Equine Colic: V. Treatments for Colic

1. Decompression

A primary method to alleviate abdominal pain is decompression of the distended stomach or intestine. Nasogastric intubation can help relieve gastric tympany or remove gastrointestinal reflux due to a small intestinal obstruction or ileus. The tube can be left in place for chronic decompression after surgery or in horses with proximal enteritis but should be checked every 2 - 3 hours as stomach pressure may not force the fluid through the tube even with extreme distention [1]. Horses with gastric dilatation can have stomach rupture, even after the recent passage of a stomach tube or with a stomach tube left in place for passive decompression. An attempt to start a siphon should be made in all cases by filling the tube with water and then lowering the end of the tube below the level of the stomach.

The other site at which distention from gas can be relieved is the cecum. Decompression (enterocentesis) can resolve a primary cecal tympany or help relieve gas build up from a large colon or small colon obstruction. Decompression of the cecum is done in the right paralumbar fossa, midway between the last rib and the ventral prominence of the tuber coxae (Fig. 1). A 5 - 6 inch 14 - 16 gauge needle or catheter over a needle is used.

Figure 1. Percutaneous cecal decompression. (A) A 15-cm catheter or needle is placed midway between the ventral aspect of the tuber coxae and the last rib and directed perpendicular to the skin. (B) Pressing on the cecum per rectum can help evacuate the gas and the remainder of the abdominal contents and be palpated once the gas is removed. Reprinted from White NA and Edwards B, Handbook of Equine Colic, Butterworth-Heinemann, Oxford, 1999; 26 - 27.

Use of a 10 - 12 gauge cecal trocar is discouraged as it can tear the cecum or create a portal for leakage of ingesta into the peritoneal cavity. The skin should be surgically prepared, and aseptic technique used to place the needle. The needle is pushed through the flank into the cecum by keeping the needle perpendicular to the skin. The landmarks should be assessed carefully so as not to place the needle dorsal to cecum (Fig. 1). Suction is helpful for rapidly reducing cecal tympany. Concurrent palpation per rectum can help push gas into the cecal base and facilitate removing as much as possible. Once the gas is removed, saline or an antibiotic solution should be infused through the needle as it is pulled out of the cecum to avoid leaving a trail of contaminated material in the peritoneum or body wall. After the cecum is empty, a thorough rectal examination is performed to determine if the tympany was a primary problem or secondary to another condition.

Decompression of the colon can be attempted, but there is an increased risk of inadvertent tearing due to movement of the colon as the gas is released. Laceration of blood vessels is also possible depending on the position of the colon. Nevertheless, this may be needed in horses with massive colon tympany and can be lifesaving when attempting medical treatment or prior to surgery when respiratory volume is not adequate.

2. Systemic Analgesics

Nonsteroidal Anti-Inflammatory Drugs

Some of the most useful drugs for relief of pain associated with either surgical or non-surgical disease in horses are the nonsteroidal anti-inflammatory drugs (NSAIDs). They block the enzyme cyclooxygenase, thereby decreasing the production of eicosanoids formed during degradation of arachidonic acid from cell membranes. Prostaglandin (PG) E2 and I2 sensitize nerve endings to pain and possibly are responsible for amplification of pain during bowel distention, ischemia, and inflammation. Both PGF2 and PGE2 can induce smooth muscular contraction and cause vasoconstriction. PGE2 has been associated with ileus during endotoxemia [2,3]. Thromboxane, another product of the arachidonic cascade, can cause marked vasoconstriction with subsequent ischemia resulting in pain [4]. Leukotrienes are formed in the lipoxygenase pathway of arachidonic acid metabolism (not blocked by NSAIDs) and also promote inflammation [5].

The role of prostaglandins in equine intestinal disease is not fully understood. However, there is a favorable response during colic after administration of NSAIDs which inhibit their formation. Different drugs produce varying levels of analgesia, possibly due to the different concentrations of the two types of cyclo-oxygenase, COX1 and COX2, in tissues [5]. COX1 regulates the production of prostaglandins necessary for normal organ and vascular function. COX2 becomes active in response to cytokines, serum factors, or growth factors and causes marked increases in prostaglandin production. COX2 up-regulation by endotoxin is activated by p38 MAP kinase [6]. Depending on their relative ability to inhibit COX1 and COX2, different NSAIDs provide different effects. A third cycloxygense, COX3, has been identified, but its role in the horse has not been elucidated [7].

Prostaglandins have several effects on healing of the intestine (see Section III). The constitutive prostaglandins, formed by COX1, help regulate normal function such as motility and mucosal healing. PGE2 is needed to maintain the intestinal mucosa and glandular mucosa in the stomach. Excess use of non-selective COX inhibitors predisposes horses to gastric and intestinal ulceration. This creates a dilemma when treating horses for colic, as the common NSAIDS, phenylbutazone, flunixin meglumine [a], ketoprofen [b], and aspirin inhibit COX1 and COX2, although apparently with different levels of effectiveness[8].

Flunixin meglumine (flunixin) is the most effective of the NSAIDs used to treat acute abdominal disease in the horse. It blocks the production of prostaglandins, specifically thromboxane and PGI2, for 8 - 12 hours after a single dose [9]. Advantages of this therapy are the maintenance of normal blood flow to the bowel during obstruction and a return of intestinal motility. In cases where a strangulated segment of intestine is suspected, the use of flunixin preoperatively can be helpful in diminishing the detrimental response due to the endotoxin release. After treatment, horses with impactions or peritonitis will have increased comfort (6 - 8 hours) and return of borborygmi. Flunixin can obscure the signs of endotoxemia and distention or strangulation to some degree. The inability to eliminate pain with flunixin suggests a disease exists which requires more than simple medical treatment. For this reason, horses given flunixin should be observed carefully after its administration. If signs of colic return, particularly after a short period (1 - 2 hours), the horse should be immediately suspected of having more than a simple medical colic (see Section IV). The dose of flunixin can be reduced to 1/4 to 1/2 of the manufacturer’s recommended dose (1.1 mg/kg) in some cases of impaction, enteritis, and postoperatively for suppression of signs of endotoxemia [9].

Clinical observation suggests phenylbutazone is not as good an analgesic for colic as flunixin. Its use appears to be more helpful for musculoskeletal problems than for visceral pain, perhaps because of differences in tissue concentrations. There is evidence that indicates phenylbutazone is more effective in reducing PGE2, thereby reversing ileus during endotoxemia [3]. The dosage response for this is not known, but 0.5 to 2 mg/kg has been used. The author has used a combination of flunixin (1.0 mg/kg IV, BID) and phenylbutazone (0.5 - 1.0 mg/kg IV, BID) by alternating administration of each drug every 6 hours. Whether this is more beneficial than either drug alone is not known.

Ketoprofen has been used clinically for the treatment of colic. It is effective in alleviating some clinical responses after experimental administration of endotoxin, similar to flunixin. Gastric ulceration is also said to be less with this drug, although at low doses this is not considered a problem with flunixin. Anecdotal reports suggest ketoprofen is less effective as an analgesic for colic than flunixin meglumine.

Eltenac [c] has been tested in horses and has some adverse effects at 2 - 3 times the normal dose [10]. Its effects in blocking the deleterious effects of endotoxemia are similar to those of flunixin [11]. Eltenac is reported to be less ulcerogenic that the commonly used NSAIDs in horses [10]. It has not yet been used extensively for colic.

Disadvantages of the NSAIDs, particularly phenylbutazone, include the potential for adverse side effects such as mucosal ulceration of the gastrointestinal tract or renal damage [12-14]. This is particularly true if these drugs are administered orally, for long periods, during periods of dehydration and/or in combination with aminoglycoside antibiotics. Non-selective NSAIDs with COX1 activity can decrease intestinal healing and, when used chronically, may cause decreased intestinal motility [15,16]. The use of COX2 inhibitors is limited to experimental use in horses [8,17]. Carprofen [d] has been used as an anti-inflammatory after colic surgery (0.7 mg/kg SID or BID) because it is potentially less ulcerogenic, but its efficacy has not been clinically or scientifically proven.

Alpha2 Agonists

Several alpha2 agonists are potent analgesics and cause muscle relaxation and sedation. This drug group includes xylazine [e] and detomidine [f], both of which have been used for control of abdominal pain in horses. These drugs appear to act by stimulation of central alpha2 adrenoreceptors, which modulates the release of norepinephrine and directly inhibits neuronal firing. This causes sedation, analgesia, bradycardia, and, in the horse with colic, relief of pain [18-20]. Other responses to these drugs are important as they can affect their use in horses with shock. The heart rate can be markedly reduced to less than twenty beats per minute by second-degree heart block. This causes a significant reduction in the cardiac output for a short period and may have a detrimental effect on the horse that already has a critical reduction in circulating blood volume. There is also a brief period of vasoconstriction, which in the normal horse is of minimal concern, but which may cause complications in horses where poor tissue perfusion is already present due to shock. Alpha-2agonists reduce blood fow of obstructed large intestine and decrease intraluminal pressure [18,19].Similarly, in experimental small intestinal ischemia, xylazine reduced blood fow and increased oxygen utilization. There is a transient increase in urine production, which may complicate dehydration and circulatory shock [21].

Xylazine also has potent effects on intestinal motility. The jejunum and large intestine have less activity for up to 2 hours after a 1.1 mg/kg dose [22-25]. This is a profound effect, giving relief from both somatic and visceral pain caused by distention or strangulation [18,23,26,27]. Xylazine may be indicated to help relax contracting intestine or to help restrain a horse in order to prepare for surgery. The short period of ileus is not detrimental and is often followed by resumption of intestinal transit. Analgesia may only last 10 - 30 mins or have minimal effect in horses with strangulating lesions such as large colon torsion. In horses with large or small colon impactions, xylazine appears beneficial in relieving the spasm of the intestine around the obstructing mass, thereby allowing passage of gas and rehydration of ingesta. This can often be accomplished with doses of 0.1 to 0.3 mg/kg intravenously and titrated to effect. If a prolonged effect is desired, xylazine can be administered intramuscularly at doses of 0.4 to 2 mg/kg. The lower the dose, the less the risk of untoward reactions. Because of the possible complicating effects of lowered blood fow to the intestine, xylazine should be used in horses with normal hydration and perfusion. Xylazine has been used repeatedly in horses with various types of intestinal disease, including chronic cases, with satisfactory results.

Detomidine is an alpha-2 agonist like xylazine and is a potent sedative. It can produce complete cessation of colic for up to 3 hours and, during experimental cecal distention, provided analgesia for a mean of 45 and 105 mins at 20 µg/kg and 40 µg/kg, respectively [24,28]. Horses stand with their heads lowered and are reluctant to move. Its action is centrally mediated, similar to xylazine but with a much longer duration. Second-degree heart blocks are common. Detomidine will reduce intestinal motility similar to xylazine, and it can obscure signs which might help the clinician diagnose the cause of the colic. Because this is such a potent drug, any signs of colic observed within 30 - 60 mins of administration are an indication that a severe disease is present, and the horse may require surgery. The dosage can be titrated in 5 - 10 µg/kg increments [26].

Both xylazine and detomidine are potent sedatives. Their use facilitates rectal examination by providing restraint and some relaxation of the rectum and abdominal muscles. Care should be taken during the rectal examination as horses can kick suddenly when first touched. Both xylazine and detomidine have been used as pre-anesthetic medications in critical horses without compromising the patient during general anesthesia.

Opioids

The pure opioid agonists, such as morphine and oxymorphone, are potent analgesics, but they may cause excitation in the horse unless used in combination with drugs such as xylazine. Morphine reduces progressive motility of the small intestine and colon while potentially increasing mixing movements and increasing sphincter tone [29,30]. This can delay transit of ingesta. The disadvantages of morphineand oxymorphone in the horse with abdominal disease are sufficient to discourage their use. Epidural morphine (0.1 mg/kg qs to 30 cc of saline) can provide analgesia for 8-16 hours without CNS excitation.

Meperidine is an opioid agonist with few adverse effects in the horse. Analgesia is slight and variable depending on the source of pain and does not provide long-term analgesia. Used repeatedly, it is believed to potentiate intestinal obstruction due to impaction by reducing progressive motility in the colons. When used for visceral pain, its effect over time is similar to oxymorphone and pentazocine [g].

Butorphanol [h] is a partial agonist and antagonist which gives the best pain relief with the least adverse effects of the opioids [18,20,31]. It can be used in combination with xylazine or detomidine. The dosage can vary from 0.05 to 0.1 mg/kg, the high dosage being necessary for the most severe colic. Exceeding 0.2 mg/kg may cause an increase in heart rate, systolic blood pressure, and excitation in horses. Butorphanol can also be administered as a constant rate intravenous infusion at up to 23.7 µg/kg/hour. Butorphanol reduces small intestinal motility, yet has minimal effect on pelvic fexure activity [20,32]. The drug is potent enough to stop colic due to severe intestinal disease for short periods of time, although the pain from large colon torsion or small intestinal volvulus may not be altered. Butorphanoldoes not affect the cardiovascular system except at higher doses and, therefore, can be administered to the horse suffering from circulatory shock and as part of a pre-anesthetic protocol. Repeated use has the risk of delaying intestinal transit and causing impaction formation as seen with other opiate-like drugs. An overdose can be partially reversed with equal doses of naloxone [i].

Spasmolytics

Spasmolytic drugs can indirectly provide analgesia by reducing spasms of the intestine. Increased frequency of intestinal contractions or spasms occur oral to intraluminal obstructions such as an impaction. Spasmolytic drugs include cholinergic blockers such as atropine. Atropine can cause colic when administered to the normal horse by causing ileus and secondary tympany. Though not recommended, atropine has been used to treat colic and is effective by relaxing the intestinal wall and preventing intestinal contractions. The effect, unfortunately, can extend from several hours to several days, allowing tympany and complicating the initial problem with ileus. The administration of Bell’s solution, an oral tonic containing belladonna, to horses with colic was once a common practice in the United States and Canada. Because of the potential for prolonged intestinal stasis, its use for treatment of the equine acute abdomen is contraindicated.

The combination of hyoscine N-butylbromide and para-aminophenol derivative (dipyrone) [j], is popular in Europe for treatment of horses with colic, specifically spasmodic colic and impactions [33,34]. Hyoscine has shorter-acting muscarinic cholinergic blocking effects compared to atropine and is effective in relaxing the bowel wall to prevent contraction. The drug can be detrimental in horses with ileus, where inhibition of motility causes tympany and complicates the abdominal stasis, which was already present [35]. Hyoscine, by itself, is now available in the United States and is an effective antispasmodic. The drug is effective for treatment of spasmodic colic and impactions. Hyocine gives excellent relaxation of the rectum, facilitating examination per rectum. Lack of response to the drug suggests that there is a more serious problem, which may require surgery or more aggressive treatment.

Lidocaine

Lidocaine has become popular as a pro-kinetic drug for use in the treatment of ileus [36-38]. Its effects appear to include both stimulation of gut motility and analgesic effects [39]. Lidocaine decreases infammation by preserving microvascular integrity, preventing neutrophil migration, and inhibiting cytokine production [40-43]. Lidocaine is effective in treating pain for medical problems such as impactions and duodenitis-jejunitis, as well as postoperative pain. An initial bolus of 1.3 mg/kg is followed by a constant rate intravenous infusion at 0.05 mg/ kg/min. Administration can be continued for 24 - 72 hours or longer with careful monitoring. Toxicity is exhibited as muscle fasciculation, erect hair, and weakness or recumbency [37]. These signs quickly disappear by discontinuing the infusion. Use of lidocaineconcurrently with cimetidine and metronidazole can increase lidocaine toxicity.

3. Stimulating Intestinal Motility

Initiating or enhancing intestinal motility has been frustrating for veterinarians who treat severe colic. Distention, endotoxemia, sympathetic stimulation, and bowel wall infammation inhibit motility. The classic mechanisms of the sympathetic balanced with parasympathetic or cholinergic versus adrenergic stimulus no longer explains all the mechanisms controlling intestinal motility. The chief clinical problem is postoperative ileus involving the small intestine. Numerous drugs have been evaluated in normal horses. Few clinical trials have examined the efficacy of pro-kinetic drugs for treatment of equine postoperative ileus, and those reporting success are limited to cisapride [44], metoclopramide [45-47], erythromycin [48], and lidocaine [36,37]. Recent research has supported the lack of usefulness of these compounds in horses with clinical disease [48,49].Infammation from intestinal distention or ischemia potentially prevents the enteric nervous system or agents acting directly on muscle from stimulating progressive motility [49]. Only lidocaine appears to be of some value for treatment of postoperative ileus in horses with injured intestine, possibly due to its potential anti-infammatory or analgesic effects rather than from direct stimulation of intestinal motility. New compounds that have yet to have reported use in clinical cases include tegaserod [k], a selective serotonin subtype-4 receptor agonist and methylnaltrexone [l], an opioid antagonist. Both stimulate pelvic fexure and jejunal motility in vitro [50,51]. Although the use of prokinetics is logical to help stimulate motility as soon as possible, use of anti-infammatory agents is just as important to help reduce the infammatory response known to occur in previously distended or ischemic intestine (see Section III) [52-54].

4. Hydration

Hydration of the acute abdominal patient can be the most important treatment and often determines success or failure in horses suffering from shock. Immediate hydration of horses with ileus and distention of the small or large intestine is associated with increased motility and resolution of colic. Because a diagnosis is not always determined in these cases, the mode of action of intravenous fuids can only be speculated.

Hydration is usually accomplished with administration of balanced electrolyte solutions such as Ringer’s, lactated Ringer’s, or acetated Ringer’s solutions. The greatest need is to replace total body water. Sodium replacement with the appropriate solution is needed to maintain water in the extracellular fuid (ECF) space without sacrificing potassium levels during long-term fuid administration. The level of dehydration is determined by evaluation of capillary refill, skin turgor, packed cell volume (PCV), and total protein (TP). The volume needed is calculated by estimating the water loss as a percent of the body weight or the percent of the blood or ECF change. An estimate can be calculated from the PCV and TP in the following formula:

Calculation for Initial Fluid Replacement (measured PCV or TP)−(normal PCV or TP) × 100

                                                         (normal PCV or TP)

                                               = percent change in the PCV or TP

This percent change represents the change in the blood or the ECF volume from normal. The calculated percentage multiplied times the blood volume (7% of the body weight in kg equals liters of blood) is the estimated amount of fuid which needs to be replaced immediately to provide an adequate circulatory volume, an estimate which is critical for the horse requiring surgery. The same estimate calculated on the ECF volume (30% of the body weight in kg equals liters of ECF) calculates the total replacement required for rehydration of the ECF space. Because the PCV can vary widely in horses during colic, calculations using total protein may give a better estimate.

The effect of dehydration should not be underestimated as a cause or sequela of colic. Horses with slight intestinal distention and ileus with accompanying pain often respond immediately to fuid replacement. Intravenous fuid administration has also been helpful in increasing the available fuid for intestinal secretion. The constant secretion of the intestinal tract provides the needed water to soften an impacted food mass. This "over-hydration" technique can be used as a primary treatment for pelvic fexure and cecal impactions and should be used rather than repeated administration of oral laxatives in refractory cases.

The goal of over-hydration is to maintain a slightly increased circulating water volume, which will equilibrate with the extracellular space. Theoretically, this equilibration causes secretion into the bowel, particularly at sites of intestinal distention where secretion is initiated by the increase in the capillary filtration. The fuid can be administered intravenously over a 24-hour period or as a bolus. Over-hydration of ingesta can also be achieved by frequent oral water administration [55]. Up to 10 liters every 30 mins has been administered via stomach tube with the result of increasing fecal water content in horses with colon impaction [56]. This should only be used if retention of fuid in the stomach and small intestine is not a problem.

The intravenous replacement fuid needs to be balanced, supplying sodium and chloride with adequate potassium and calcium replacement. The over-hydration effect is monitored by repeated evaluation of PCV and plasma protein concentration (every 6 hours). By regulating intravenous fuid administration to maintain the plasma protein at 5.0 to 5.5 g/dl (normal 6.0 - 6.5 g/dl), a state of over-hydration will be maintained with adequate fuid available to help intestinal secretion. This normally requires a fuid administration rate of 2 - 4 liters per hour, double or triple maintenance requirements. When a bolus of fuids is administered, 20 liters in 1 - 2 hours is usually sufficient to decrease the plasma protein concentration.

In horses with severe dehydration, including horses with endotoxic shock, administration of hypertonic saline can be used as an emergency measure to restore circulating volume [57]. A 7.5% saline solution is administered at 4 - 5 ml/kg as rapidly as possible. This rapidly draws water from the extracellular and intracellular space into the vascular space. This will improve perfusion and lower heart rate, but it must be followed with adequate replacement fuids to help restore hydration. Hypertonic saline is very useful in resuscitating horses in severe shock, and its use should be reserved for those horses. Hypertonic saline (4 ml/kg) can also be combined with hetastarch [m] or pentastarch [n] (6-10 ml/kg) to provide colloid support in horses with decreased protein concentrations [58].

Electrolyte imbalances are not common in horses with acute simple colic. However, decreased serum calcium concentrations occur more frequently in horses with large colon displacements or small or large colon strangulations [59]. Calcium gluconate or calcium borogluconate are commonly used to replace calcium at 0.2-1.0 ml/kg of a 20% solution [58].

Hypomagnesemia is less commonly associated with colic and is most common in horses that are off feed without electrolyte supplementation. Depression, anorexia, and cardiac dysrhythmias are signs associated with hypomagnesemia. Intravenous administration of magnesium sulfate or magnesium chloride at 2 mg/kg/min should not exceed 50 mg at one time [58]. Oral supplementation with magnesium oxide at 20 - 30 mg/kg/day may also be considered.

All horses being treated for dehydration or shock should be monitored carefully. This may include measuring serum osmolality and urine output and specific gravity to ensure adequate systemic hydration.

5. Treatment of Impactions

Impaction colic is the most frequent type of simple obstruction causing colic [60,61]. Factors associated with impactions include poor dentition, lack of access to water, coarse feeds, acute cessation of routine exercise with confinement, and treatment for musculoskeletal diseases [26,62]. Damage or dysfunction of the enteric nervous system may also cause alterations in motility leading to impaction. Intestinal adhesions, which are suspected to alter motility patterns at the pelvic fexure, are also known to cause colon impactions [63]. Most reports agree that alterations in motility, with subsequent dehydration of ingesta, will lead to impactions, although the actual cause of the stasis with eventual obstruction is unknown.

Although acute systemic dehydration will cause dehydration of the ingesta in the colon, an acute decrease in water intake rarely results in the classic accumulation of ingesta found with colon obstruction. Clarke et al [64]. suggested that an internal fuid fux occurs when feeding boluses of grain twice daily, compared to feeding the same amount divided into frequent intervals. Based on the response of aldosterone to bolus feeding, it was hypothesized that feeding large quantities of grain causes a relatively rapid fermentation with subsequent systemic dehydration as water moves into the colon. The subsequent movement of water out of the large colon, which occurs during fatty acid absorption, causes dehydration of the ingesta and, hypothetically, sets up the conditions which could result in colon impaction. Though recent experiments did not confirm the cyclic changes in hydration of colon contents, when grain was part of an ad lib hay diet, right colon dry matter content increased by approximately 40 - 50% [65]. This change was most likely due to a decrease in the amount of fiber, which binds to water. Ingesta collected from the right dorsal colon in horses on a hay grain diet had gas bubbles throughout the ingesta, whereas gas was not observed in ingesta from horses on a hay only diet.

The basic premise for treating colon impaction is relief of pain, softening the consistency of the impacted ingesta, and stimulating motility to increase fecal transit. Xylazine, detomidine, hyoscine/dipyrone, and funixin meglumine are efficacious, at least in part, by reducing intestinal spasm at the obstruction [26,61,62]. Differences of opinion about which drug is best are probably without merit, as clinicians have learned to use these drugs or their combination to effectively treat most colon impactions. In the author’s experience, titration with xylazine or detomidine appears sufficient to relieve the pain and initiate transit without excessive decreases in motility, as seen with the alpha agonists. The combination of alpha agonists with funixin meglumine also appears effective for managing impactions, which can take several days to soften and move from the colon [62]. If these drugs do not control pain, most likely the impaction is severe enough to require surgery or another surgical disease is present.

Though administration of mineral oil via nasogastric tube is widely recommended for treatment of impaction colic, there is evidence that administration of oral or intravenous fuids may be preferable when an impaction is resistant to routine analgesic and laxative therapy. Administration of intravenous fuids has been used to help "over-hydrate" the circulatory system, thereby stimulating secretion into the dehydrated ingesta in the colon [62]. The benefit of this treatment was first recognized when horses referred for possible surgery were automatically treated with fuids upon arrival at the hospital. It became apparent that many large colon impactions, initially felt to need surgery, resolved by treatment with a combination of analgesics and intravenous balanced electrolyte administration without further administration of a laxative [26]. Beyond systemic hydration afforded by the fuid administration, the dilution of the plasma protein in the vascular system reduces the plasma osmotic pressure, allowing water diffusion into tissues and, specifically, in regions of distended bowel. However, fuid treatment administered at 10 ml/kg per hour for 12 hours did not significantly alter colon hydration in normal fistulated horses (Fig. 2) [55]. Other than the observed clinical response in horses with colon impactions, there is no proof that intravenous fuid therapy increases colon water content. However, the systemic hydration appears to allow normalization of colon ingesta water content.

Treatment of colon impactions with water administered via nasogastric tube (10 liters every 30 - 60 mins) until the impaction is resolved is effective, however, alterations in serum electrolytes can result from prolonged treatment [56]. Administration of MgSO4 (1 g/kg in 1 - 2 liters of water via stomach tube) does not increase colon ingesta hydration, but hydration of the feces did occur. Sodium sulfate (1 g/kg in 1 - 2 liters of water via stomach tube) significantly increases colon content hydration and created hypernatremia. Saline, originally prescribed for sand colic, increased colon water content but resulted in hypernatremia and hyperchloremia. Administration of a balanced electrolyte solution containing 5.37 g NaCl, 0.37 g KCl, and 3.78 g NaHCO3 per liter is as effective as any laxative in hydrating colon contents without altering serum electrolyte values (Table 1).

Figure 2. (A) Water content of ingesta in the right dorsal colon increased significantly after enteral treatment with Na2SO4 (1.0 g/kg) and with 5 l/hr for 12 hrs of a balanced electrolyte solution. Enteral water, MgSO4 (1.0 g/kg), and intravenous lactated Ringer’s solution at 5 l/hr for 12 hrs did not affect water content in the colon. (B) Water content of the feces was increased by Na2SO4 (1.0 g/kg) and MgSO4 (1.0 g/kg) but not by enteral water, a balanced electrolyte solution (5 l/hr for 12 hrs), or IV lactated Ringer’s solution (5 l/hr for 12 hrs).

Figure 3. Enteral fluids can be continuously administered via a feeding tube, which is passed into the stomach through the nostril and attached to the halter and head (A). If necessary, placement of the tube can be checked by endoscopy (B).

The balanced electrolyte solution is administered via a feeding tube at 5 - 10 liters per hour (Fig. 3). This hydrates colon contents as well as restoring systemic hydration.

If dehydration is present, concurrent intravenous therapy with acetated or lactated Ringer’s solution is recommended until normal blood volume is established. If gastric reflux or ileus is present, enteral administration is curtailed until there is evidence of adequate gastrointestinal transit.

Research suggests that colon hydration is increased when fasted horses are fed hay. Though feeding may increase motility and oral water intake, feeding horses with impactions should be delayed until there is evidence that the impaction is moving or is resolved [26,62]. When initiating feeding after the impaction has moved out of the colon, a laxative diet without grain, such as grass or alfalfa hay, is preferred. Use of bran as a laxative should be avoided. Though pure bran is high in fiber, most milled bran contains large amounts of carbohydrate, which reduces total fiber content and potentially decreases colon water content in the colon.

6. Treatment of Reperfusion Injury and Inflammation

Therapeutic options for reperfusion injury, including pharmacologic mediators that target the effects of one part of the reperfusion pathway, have yielded variable results [66,67]. Use of multimodal treatments and treatments specific for repair of damaged mucosa or vascular injury during reperfusion appear to be the most effective. The goal of therapy is to stop the biochemical reactions which initiate the reperfusion cascade. This is not always possible as reperfusion may be initiated before the veterinarian sees the horse or diagnoses the problem. Because the inflammation initiated by reperfusion can continue for days to weeks, treatment during the early phase of the process may prevent some of the patho-logic sequelae. Treatments should be aimed at 1) preserving cell integrity, 2) preventing the formation of oxygen radicals, 3) preventing neutrophil activation and migration, and 4) treating the vascular and tissue damage caused by inflammation.

Few of the compounds known to block superoxide radical production appear to be efficacious in protecting the equine intestine during or after reperfusion injury. Allopurinol inhibits xanthine oxidase and, when used as a pre-treatment by enteral administration, has been effective in preventing the increase in microvascular permeability and neutrophil adherence and infiltration associated with intestinal ischemia reperfusion injury in cats [68-70]. Intravenous administration of allopurinol to ponies immediately after correcting 3 hours of venous or arteriovenous ischemia failed to attenuate small intestinal injury, though this ischemic period may have extended beyond the limit for bowel to respond to reperfusion [71]. After 3 hours of large colon low-flow ischemia, administration of intravenous allopurinol 30 mins before reperfusion did not decrease the severity of injury to the mucosa [72].

Superoxide dismutase protects some cellular functions in equine jejunal mucosa during reoxygenation in vitro without a corresponding improvement in structure [73]. This treatment has not been evaluated in clinical cases. The administration of other enzymatic free radical scavengers, such as catalase or glutathione peroxidase, has been evaluated in cats but not in equine intestinal ischemia reperfusion [66]. Catalase decreases neutrophil filtration into the feline intestinal mucosa, but neither compound has been used clinically in horses.

Dimethylsulfoxide (DMSO), which is a commonly used anti-inflammatory agent, scavenges hydroxyl radicals and attenuates increased microvascular permeability and increased neutrophil adherence associated with ischemia reperfusion in the intestine of cats and rats [74 - 76]. When administered intravenously at 1.0 g/kg before ischemia or after release of a vascular occlusion, no beneficial effects were demonstrated on the equine jejunal mucosa [77,78].When the same dose was administered in the same manner prior to ischemia or 30 mins prior to reperfusion, there was no decrease in the severity of the equine large colon mucosal lesions [79]. In fact, Moore et al [72]. found a tendency toward a greater estimated percentage depth of mucosal loss in horses administered DMSO (1.0 g/kg) compared with those administered the vehicle control solution. When DMSO reacts with the hydroxyl radical, methyl radicals and methylperoxy radicals can be generated [80]. These free radicals are less potent than the hydroxyl radical but can still react with cell membranes and may potentiate injury.

When used in a model of low-flow ischemia, DMSO (20 mg/kg, IV) administered prior to reperfusion was partially effective in attenuating the ischemia reperfusion induced permeability changes in the equine jejunum [53]. This dose, administered at the time of reperfusion and twice daily for 72 hours, prevented adhesion formation in foal intestine 10 days after total ischemia for 60 mins and is suggested as a treatment for horses with ischemic or distended small intestines [81]. Based on research, early treatment is essential and continued treatment for several days may be beneficial. The author recommends 20 mg/kg intravenously twice daily for 2 - 3 days or for as long as clinical signs, such as ileus, fever or pain, or shock, suggest that intestinal inflammation is still present. The true efficacy of DMSOadministration to clinical cases is still unknown.

Figure 4. Graph of ratios of protein concentrations in lymph to protein concentrations in plasma. Protein leakage from the capillaries due to ischemia is increased (yellow line) during reperfusion. Carolina rinse (green line) maintains the normal capillary permeability after ischemia similar to the permeability in control intestine (red line).

Manganese chloride is a simple inorganic salt that has an activity similar to superoxide dismutase and is reported to be almost as effective as superoxide dismutase at scavenging superoxide anions [82]. Manganese chloride is relatively nontoxic and is also widely available and much less expensive than superoxide dismutase [72]. When administered intravenously to horses, there was a dose-related increase in plasma superoxide scavenging ability for 1 hour after infusion, and there were minimal to no adverse effects on the systemic cardiovascular system [82]. Administration of a 10 mg/kg dose resulted in an increased scavenging ability compared to 5 mg/kg. Administration of the 10 mg/kg dose after 2.5 hours of low-flow ischemia of the large colon failed to attenuate mucosal damage associated with 3 hours of ischemia and 3 hours of reperfusion. There was, however, an increase in heart rate, cardiac output, and mean arterial blood pressure, which could possibly be detrimental to a horse in circulatory shock [72]. There are no reports of the clinical use or efficacy of manganese chloride.

Other compounds, such as deferoxamine, an iron chelator which inhibits the iron catalyzed formation of hydroxyl radicals from hydrogen peroxide, could theoretically be used to treat reperfusion injury [83]. This compound attenuates the microvascular permeability and the neutrophil infiltration in feline small intestine when used as a pre-treatment [76]. Exogenous protease inhibitors (soybean trypsin, aprotinin, and turkey ovomucoid) decrease mucosal injury caused by partial ischemia followed by reperfusion of the feline intestine [84]. To the author’s knowledge, these compounds have not been investigated in the horse except as part of a multimodal therapy.

Figure 5. Photomicrographs (same magnification) of jejunum 10 days after being subjected to 2 hrs of ischemia and subsequent reperfusion. Intestine perfused with lactated Ringer’s solution. (A) had serosal fibrosis without mesothelial healing. The intestine perfused with Carolina rinse (B) had decreased serosal fibrosis and evidence of a healing mesothelium.

Figure 6. (A) Jejunal adhesion in a 6-week-old foal 10 days after 60 mins of total ischemia. All untreated foals had intestinal adhesions with mesenteric constriction. (B) Jejunum from a 6-weekold foal 10 days after 60 mins of ischemia. This is representative of foals treated with DMSO (20 mg/kg, IV, BID for 72 hrs) or flunixin (250 mg/kg, IV, QID, for 72 hrs) and an antibiotic combination (penicillin 22,000 U/kg, IV, QID and gentamicin 2.2 mg/kg, IV, QID).

Intraluminal oxygen has also been investigated as a therapy for reperfusion injury. Light microscopy and scanning electron microscopic changes indicate that the administration of gaseous oxygen into the lumen just prior to reperfusion prevented sequential mucosal degeneration during subsequent reperfusion. This was true if the villous lesion had not already progressed past a Grade II lesion (loss of epithelial cells from the tip of the villus and minimal hemorrhage into the lamina propria) [85]. However, in other studies, intraluminal oxygen insuffiation at the time of release of an arteriovenous or venous obstruction did not significantly alter the injury noted after 1-hour of reperfusion or the degree of mucosal regeneration after 48 hours of reperfusion [78,86].

Figure 7. Photomicrographs of foal jejunum 10 days after 60 mins of ischemia. Foals treated with systemic heparin (80 U/kg, IV, TID for 72 hrs) had serosal fibrosis similar to untreated foals with new fibrous tissue extending two to three times the thickness of the normal serosa and no healing of the surface mesothelium (A). Foals treated with DMSO and a flunixin-antibiotic combination had minimal new serosal fibrosis and healed or healing mesothelium (B).

The 21-aminosteroids, which have a modified glucocorticoid structure [87], can scavenge superoxide radicals and lipid hydroperoxides and can inhibit ironcatalyzed lipid peroxidation and arachidonic acid release [88]. When the 21-aminosteroid U-74389G was administered to horses intravenously at 3 g/kg and 10 mg/kg 15 mins before reperfusion after 2 hours of arteriovenous occlusion, large colon mucosal surface area was protected [89]. However, another study [72] demonstrated no protective effect after administration at a dose of 5 mg/kg IV to horses 2.5 hours after low-flow ischemia in an experimental model, which resulted in 3 hours of ischemia and 3 hours of reperfusion. Similarly, increased vascular permeability was not prevented when 21-aminos-teriods were administered prior to reperfusion of a segment of jejunum after 60 mins of low-flow ischemia [53].

Figure 8. Rabbit small intestine subjected to 2 hrs of ischemia. After 10 days, rabbits treated with intra-abdominal hyaluronic acid (5mg/kg) had no adhesions (B) while all control rabbits had mesenteric and intestinal adhesions (A). Fibrosis of the serosa was present in both groups. (NA White, unpublished data, 2006).

Lidocaine is being used commonly as a pro-kinetic and analgesic agent after surgery for intestinal strangulation or obstruction [36]. Recently, lidocaine has been shown to inhibit nitric oxide production from activated murine macrophages [90]. Lidocaine has also been shown to prevent permeability changes in bowel during endotoxic shock, suggesting that it can prevent the endothelial cell responses during changes in blood flow [91]. Though used as a therapy for ileus, some of lidocaine’s beneficial effects may come from inhibiting inflammatory mediators or protecting endothelial cells. Currently, the author recommends initiating lidocaine therapy during or immediately after surgery and continuing until there are no longer clinical signs of pain, shock, or ileus. Lidocaine pharmacokinetics are not altered in horses with gastrointestinal disease except that clearance is increased when used during anesthesia [92]. The dosage is 1.3 mg/kg administered as bolus and followed immediately with 0.05 mg/kg/min as a constant rate intravenous infusion. Initial use during anesthesia suggests it may be of benefit in decreasing anesthetic requirement, and it does not appear to interfere with cardiovascular performance [92,93].

Rinse solutions are a relatively new multimodal treatment for reperfusion injury. Rinse solutions originated as donor organ perfusates used to help prevent reperfusion injury during liver transplantation. These solutions are a combination of substances for improving circulation, preserving endothelium, and scavenging free radicals[94]. Carolina rinse contains electrolytes similar to plasma, allopurinol, glutathione, deferoxamine (iron chelator), nicardipine (calcium channel blocker), glycine (cell preservative), adenosine, and fructose and glucose (Table 1) [95]. Carolina rinse prevented Kupffer cell injury, decreased tumor necrosis factor production, preserved sinusoid endothelial cells, and improved transplant survival in liver transplantation in rats [94]. It was also shown to be beneficial in attenuating reperfusion induced capillary permeability changes and edema formation in the equine jejunum when the solution was perfused into the jejunal artery of an experimental segment 10 mins prior to reperfusion (Fig. 4) [53,56].

When Carolina rinse was compared to lactated Ringer’s solution as an arterial perfusate in a segment of ischemic jejunum, the vascular permeability was maintained near normal; there were significantly fewer neutrophils in the serosa; and 10 days after the ischemic episode, there were fewer intestinal adhesions and serosal fibroplasia (Fig. 5) [96]. Carolina rinse was also effective when used topically and intraluminally on ischemic jejunum but only partially effective when applied to distended jejunum prior to reperfusion [54]. This solution is for local perfusion or topical application rather than systemic use because adenosine can cause significant hypotension due to vasodilatation. When administered systemically to horses under general anesthesia at 0.05 ml/kg, there was a transient decrease in the pulmonary artery pressure at the end of administration [o]. It may be possible to use a lower systemic dose to provide some protection during reperfusion.

Another customized rinse solution was infused into a segment of jejunum maintained in an extracorporeal circuit during ischemia and then at a higher flow rate during reperfusion [97]. The customized solution contained electrolytes, energy sources, glutamine, adenosine, allopurinol, deferoxamine, dimethylsulfoxide, and prostaglandin E2 dissolved in lactated Ringer’s solution. Intestine perfused with the solution had a lower mucosal grade and less structural damage; mucosal area and length were greater in the group treated with the solution in this study [97]. As with the topical/intraluminal application of Carolina rinse, future modifications in the customized solution may allow luminal exposure, which may mean that treatment could be performed through an enterotomy site at surgery. Recent clinical use of the customized solution will likely provide information about the effectiveness of this type of therapy. These multimodal treatments affect more than one pathophysiological pathway of reperfusion, which may explain why they are more effective than any one of their single components [94,98].

Modulation of nitric oxide production has also been investigated as a way to prevent reperfusion injury. Nitric oxide is an endogenous vasodilator that functions as an inhibitory neurotransmitter to circular smooth muscle of equine jejunum [99]. Nitric oxide may play a role in inhibiting smooth muscle, thereby contributing to the ileus observed after reperfusion injury. Nitric oxide also mediates a component of the inhibitory transmission to circular muscle and taenia of the large colon but not to the longitudinal muscle [100]. In this study, nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) maintained muscular activity and may be a potential treatment for ileus [100]. Conversely, L-NAME, when administered to cats, caused a reduction in blood flow, increased microvascular permeability, and increased leukocyte adherence. Nitric oxide production stimulated by L-arginine or nitroprusside can maintain blood flow and prevent neutrophil adhesion during reperfusion [101]. This treatment has not been used in the horse. An effective dosage that will not have detrimental effects on motility while creating increased blood flow needs to be tested prior to clinical use. It may be that maintaining the normal physiologic concentrations of nitric oxide will be the most important treatment for intestinal ischemia.

Dextran and hydroxyethyl starch are colloids which are mainly used as acute volume expanders. These molecules decrease microvascular permeability, which is seen during reperfusion injury, by sealing endothelial cell separation [102]. Administration of high molecular weight dextran to horses subjected to a low-flow ischemia reperfusion of the large colon did not prevent or decrease the mucosal damage, but no deleterious effects were observed in the study [103]. The severity of circulatory shock from ischemia reperfusion could be reduced by increasing vascular volume with hydroxyethyl starch without a detrimental effect on the colon. These macromolecules are effective in the treatment of ischemia reperfusion in multiple organs in other species and may have a role in multimodal therapy of equine intestinal ischemia reperfusion injury.

Inhibiting selected pathways of phospholipid metabolism has been shown to protect against reperfusion injury. It would seem logical that corticosteroids, which have a phospholipase A2 inhibitory effect, could help prevent the release of arachidonic acid and subsequent prostaglandin and leukotriene production [66]. When tested in a low flow ischemia model, corticosteroids were not protective and, subsequently, these compounds have not been used as treatments [104].

Though not the first part of the reperfusion cascade which causes inflammation, prostaglandins are involved in both helping and hindering motility and causing inflammation of the intestine after ischemia reperfusion injury. Despite the findings that prostaglandins have a pro-inflammatory role, there is also evidence supporting their cytoprotective effect in the gut [15,105]. Recent experimental studies have shown that NSAIDs can inhibit healing or restoration of intestinal barrier function after strangulating obstruction. At the same time, cyclooxygenase and lipoxygenase inhibitors provide protection from mucosal injury due to reperfusion and decrease bowel inflammation and pain in the postischemic period. Flunixin meglumine is routinely administered to horses with colic to combat the effects of endotoxemia, provide analgesia, and protect against adhesion formation [81]. In experimental studies on equine jejunum, decreased scarring and adhesions and rapid mucosal healing of ischemic bowel could be attributed to flunixin meglumine [81,106].

When administered at the time of reperfusion and for 72 hours after 60 mins of ischemia in foal jejunum, flunixin (250 mg/kg, IV, QID) combined with penicillin (22,000 U/kg, IV, QID) and gentamicin (2.2 mg/kg, IV, QID) prevented intestinal adhesions which formed in untreated foals (Fig. 6). In foals treated with the flunixin antibiotic combination, the amount of serosal fibrosis was significantly decreased in the experimental segment, compared to control intestine or intestine from foals treated with intra-abdominal carboxymethylcellulose (500 ml of 3.0%), heparin (80 U/kg IV, BID), and intravenous DMSO (20 mg/kg, IV, BID) (Fig. 7).

If the intestine is not irreversibly injured during ischemia reperfusion, two events occur after the insult: 1) contraction of the villi and 2) epithelial restitution [105]. The villi contract in response to certain signals (e.g. prostaglandins) which reduce the denuded portion of the villus and facilitate epithelial restitution. During restitution, epithelial cells loosen their attachment to the basement membrane and migrate across the denuded membrane in response to specific signals, such as epidermal growth factor, transforming growth factor-beta, and transforming growth factor-alpha [105]. Before the intestinal barrier is complete, the epithelial tight junctions must close. This process appears to be dependent on prostaglandins [105].

These compounds are used individually or in combination. Early administration of each of these drugs is recommended for the optimal effect.

In a recent study, flunixin inhibited production of PGE2 and PGI2 in the treated ischemic tissue with no evidence of recovery based on transepithelial resistance [107]. Use of a new COX2 inhibitor resulted in significant increases in PGE2 and PGI2 and significant recovery of transepithelial resistance, similar to that observed in intestine from untreated horses. These findings suggest that specific COX2 inhibitors may be a better alternative to the nonspecific cyclooxygenase inhibitors in horses with injured intestinal mucosa [107]. However, treatment with flunixin is still recommended for treatment of colic and ischemic bowel disease until one of the COX2 inhibitors has been shown to ameliorate the problems, such as pain, adhesions, and intestinal inflammation, which are now successfully treated with flunixin in clinical cases. Lower doses of flunixin meglumine can be recommended as long as an adequate clinical response is seen.

Intestinal adhesions are a possible complication after abdominal surgery. The inflammatory response to distention or ischemia and bacterial contamination can predispose to adhesions. Intra-abdominal infusion of anti-inflammatory agents can prevent adhesions. Carboxymethylcellulose acts as a lubricant or barrier and prevents adhesions without interfering with healing of jejunal anastomosis in horses [108]. This was not true in 6-week-old foals, in which there was no difference in adhesion formation compared to control intestine after 60 mins of total ischemia. Sodium hyaluronate decreases adhesion formation and decreases the inflammatory response in the peritoneum. In an ischemia model in rabbit intestine, gross adhesions were prevented by infusion at 5 mg/kg at the time of surgery and 48 hours after surgery (Fig. 8). This response most likely represents the anti-inflammatory activity of hyaluronic acid on mesothelial surfaces as documented in synovial structures [109]. Treatment with hyaluronic acid is supported by the observation of decreased adhesions after jejunal anastomosis and laparoscopic lysis of adhesions [110,111].In particular, the author recommends coating foal intestine with hyaluronic acid during surgery and systemic treatment weekly in an attempt to prevent adhesions.

It is apparent there is no one treatment that can effectively control the response to intestinal ischemia and subsequent reperfusion. The author currently uses a combination of drugs during the intraoperative and postoperative period (Table 2) [67]. This area of abdominal disease deserves more research as a truly effective treatment for equine intestinal inflammation after distention or ischemia has yet to be discovered.

Footnotes

[a] Banamine, Schering Plough Animal Health, 1095 Morris Ave., Union, NJ 07083.
[b] Ketofen, Fort Dodge Animal Health, P.O. Box 25945, Overland Park, KS 66225.
[c] Eltenac, Schering Plough Animal Health, 1095 Morris Ave., Union, NJ 07083.
[d] Rimadyl, Pfizer Animal Health, Exton, PA 19341.
[e] Xylazine, Vedco, Inc., St. Joseph, MO 64507.
[f] Dormosedan, Pfizer Animal Health, 812 Springdale Dr., Ex-ton, PA 19341.
[g] Talwin, Thomson Healthcare, Stamford, CT 06901.
[h] Torbugesic, Fort Dodge Animal Health, P.O. Box 25945, Overland Park, KS 66225.

[i] Narcan, Endo Pharmaceuticals, 100 Painter Dr., Chadds Ford, PA 19317.
[j] Buscopan, Boerhinger Ingleheim, Vetmedica, Inc., St. Joseph, MO 64506.
[k] Zelnorm, Novartis Pharmaceuticals, One Health Plaza, East Hanover, NJ 07936.
[l] Methylnaltrexone, Progenics Pharmaceuticals, Tarrytown, NY 10591.
[m] Hetastarch, Baxter, One Baxter Parkway, Deerfield, IL 60015.
[n] Pentastarch, Dupont Pharma, 974 Centre Rd. Chestnut Run, Wilmington, DE 19880.
[o] Equine Medical Center, unpublished data.