs relatively soon after the
start of exercise, particularly in fit horses receiving high-concentrate rations on a day following a rest day. The clinical signs vary from mild hind-limb stiffness to a total reluctance to move, sweating and obvious severe pain. The muscles of the back and hindquarters may feel unusually firm. The exact cause of the condition is unknown. Some horses seem prone to recurrent attacks. Highly strung individuals, especially mares, seem particularly susceptible. Vitamin E and/or selenium deficiency has been
suggested as a possible cause, but there is little data to support this hypothesis and it is probably a multifactorial condition.

What actually happens? Whatever the actual cause, it results in damage of the muscle cells (myopathy). Their outer membranes become more leaky, permitting loss from the cells of two enzymes, creatine kinase and aspartate aminotransferase. As a result, the concentration of these enzymes increase in the blood. This rise in concentration reflects accurately the severity of muscle damage. Within minutes of the onset of clinical signs a measurable increase in the concentration of these enzymes may occur, and their concentration continues to rise for the following twenty-four hours. Thus there is a reliable blood test which can confirm a clinical diagnosis of azoturia.

If the damage to the cells is severe, a muscle pigment, myoglobin, may be released into the blood. This is a large molecule which is excreted via the kidneys causing dark discolouration of the urine. The name azoturia refers to this. Because of their large size, myoglobin molecules may impair the filtration mechanism of the kidney and, in extremely severe cases, cause irreparable kidney damage.

The muscle damage causes release of lactic acid (a substance responsible for muscle cramp) and pain. Continuing to work a mildly affected horse may exacerbate considerably the degree of muscle damage and pain, therefore, if azoturia is suspected, work should stop immediately and the horse returned carefully to his stall. If some distance from home, the horse should be transported back if at all possible.

In some horses with a recurrent problem selected blood and urine tests (creatinine clearance test) indicate a deficiency of sodium, potassium and/or calcium, and appropriate supplementation of the diet with these minerals has been most effective. Severely restricting the protein intake by the substitution of bran may be a complicating factor because bran contains a substance called phytate which can bind dietary calcium and prevent its absorption by the gut, thus effectively limiting the body`s supply of calcium.

Hope this helps clear up some questions.

Any discussion of tying up (exertional rhabdomyolysis) requires either brevity or verbosity. The whole issue of the disease requires the latter while some selected portions of it may be dealt with by the former. In any case, I would like to throw out a few ideas about the relationship of acid-base balance (especially alkalosis) to tying up. For those of you who have already read more than you care to know, it is appropriate to hit the delete key now. :)

The endurance horse is alkalotic, as has been noted in previous posts by Tom Ivers, Susan Evans, and others. They can get this way, as has also been noted, by blowing of carbon dioxide accessory to the attempt to cool themselves during hot, humid rides. This is termed respiratory alkalosis for the fall in body concentration of hydrogen ions increases the pH, which is alkalosis.

Endurance horses can also become alkalotic in other ways. The first of the two most common ways is to retain bicarbonate (HCO3-) because of the loss of chloride (Cl-) in sweat. The retention of a base to accomodate electrical neutrality is the most common cause of metabolic alkalosis.

The second common manner in which the endurance horse becomes alkalotic is by the loss of potassium (K+) in sweat resulting in hypokalemia or low blood potassium. Normaly, potassium is exchanged for sodium in the tubules of the kidney under the influence of the hormone aldosterone. When potassium is not present sufficiently, the body will exchange hydrogen for the sodium. (Hydrogen is lost in the urine as sodium is returned to the blood.) The loss of an acid, the hydogen ion, causes the body to become alklotic. This is consistent with the concept of survival priority, in that it is more important to maintain blood volume than fine tune electrical activity on the membranes of cells.

Lastly, endurance horses may occassionaly become alkalotic through inappropraite administraion of alkalyzing intravenous fluids by veterinarians or by riders giving horses electrolytes containing sodiun bicarbonate.

OK, get back into your chair seats before you fall off of the edge and quit yawning. What is the practical implication of alkalosis to tying up? Alkalosis has an effect on the availability of calcium and potassium. Unavailable calcium may predispose the horse to Thumps (Synchronous Diaphragmatic Flutter) which is not the subject at hand. Alkalosis causes potassium to be driven into cells (acidosis causes potassium to be driven into the blood). The result of alkalosis causes a double whammy to the endurance horse -- it is losing potassium in the sweat and the remaining blood levels decline further as postassium is driven into the cells.

ONE of the functions of potassium is to dilate capillary beds to tissues requiring oxygen, energy, and waste removal. In the working endurance horse, the hardest working tissues are the skeletal muscles, especially those driving muscles of the croup and hamstrings. If lowered blood potassium diminishes perfusion of these muscles with blood (and therefore oxygen), the muscles start forming energy anaerobically with the end product being the formation and accumulation of lactic acid. If exercise continues, tying up is the end result.

Therefore, tying up may be the result of an error in carbohydrate metabolism, but its occurrence may also be the result of many other factors, of which the above is only one. Tying up may also be proceeded by alkalosis which may be a prime effector of the condition under some circumstances (ty ups occuring late in the ride especially for horses underconditioned or with a history of repeated episodes ,- the recurrent tying up candidate. LOW BLOOD POTASSIUM IS PROBABLY NOT THE UNDERLYING CAUSE OF THE HORSE THAT TYES UP AFTER A FEW MILES OF EXERCISE.

I hope this post has not muddied the waters further as my intention as been to shed a small amount of light in a small corner of the tying up syndrome. The discussion on this list have been fascinating.

Dane L. Frazier DVM


I would like one of you out there to detail for me the physiological details of tying up and its resulting effects on the kidneys, etc., not in layman`s terms, but in biochemical and physiological terms.

Okay, here goes. Details you want, details you got, brace yourself :

The complete pathophysiology (Why It Happens) of tying up ("exertional rhabdomyolysis") is still not completely understood. Currently, the conditions that are known to be factors in causing tying up are 1) resting a conditioned horse on a full-grain diet, followed by exercise ("Monday morning disease"); 2) whole-body potassium depletion; 3) selenium deficiency; 4) an unaccustomed level of exercise; 5) postviral infections, particularly rhino; 6) intoxications with ionophores (a substance which increases cellular permeability to a specific ion, which would in turn disrupt the electrical potential of the cell), blister beetle, mercury, coffee bean (cassia) or gossypol from raw cottonseed. Other factors which have been suggested as being contributory are hypothyroidism, some high-performance lines of horses, nervous horses, fillies, estrus, hyperestrogenism (resulting from possibly a granulosa cell tumor), cold damp weather, heavy muscling, and low-sodium rations.

One of the current hypotheses is that when a conditioned horse is not worked and kept on full feed high in soluble carbohydrates, the horse will accumulate carbohydrates in the muscles. If there is a sudden demand for work, the cannot adequately remove the rapidly accumulating lactic acid in the muscles. This in turn causes vasospasms and ischemia---which means essentially that the surrounding blood vessels "clamp down" so that the lactic acid waste product cannot be removed, intracellular pH drops, the muscle cell is disrupted and you get the hard, crampy muscles you see when a horse ties up. Other theories of the biochemical mechanism is that there is a deficiency of the high-energy phosphates in muscle cells following maximal, anaerobic exertion, and/or a depletion of muscle glycogen after prolonged, slow (endurance-type) exercise. High body temperatures and electrolyte imbalances/depletions are also probably contributing causes, and certainly major factors in endurance horses that tie up during competitions.

Unless you`re a biochemist, all of these different theories essentially boil down to the same net effect---the ion pumps (ie, sodium/potassium, calcium/magnesium and calcium/ATPase) in the membrane surrounding the muscle cell which move substrates in and out of the cell are disrupted, and so the interior environment of the muscle cells either cannot get rid of waste products of metabolism, OR has too much of a metabolic substrate to be able to function, OR can`t get enough of a metabolic substrate to be able to function. And so the muscle cell simply shuts down. When muscle cells shut down, they don`t do so in the relaxed position, they freeze up in the contracted position, which is why you get those rock-hard muscles. Biochemically, it`s not all that different from rigor mortis.

The effect on kidneys comes in when the connective tissue (the sarcolemma) surrounding and enclosing the muscle cell is disrupted, releasing the contents of the muscle cell into the bloodstream. There are lots of different proteins and substrates and whatnot in a muscle cell, but the important one for this particular discussion is myoglobin. Myoglobin is a protein pigment which is responsible for oxygen transport in the muscle cell. Hemoglobin transports oxygen in the bloodstream, myoglobin transports oxygen in the muscle cell. When myoglobin is released from a disrupted muscle cell into the bloodstream, it travels to the kidneys and is filtered out. In being filtered out of the bloodstream (and keep in mind, there`s probably alot of it from the kidney`s point of view), it causes (or CAN cause) kidney damage or even total renal failure by overwhelming and clogging up the kidney tubules and restricting the blood (and therefore oxygen) supply to the kidneys. This effect will be worsened if the animal is hypovolemic, meaning he`s dehydrated and therefore his total blood volume is less, and the blood is thicker and harder to circulate, meaning harder to circulate oxygen and substrates, etc etc etc. A vicious cycle sort of thing. So while myoglobin does not directly damage the kidneys, in great enough concentration it will cause damage indirectly by clogging them up and creating what is called myoglobinuric nephrosis and possibly renal failure. It`s also the myoglobin being filtered out that shows up as very dark urine. The dark urine itself is not what you have to worry about---what you DO have to worry about is the fact that myoglobin in the urine means that significant muscle disruption and damage has occurred in the system, and that the kidneys are being overwhelmed with a whole lot of waste product to try and get rid of. Needless to say, this is serious s**t from the physiological point of view. However, as Heidi explained, dark urine doesn`t neceesarily mean myoglobinuria, dark urine can be caused by other things as well. But if your horse is dehydrated, won`t move and is standing there hunched up and miserable AND is peeing coffee, you`ve got problems.

OK, some of the other things a DVM will look for in a tying-up horse are elevated enzymes in the blood plasma, specifically CK (creatinine kinase) and AST (aspartate aminotransferase). AST is also referred to as SGOT, but both refer to the exact same enzyme. There are other things the vet will look for as well, like creatinine, urea, electrolytes and so on, but enzyme levels are at the top of the list. CK and AST are both enzymes contained in the muscle cell (as well as other types of cells) which are also released into the blood when the muscle cell is disrupted. Therefore, if the enzyme levels are elevated in the blood panel, it must mean that tissue cells somewhere are being (or were being) damaged. The tricky part in diagnosis is figuring out where tissue damage is occurring---AST occurs in both muscle and liver cells, so elevated levels could mean problems in either muscle OR liver (and for that matter, AST levels can also be elevated by certain drugs or toxins). CK levels will indicate muscle damage, while other elevated enzymes in the blood panel will indicate liver damage. And to make things even more confusing, there are various isoforms of yet another enzyme, LDH (lactate dehydrogenase) which will indicate whether muscle damage occurring is from skeletal or cardiac (heart) muscle. However, while I assume LDH isoforms are a big deal in cardiac patients, I don`t know whether LDH is commonly included on a standard equine blood panel.

The elevation in CK will occur pretty rapidly and peak within about 24 hours, then decline fairly rapidly---the half-life for CK is six hours, meaning that half of the remaining amount is removed within six hours. So 50% is gone within 6 hours, 75% is gone w/i 12 hrs, 87.5% is gone w/i 18 hrs, and 93.75% is removed w/i 24 hrs, and so on. The concept of "half-lifes" doesn`t refer only to enzymes, by the way, the same general idea applies to drug half-lifes, isotope half-life, etc etc (just a little extra trivia for you)(I know, riveting.) The levels of AST will begin approximately 24 hours after the onset of the clinical signs of tying up, and decline much more slowly---AST has a half-life of about 14 days, so with significant muscle damage, it`ll be awhile before levels are really back to normal. The relative levels of these two enzymes, among other things, are what a DVM will look at in determining the extent of damage, whether damage is still occurring and how long ago the initial damage occurred. For example, if a horse transport company delivers a tied-up horse to you and swears the horse must have injured himself last week, but the blood analysis shows screaming CK levels (indicating recent muscle damage) but relatively low AST levels (also indicating recent damage), then it comes under the heading of I Don`t Think So Chuckles. See?

I sure hope this answers your questions about the specifics of tying-up. I think I might have given myself an aneurysm typing it.

Susan Garlinghouse

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