Endotoxin Enters the Circulation

Although endotoxin is ubiquitous in the environment, both free and as a component of gram-negative bacteria, it normally is excluded from the body by the skin and mucous membranes. If the protective integument or mucosae are subjected to gram-negative bacterial infection or otherwise damaged, endotoxin may reach the blood in sufficient amount (<1 μg of purified LPS in experimental situations) to cause clinical signs. Gram-negative bacterial enterocolitis (e.g., salmonellosis), metritis, pleuropneumonia, wound infection, and neonatal septicemia are common examples. Because gram amounts of free endotoxin normally are safely sequestered within the intestine of the adult horse, damage to the gut wall as a result of local (e.g., intestinal volvulus, infarction, incarceration) or systemic (e.g., hypovolemic shock) causes of tissue hypoxia, inflammation (e.g., DPJ or clostridial enteritis), mechanical trauma (e.g., rectal perforation, prolonged exercise), or intraluminal acidification (e.g., grain overload) is particularly likely to result in endotoxemia. In highly contaminated environments, potentially harmful amounts of endotoxin can be introduced into the lungs via inhalation.³²⁶ Endotoxin may even be delivered directly into the blood via parenteral solutions (e.g., homemade intravenous fluids).

Endotoxin Interacts with Pattern Recognition Receptors

In 1985 almost nothing was known about the way in which LPS molecules interacted with cells of the immune system. In fact, endotoxin was widely believed to enter cells not via engagement of cell-surface receptors but by hydrophobic insertion into the membrane (Fig. 32-42). Since then, sequential discoveries of a plasma LPS-binding protein (LBP; 1989 for humans,³²⁷ 2005 for horses³²⁸), CD14 (1990 for humans,³²⁹ 2003 for horses³³⁰), and TLRs (1998 for humans,³³¹ 2005 for horses³³²) have elucidated the molecular processes of endotoxin binding and signaling (see Fig. 32-42). LPS first interacts with LBP, a normal plasma acute-phase protein; this interaction facilitates binding to the soluble or cell-associated co-receptor CD14. The LPS/LBP/CD14 complex recruits and activates TLR4 dimer and an accessory component MD-2 in preparation for LPS signaling. On ligation of the receptor, the conserved intracellular domain of TLR4 (Toll-IL-1 receptor [TIR]) initiates multiple downstream pathways that culminate in translocation to the nucleus of inducible transcription factors including nuclear factor (NF)–κB and activator protein 1 (AP-1).³³³ NF-κB binds to consensus sequences on the promoter or enhancer regions of an array of genes whose products are involved in the inflammatory response.³³³ It has recently been argued that the global activation of TLR4 typical of sepsis requires the actions of endogenous agonists (e.g., proteases).³³⁵ Endotoxin also may activate NF-κB via TLR4-independent interactions with β₂-integrins, heat-shock proteins, and the intracellular Nod-1 receptor.³³⁶ Although endotoxin binds predominantly to TLR4, a still-growing family of TLRs (12 in rodents, 11 in humans, unknown in horses) is available to bind to other DAMPs (Table 32-5).³³⁶ During sepsis, this diversity of TLRs allows redundant signaling of inflammatory cells. For example, non-LPS components of gram-negative bacteria may bind other TLRs (e.g., lamellin binds to TLR5, lipoprotein and peptidoglycan to TLR2), whereas PAMPs from gram-positive bacteria or fungi bind different TLRs in the course of polymicrobial sepsis. Tissues subject to attack by mediators produced after the initial round of TLR binding can feed back and amplify the inflammatory response by releasing alarmins (e.g., high-mobility group box 1 [HMGB1]³³⁸), which in turn can bind to TLR or other PRRs.

Fig. 32-42 Binding of lipopolysaccharide (LPS) to mammalian cell membranes. In 1985 it was widely believed that LPS initiated cellular signaling by hydrophobic interactions with the plasma membrane. By 2007 the components of the signaling complex were more fully understood. In addition to the extracellular receptor components (discussed in the text), the intracellular Toll-IL-1 receptor (TIR) domain is shown interacting with four adaptor molecules (MyD88, TIRAP, TRAM, TRIF) to initiate a molecular signaling cascade that ultimately leads to gene activation.

Table 32-5 Ligands for Human Toll-like Receptors^316,317

LPS, Lipopolysaccharide; TLR, Toll-like receptor.

Simultaneous with cellular activation, endotoxin interacts with soluble PRRs normally present in plasma. Of particular importance, endotoxin binds to complement proteins to initiate the lectin-dependent and alternative pathways of complement activation and activates coagulation factor XII (Hageman factor) to set off the “contact” system of coagulation.

Mediators are Released

As described earlier, endotoxin engages TLR4 on cells of the innate and adaptive immune systems, especially mononuclear phagocytes (monocytes and macrophages), neutrophils, endothelial cells, and dendritic cells. Pulmonary intravascular macrophages³³⁹ and Kupffer cells likely are the most important mononuclear phagocytes in this regard. Endotoxin causes NF-κB activation in these and many other cell types via multiple signaling pathways resulting in the expression of more than 200 genes, many of which are involved in the pathogenesis of sepsis.³³³ These include genes for proinflammatory cytokines (e.g., TNF, IL-1β, IL-6, IL-8, IL-12, IL-18), chemokines (e.g., IL-8, MIP), type 1 IFNs, procoagulants, adhesion molecules, immunoreceptors (e.g., TNF receptors), enzymes (e.g., elastase), and acute-phase proteins (e.g., fibrinogen).³⁴¹ NF-κB activity is further amplified by the paracrine actions of these proinflammatory cytokines, and by other DAMPs, cellular hypoxia, cellular necrosis, and chemical stress (including oxidant stress). Two of the cytokines secreted by macrophages, IL-12 and IL-18, stimulate IFN-γ synthesis and secretion from NK (natural killer) and other cells.³⁴² Because IFN-γ is a potent stimulator of both innate and acquired immune responses, it is considered to be a principal link between the two systems.

Endotoxin activates coagulation factor XII (Hageman factor) leading both to liberation of bradykinin and to initiation of intravascular coagulation. Even more important, complement is activated by alternative, lectin-mediated, and classical pathways to yield numerous active peptide products.

Clinical Signs

The clinical signs of horses given intravenous endotoxin experimentally may range from fever without obvious malaise to multiple organ failure and death. Obviously, signs that are not due exclusively to endotoxin (e.g., severe pain caused by intestinal strangulation or diarrhea in horses with Salmonella colitis) may greatly influence the overall clinical presentation of horses with naturally acquired endotoxemia.

Typically in an adult horse given a moderate sublethal dose of endotoxin (e.g., 0.1 to 1 μg of LPS per kilogram of body weight), an early period of mild tachypnea peaks within 30 minutes and resolves within 2 hours. During this period, mucous membranes are pale. Beginning within 90 minutes of LPS injection, depression, restlessness, and inappetence are present and rectal temperature begins to rise. Auscultable intestinal sounds usually cease during this period and remain depressed for several hours. Intermittent signs of colic usually are seen, including recumbency (usually without rolling). Small amounts of loose feces usually are passed. Heart rate peaks during the stage of maximal abdominal discomfort (approximately 2 hours after administration of endotoxin), then temporarily declines. During this time, mucous membranes become congested, the capillary refill time is prolonged, and a dark “toxic” line may become apparent around the gingival margins of the teeth. Beginning at 4 to 6 hours after endotoxin administration, there is a secondary phase of tachycardia and tachypnea that likely is related to development of systemic hypotension and fever. This secondary phase persists for several hours. Horses presented clinically with mild to moderate endotoxemia usually resemble experimental animals during the period 2 to 6 hours after intravenous endotoxin administration.

At higher LPS doses (e.g., 100 μg/kg) in experimental animals or in patients with severe endotoxemia, signs of circulatory failure and disordered hemostasis dominate the clinical picture. Usually these horses are stuporous and totally anorectic. Signs of dehydration such as reduced skin turgor, dry mucous membranes, and sunken eyes are obvious. As systemic blood flow becomes more compromised, rectal temperature may drop into or below the normal range. Urine output is reduced or nonexistent. There are dark, congested mucous membranes, rapid and weak peripheral pulses, cold extremities, and sweating, and the horse may have muscle tremors and become recumbent.

Vascular damage may be seen as petechial and ecchymotic hemorrhages on mucous membranes. A poor prognostic sign is the development of a hypercoagulation syndrome, during which routine venipuncture or catheter placement initiates thrombosis along the entire visible length of the jugular veins (or other superficial veins). If both jugular veins are thus occluded, there usually is massive swelling of the soft tissues of the head, and associated laryngeal edema may cause signs of upper respiratory tract obstruction. In some horses, thrombosed superficial vessels can easily be palpated through the skin of the legs and abdomen. Infarction of bowel segments or lungs may cause severe clinical signs that are unresponsive to treatment. A rare syndrome of thrombosis of major limb arteries found in young foals is likely a result of sepsis syndrome.^370,371 At the time that hypercoagulation syndrome is recognized clinically, there is often evidence of a secondary bleeding tendency (a consequence of platelet and clotting factor depletion and uncontrolled activation of fibrinolysis), seen as prolonged hemorrhage from venipuncture sites and widespread mucosal petechiation. In cases with a severe pulmonary component, there may be hemorrhage into the respiratory tract with progressive tachypnea and dyspnea.

If moderately to severely affected animals survive for more than 24 hours, there usually is visible edema of the ventral abdomen and limbs. Signs of laminitis may first become apparent at this stage and may progress in severity even while the other systemic signs of endotoxemia improve.

Clinicopathologic Signs

Although the measured concentration of endotoxin in blood does not correlate well with severity of clinical signs, demonstration of circulating endotoxin obviously is definitive proof of endotoxemia. In one study, 12% of horses with acute gastrointestinal disease had detectable plasma endotoxin.³⁷² Reported concentrations in these horses were 0 to 30,400 pg/mL with a mean of 218 pg/mL. Experimentally, plasma endotoxin usually is assayed by some variant of the Limulus amebocyte lysate assay. A simple horse-side test for endotoxin that was marketed for use in clinical practice is no longer commercially available.

There is early and profound leukopenia principally caused by neutropenia (usually accompanied by left shift and a toxic appearance of stained cells). Lymphopenia (<1000/μL) is found in the most severe cases and likely reflects sepsis-induced apoptosis and immunosuppression. Adult horses often are hyperglycemic at presentation, whereas neonates with sepsis are usually hypoglycemic. Other abnormalities are nonspecific and reflect altered tissue perfusion and organ dysfunction (see Table 32-4).

In moderate and severe cases of endotoxemia, there also may be evidence of disordered hemostasis; values affected in blood may include any to all of the following: reduction in the circulating platelet count (<100,000/μL), reduction in plasma fibrinogen concentration, prolongation of the activated partial thromboplastin, prothrombin, or thrombin time, increased activity of PAI-1, and increased concentration of fibrin degradation products. In horses with acute gastrointestinal diseases, there also is increased activity in peritoneal fluid of many of the elements of the fibrinolytic system, including TPA. Depletion of key clotting factors can most simply be detected as prolongation of plasma recalcification time.³⁷³

Cardiovascular Resuscitation

Expansion of blood volume remains the cornerstone of treatment for horses with serious sepsis or endotoxemia. Most cases (e.g., adults with blood lactate of 2 to 4 mmoles/L) can be treated successfully with intravenous balanced polyionic solution according to guidelines for estimating water deficits provided in the fluid therapy section of this chapter. Urination should begin during the rapid replacement of estimated losses. Ideally the fine control of fluid replacement should be based on serial measurements of packed cell volume (PCV) or plasma protein concentration and further guided by following blood lactate concentration. Some clinicians prefer the early use of compatible plasma (5 L for a 450-kg horse, 1 to 2 L for a neonate) or other colloid solutions such as 6% hydroxyethyl starch solution (6% hetastarch in 0.9% saline; Abbott Laboratories, North Chicago, IL) to replace the extravasated colloid lost as a result of capillary leak. Plasma has the advantage of providing immunoglobulin, acute-phase proteins, and anticoagulants (see Laminitis Prevention).

In horses with the most life-threatening forms of endotoxemia and sepsis (lactate >4 mmoles/L [>5 mmoles/L in neonates <24 hours old], MODS/L, septic shock), aggressive hemodynamic monitoring and EGDT are indicated. Because such treatment still carries at best a guarded prognosis for survival, financial commitment often in the range or $5000 to $20,000, and transfer to a referral center, a decision to continue treatment requires that a very clear and realistic discussion of these issues take place with the horse’s owner. Early intervention is essential in sepsis therapy, in critical care parlance, terms such as the “golden 6 hours” and the “silver 24 hours” exemplify this concept.⁴¹⁰

Relatively simple equipment and supplies but time-intensive monitoring and treatment are needed for effective EGDT. A central venous catheter (e.g., for 50-kg neonates, two-lumen indwelling catheter, 7 Fr × 30 cm [ES-14702], Arrow International, Reading, PA; 500-kg adults, two-lumen Hickman 9 Fr × 90 cm, Bard Access Systems, Salt Lake City, UT), a blood gas and lactate analyzer, an indirect arterial blood pressure monitor, and a central venous blood pressure monitor (transducer and data display and recorder or water monometer) are required for the full EGDT bundle; however, much can be achieved with a jugular catheter, water manometer, and lactate analyzer. The details of an intensive approach to EGDT for the first 6 hours after admission are shown in Fig. 32-45. ScVO₂ has been shown to correlate well in this context with cardiac index. Unfortunately, although measurements obtained via a typical jugular intravenous catheter can be used to approximate arterial lactate concentration and CVP in humans^412,413 (although not in dogs and cats⁴¹⁴), jugular blood SO₂ did not correlate with central measurements in endotoxemic pigs⁴¹⁵ and probably should not be used for that purpose. Although labor-intensive, none of monitoring techniques is technically difficult. One advantage of being able to measure both lactate and ScVO₂ is that inferences can be made as to the particular hemodynamic derangement responsible for signs of global tissue hypoxia (see Table 32-6).

Fig. 32-45 Protocol for early goal-directed therapy. An initial 20 mL/kg bolus of isotonic crystalloid (or equivalent colloid) is given, followed by boluses of 10 mL/kg every 30 minutes until CVP reaches 8 to 15 mm Hg. If the heart-base adjusted MAP is still less than 65 mm Hg, vasopressors are given to effect. Norepinephrine, dopamine, or vasopressin can be used according to the clinician’s preference. If the ScVO₂ is still less than 70%, dobutamine continuous rate infusion can be increased in increments up to 15 μg/mL. If the PCV is less than 21% after the preceding steps and ScVO₂ is less than 70%, packed cells should be given to increase oxygen-carrying capacity. CVP, Central venous pressure; MAP, mean arterial pressure; PCV, packed cell volume.

When the goals of EGDT are met, fluid management should continue according to standard protocols (see Fluid Therapy section) but with adjustments made according to the results of continued monitoring (PaO₂, CvO₂, lactate, CVP, mean arterial pressure [MAP]). If the blood bicarbonate concentration is <16 mmol/L after EGDT goals are met (or plasma total CO₂ concentration is <17 mmol/L), sodium bicarbonate should be given IV to replace calculated deficits. During correction of acidemia, intravenous fluids should be supplemented with potassium (10 to 20 mmol/L) to prevent correction-induced hypokalemia. A maintenance-rate infusion of glucose should be given to neonates with sepsis (4 mL of 5% dextrose—containing fluids per kilogram per hour) and hypoglycemic adults (2 mL of 5% or 0.2 mL of 50% dextrose per kilogram per hour). Glucose concentration should be regularly monitored, and the use of concurrent insulin infusion should be considered, especially if blood glucose is normal or high (see Laminitis Prevention section).

Laminitis Prevention

Adult horses with serious sepsis are at high risk for the development of laminitis. Among the clinical risk factors likely operative in the setting of sepsis are body condition score ≥ 5, being a pony, ≥24 hours since onset of signs of endotoxemia or sepsis, rectal temperature >101.5° F, CRT >2 seconds, or cold extremities. The digital laminae are injured early in the period of hot sepsis, perhaps irreversibly, by processes associated with cytokine storm and global tissue hypoxia. Insulin resistance, hyperglycemia, microvascular injury and thrombosis, and protease activation all may be involved in sepsis-associated laminitis. The laminitis prevention bundle provided in Box 32-3 provides a reasonable preventative strategy, but it must be implemented very early (preferably before increased digital pulses are detected). Global tissue hypoxia is addressed with standard or EGDT fluid resuscitation, small vessel plugging with flunixin (reduced TXA₂), pentoxifylline (vasodilation with PGI₂, suppression of inflammatory cytokines, increased RBC deformability), and plasma and heparin (increased active AT-III), and hyperglycemia and insulin resistance with continuous-rate infusions of regular insulin and glucose (prevention of the damaging effects of hyperglycemia; possible salutary, glucose-independent effects of insulin). If laminitis is already present, or if it develops during the course of treatment, it should be treated as described in Chapter 38.

Removal of the Cause(s) of Endotoxemia and Sepsis

Removal of the cause of endotoxemia usually involves both removal of the source of endotoxin and correction of the abnormality that allows access of endotoxin to blood. In some cases a source of endotoxin can be mechanically removed; for example, gram-negative bacteria and associated inflammatory effusion can be drained from pleural or peritoneal cavities or carefully siphoned from the postpartum uterus. Antimicrobial therapy for gram-negative infection also is essential. In general, broad-spectrum bactericidal drugs should be selected because endotoxemic horses may be immunosuppressed. In horses in which endotoxemia is associated with diarrhea or other signs of colitis or typhlitis, the use of antimicrobial drugs is controversial because of their causal association with severe colitis. They probably should be given only in the following situations: (1) the horse is <3 months old; (2) there is suspicion of clostridial or antimicrobial-associated enteritis (metronidazole or vancomycin); (3) there is degenerative left shift or total neutrophil or lymphocyte count of <1000 μg/mL; or (4) there is clinical evidence of dyshemostasis (e.g., jugular thrombosis or abnormal coagulogram). It should be noted that effective antimicrobial therapy could temporarily worsen clinical signs by causing the release of endotoxin from killed bacteria. This possibility should be anticipated and minimized by the timely use of NSAID or other antiendotoxic therapy (see following paragraphs).

When intestinal strangulation is the cause of endotoxemia, surgical correction obviously is of paramount importance. For the purposes of perioperative management, however, it should be noted that resumption of intestinal blood flow could worsen endotoxemia: sequestered endotoxin may be flushed into the circulation through compromised intestinal walls. At least in the case of small intestinal ischemia, the mucosal barrier to endotoxin may be further compromised by ischemia-reperfusion injury when full blood flow is restored by luminal decompression or other manipulation. Again, prophylactic use of NSAIDs and/or ROS scavengers may be warranted.

Neutralization of Circulating Endotoxin

Inhibition of Endotoxin-Induced Inflammation

Miscellaneous Treatments

Naloxone, a narcotic antagonist, at a dose of 0.2 mg/kg, blunted some of the cardiovascular effects of high-dose endotoxin in one study,⁴⁵⁵ but a dose of 1 mg/kg had no effect in another.⁴⁵⁶ Of importance, 0.75 mg/kg naloxone caused signs of colic in conscious horses,⁴⁵⁷ probably by blocking the actions of endogenous β-endorphins at the high affinity μ-receptor. The detergent tyloxapol was remarkably effective in preventing the effects of endotoxin in anesthetized horses.⁴⁵⁸ The mechanism of antiendotoxic action of tyloxapol is unknown, but the detergent has been shown to have wide-ranging effects on cells and proteins, some of which may preclude its use in clinical cases. For example, the detergent has been shown to inhibit cellular phagocytosis, an important event in innate immunity. Also, this agent induces marked hyperlipidemia (up to 100-fold higher than controls) in horses because of interference with lipoprotein metabolism. Similarly, a phospholipid emulsion effectively prevented adverse effects of subsequent endotoxemia; however, the treatment induced hemolysis sufficient to preclude its use in clinical cases.⁴⁵⁹ A published report⁴⁶⁰ on the use of the sulfonyl analog of the alpha-phenyl-N-tert-butyl-nitrone spin trap molecule suggests that this agent was effective in reducing clinical signs in horses given endotoxin. A cautionary note was the observation that some rodents given the same agent at high doses actually suffered enhanced endotoxin-induced mortality.

PAF inhibitors have been effective antiendotoxic agents in some species but have not yet shown much positive clinical effect in horses or humans.⁴⁶¹ In dogs and other experimental animals, inhibitors of NO production such as N^G-monomethyl arginine reverse endotoxin— or TNF-induced hypotension⁴⁶²; however, NOS inhibitors generally have no protective effect in sepsis models. Furthermore, NO production may not be increased in horses with endotoxemia.⁴⁶³

A promising method of treatment may be the use of ketamine CRI. Ketamine has been shown in vitro to suppress the production of inflammatory mediators by LPS-stimulated equine peritoneal macrophages.⁴⁶⁴ Constant-rate infusion of ketamine at 1.5 mg/kg/h for 320 minutes achieves blood concentrations compatible with this inflammatory effect and has been shown to be safe and nonsedating.⁴⁶⁵ The antiinflammatory actions of ketamine appear to be mediated by the actions of adenosine on the adenosine A2A receptor.⁴⁶⁶ The equine adenosine A2A receptor was recently cloned and characterized pharmacologically and is itself a potential direct target for antiinflammatory drugs.⁴⁶⁷ Because ketamine inhibits inducible macrophage-type nitric oxide synthase and thus potentially causes vasoconstriction,⁴⁶⁸ this approach should be used with caution.

Future Treatment Considerations

Current research in horses and other experimental animals suggests that magic bullets will be very hard to find. Most antiinflammatory approaches, even if they are aimed at the “root and trunk” of the inflammatory cascade (e.g., NF-κB activation) do not work consistently in severe sepsis models (e.g., cecal-ligation puncture) or in phase III clinical trials of human patients. It is becoming increasingly clear that much of the morbidity and mortality associated with sepsis results from “cold” sepsis, the state characterized by profound immunosuppression rather than cytokine storm. Affected patients are likely to be injured further by antiinflammatory therapy. There is some indication that IFN-γ, a cytokine that is pivotal in both innate and acquired immunity, can improve survival in immunosuppressed septic mice by preventing apoptosis of lymphocytes.⁴⁶⁹ The issue of cold versus hot sepsis raises the issue of the need for accurate recognition of the stages of sepsis. Plasma procalcitonin concentration apparently is able to discriminate levels of sepsis and septic versus nonseptic SIRS.^470,471 Similarly, HMGB1 levels have been used to define sepsis categories in humans and to provide prognostic information.⁴⁷² These or equivalent markers need to be introduced into equine sepsis diagnosis.

There remains enthusiasm for strategies aimed at effective means to suppress or scavenge ROSs. In this regard, the remarkable effects of ethyl pyruvate in multiple models of inflammation, which likely mediates via its antioxidant effects, offer considerable promise.⁴⁵³

On the horizon are some different approaches that have the potential to be both effective and affordable. One of the most exciting possibilities is that gene therapy might be used to transfect host cells transiently in a targeted way with genes encoding antiinflammatory mediators (e.g., IL-10, TGF-β) or antisense RNA or ribozymes directed against mRNA of proinflammatory or even antiinflammatory or apoptotic mediators.

Pathophysiology

Ulcerative duodenitis most often affects foals and, to a lesser degree, yearling horses. Older horses are rarely affected. Lesions occur primarily in the proximal duodenum and may include erosions, focal ulceration, and diffuse inflammation with or without ulceration. The terms duodenal ulceration and ulcerative duodenitis may refer to differing clinical manifestations of the same problem, and the terms are used interchangeably in this section.

The pathophysiology of duodenal ulcer disease in foals is less well understood than gastric ulcer disease. The disorder is classically considered to be a peptic disease, one in which damage to the duodenal mucosa results from excessive exposure to hydrochloric acid and pepsin. This concept may require revision. Equine duodenal ulcer disease has been presumed to be similar to the disorder in humans, but most cases of duodenal ulcer disease in people are associated with H. pylori infection.⁴⁸⁰H. pylori bacteria have not been reported in equine gastrointestinal tissues; however, H. pylori colonize only gastric (glandular) mucosa, and infection of the duodenum must be preceded by metaplasia of areas of duodenal mucosa to gastric mucosa. This is thought to occur from chronic peptic injury. In humans the incidence of duodenal ulcer disease increases with age,⁴⁸¹ which contrasts with horses, in which duodenal ulcer occurs primarily in animals less than 1 year old.⁴⁸²

We have recognized occurrences of duodenal ulceration and inflammation in which cases were clustered geographically (same farm) and temporally. These foals all had moderate to severe gastric ulceration, and they had extensive inflammation with varying degrees of erosion or ulceration in the proximal duodenum (see Plates 10, 11). A similar temporal and geographic association was reported in two cases of ulcerative duodenitis in yearlings.⁴⁸³ These findings seem inconsistent with a purely peptic insult as the cause for the ulcerative duodenitis. In one report of seven foals with ulcerative duodenitis,⁴⁸⁴ lesions typically extended into a large area of the proximal duodenum, were characterized by mucosal necrosis, and often had a sharp line of demarcation between affected and more normal-appearing mucosa. In the foals of that report, no common microbial organism other than E. coli was identified, and a cause for the ulcerative duodenitis was not determined. In most foals with duodenal disease the lesions were not focal ulcers but rather appeared as more generalized inflammation. An infectious cause seems likely but has not been identified. In the 1980s rotavirus infection was thought to be associated with gastroduodenal ulcer disease in foals, but most foals with duodenal ulcer disease do not have rotavirus infection.

Duodenal ulcer disease in foals may have a component of peptic injury. The duodenal mucosa possesses some intrinsic properties that are protective against peptic injury, although these are not as elaborate as in the gastric glandular mucosa. The most important factor that protects the duodenal mucosa from acidic gastric secretions may be the sodium- and bicarbonate-rich secretions that probably originate from the pancreas and that will neutralize acid entering the duodenum from the stomach.⁴⁸⁵

Clinical Signs

The signs of duodenal ulceration or ulcerative duodenitis have been classically described as being the severe forms of gastric ulcer signs,⁴⁸⁶ and in many cases duodenal and gastric ulcers occur simultaneously. However, many foals with ulcerative duodenitis will not have signs similar to those of gastric ulceration until severe gastric ulceration has occurred. Thus the primary signs of duodenitis can be nonspecific; they include fever, mild to moderate abdominal discomfort, mild obtundation, and diarrhea. A CBC will often reveal peripheral blood leukocytosis and hyperfibrinogenemia.

Gastric ulceration frequently occurs along with duodenal ulceration and may be secondary to physiologic or anatomic obstruction to gastric emptying. The gastric ulceration tends to be severe (see Plate 12), often leading to gastroesophageal reflux and esophagitis. Foals with esophagitis often exhibit ptyalism. In general the sequelae of duodenal ulceration are more severe than those of primary gastric ulceration. Complications of duodenal ulceration include duodenal perforation with peritonitis or adhesions, duodenal stricture with complete or partial obstruction (Figs. 32-46 and 32-47), ascending cholangitis and hepatitis, and ascending pancreatitis.

Fig. 32-46 Proximal duodenum of a 10-month-old horse with a history of chronic poor appetite and condition. The pylorus is at the left. There are two strictures in the duodenum: S1 is orad from the major duodenal papilla, and S2 is aborad from the duodenal papilla. The segment of the duodenum between the strictures is dilated.

Courtesy Dr. M.J. Murray.

Fig. 32-47 Duodenal stricture (S1) of the horse in Fig. 32-46. The diameter of the duodenal lumen at the stricture is only 3 mm.

Courtesy Dr. M.J. Murray.

Diagnosis

Duodenoscopy is the most specific means of diagnosis. It requires an endoscope with at least a 200-cm working length in foals up to 6 months of age, and a longer endoscope is required in older foals to examine the duodenal mucosa. Because of the size of the stomach and the anatomic configuration of the duodenum in foals, it is usually not possible to advance the endoscope past the duodenal ampulla. Occasionally the endoscope can be advanced into the descending duodenum.

A diagnosis is most readily made in cases in which lesions are diffuse or located within the ampulla. Excessive enterogastric reflux of bile through the pylorus is consistent with duodenal dysfunction. Ulceration at the pylorus or pyloric antrum may accompany duodenal ulceration and thus provide an indication of potential duodenal involvement. Severe gastric ulceration in foals should alert the endoscopist to the potential for duodenal involvement. In such cases, oral H₂ receptor antagonist therapy may be less effective in resolving gastric lesions than in cases of primary gastric ulceration, because of delayed gastric emptying secondary to duodenal ulceration. Therefore if a foal has received such treatment before endoscopy and if gastric ulceration is severe, suspicion of duodenal ulceration should increase.

Other diagnostic procedures that may be helpful include evaluation of peritoneal fluid; serum liver enzymes, particularly biliary-associated enzymes (γ-glutamyltransferase [GGT], ALP); serum bile acids; and radiography. With severe duodenal ulceration, survey radiographs of the cranial abdomen may reveal accumulation of fluid within the stomach and gas ascending the biliary ducts.⁴⁸⁷ If barium contrast medium is placed into the stomach, complete emptying is usually delayed (>2 hours) and an irregular mucosal border may be noted in the descending duodenum. It should be recognized that in most cases radiography would not contribute to a diagnosis of duodenal ulcer per se, although duodenal stricture may be noted. If the descending duodenum is to be imaged, the volume of contrast medium placed in the stomach should not exceed 0.5 to 1 L in a foal and 1 to 2 L in a weanling or yearling, or the proximal descending duodenum will be obscured by contrast medium within the stomach.

Treatment

The effectiveness of treatment of duodenal ulceration or ulcerative duodenitis depends on the extent and severity of ulceration and the absence of complications, particularly perforation and stricture of the duodenum. Treatment objectives are to decrease duodenal inflammation, treat secondary gastric and esophageal ulceration, promote gastric emptying, and treat related problems such as peritonitis. If duodenal ulceration is confirmed or even suspected on the basis of clinical signs, treatment should be aggressive.

In acute cases of ulcerative duodenitis there usually is a pronounced lymphocytic infiltration of the mucosa. In more chronic cases there is a mixture of neutrophils, macrophages, fibroblasts, and fibrinonecrotic exudate. Definitive antiinflammatory therapy has not been described for these cases, and the use of corticosteroids or nonsteroidal antiinflammatory medications is controversial because they may worsen gastric ulcer disease through inhibition of protective prostaglandin synthesis.

Suppression of gastric acid secretion is still an important objective in the treatment of ulcerative duodenitis in foals, because most affected foals have gastric ulcers. Initially, acid suppression should be accomplished via parenteral administration of H₂ antagonist (cimetidine, 7 mg/kg IV q6h, or ranitidine, 1.5 mg/kg IV q8h). Oral medications are unlikely to be adequately delivered to and absorbed from the small intestine in the first days of treatment. Gastric emptying can be enhanced with bethanechol (0.02 mg/kg SC q6–8h or 0.35 mg/kg PO q8h when the foal can consume orally). In foals that have severe duodenal disease or that have required surgery, bethanechol has been given for up to 3 months. Once the foal can accept oral medication, it should be treated with the proton pump inhibitor omeprazole at a dose of 4 mg/kg once daily for the paste formulation. It should be noted that in the 24 hours after the first dose, acid suppression is incomplete, and maximal suppression of acid secretion is achieved between days 1 and 5.⁴⁸⁸ Therefore a common practice is to administer an H₂ antagonist IV for the initial 2 days of treatment with omeprazole in foals with duodenitis.

Misoprostol is a synthetic prostaglandin E₁ analogue that has been successfully used in treating duodenal ulcerations in humans. Doses of 2 to 5 μg/kg q8-12h can be used in horses, although side effects may include abdominal pain and diarrhea. Sucralfate promotes duodenal mucosal healing in humans.⁴⁸⁹ The dose of sucralfate that is effective in humans with duodenal ulceration ranges from 1 to 2 g two to four times daily. Foals treated for duodenal ulceration that do not have impaired gastric emptying should be administered 2 to 4 g of sucralfate three times daily. Sucralfate should not be used as the sole therapeutic agent for duodenal ulceration.

Foals with duodenitis must usually be prevented from nursing or eating for 1 to 3 days. During this time, parenteral feeding should be considered. Depending on the age of the foal, administration of parenteral nutrition should provide 40 to 60 kcal/kg/day.

If medical therapy is ineffective or if sequelae of duodenal ulceration cause complications, surgical intervention may be required. Gastroenterostomy has been reported to be effective in some cases through bypassing the affected portion of duodenum and allowing for an alternative route for gastric emptying.⁴⁸⁷ However, short-term survival and long-term quality of life and use are often unsatisfactory. Patients that have a successful surgical outcome require long-term aftercare and usually require long-term maintenance acid suppression and treatment with a prokinetic drug until gastric emptying is normalized. Therefore an owner should be prepared to make a significant time and financial commitment before surgery is considered.

Pathophysiology

In horses with DPJ, lesions are consistently found in the duodenum, but the severity and frequency of lesions in the jejunum are variable. Serositis is a consistent finding, characterized by bright red to dark red petechial and ecchymotic hemorrhages on the serosal surface.⁴⁹¹ Histologic lesions include hyperemia and edema of the mucosa and submucosa, villous epithelial degeneration, epithelial cell sloughing, neutrophilic pleocytosis, hemorrhages in the muscular layers, and fibrinopurulent exudation on the serosa.

With DPJ there is an increased volume of duodenogastric reflux, typically 50 to 100 mL/min. This reflux has been considered to result from increased intestinal fluid secretion and decreased motility. Mechanisms of intestinal fluid secretion include passive transmucosal exudation, secondary to mucosal and submucosal inflammation and characterized by a protein-rich fluid secretion, and active fluid secretion, caused by increased cyclic nucleotides and characterized by fluid with a high electrolyte and low protein content. The components of fluid in the intestines of horses with DPJ have not been characterized, but it is likely to result from a combination of passive and active secretion. In some horses the hemorrhagic nature of the gastric reflux implies increased capillary permeability of the duodenal mucosa, whereas in other horses the watery nature of the reflux, the presence of serum electrolyte disturbances,⁴⁹³ and the absence of peripheral hypoproteinemia are most consistent with an active secretory process.

Another potential source of the large volume of fluid secreted into the proximal small intestine and refluxed into the stomach is the pancreas. Normally there is periodic orad movement of duodenal contents into the stomach, which has been observed endoscopically and has been documented by collecting gastric contents with and without pyloric obstruction.⁴⁸⁵ The duodenal contents have a large component of water, sodium, and bicarbonate, as well as bile salts from the liver. These secretions are presumed to originate from the pancreas, as well as the liver, and pathology of either of those organs may contribute to the pathophysiology in cases of DPJ.

Suppurative cholangiohepatits has been reported in cases of small intestinal inflammation secondary to DPJ.^494,495 The pathophysiology behind this observation may be related to an increased luminal pressure in horses with DPJ, increasing the likelihood of intestinal content regurgitation into the bile ducts. It is also possible that horses with DPJ absorb inflammatory mediators or bacterial products from the small intestine via the portal blood flow or systemic circulation.

Although the exact cause of DPJ is not known, several bacteria and toxins have been implicated. C. difficile has been frequently implicated in causing the disease. One prospective study cultured toxigenic species of C. difficile from the reflux of 10 out of 10 horses diagnosed with DPJ, and only 1 of 16 horses diagnosed with other causes of nasogastric reflux. Of the strains cultured from these horses, 8 of 10 produced both A and B toxins, whereas the remaining two produced only toxin B.⁴⁹⁶ This is significant in that toxin B as been shown to cause inhibitory electromechanical disturbances to smooth muscle in the small intestine, which may be a possible cause of ileus in these horses.⁴⁹⁷ Toxin A has also been shown to promote inflammatory cell infiltration into the smooth muscle layers.⁴⁹⁸ Influx of neutrophils and release of inflammatory mediators in the intestinal wall have been shown to activate nitric oxide pathways, which results in inhibition of the enteric nervous system, increases in sympathetic tone, and a subsequent reduction of contractile activity in the gut.⁴⁹⁹C. perfringens and Salmonella species have also infrequently been associated with DPJ, but the significance of these pathogens remains unknown.

Fusarium moniliforme has been cultured from the feed of horses with naturally occurring DPJ. Under experimental conditions, F. moniliforme producing fumonosin B1 mycotoxins caused lesions consistent with DPJ.⁵⁰⁰ Neurologic lesions were also present in the horses with DPJ in that study, however, and both of those horses died with lesions consistent with equine leukoencephalomalacia. Cantharidin toxins can also cause reddening of the mucosa in the small intestine, as well as excessive gastric reflux⁵⁰¹ and may be a cause in some cases. It is possible that this one syndrome has multiple initiating causes and that no one causative agent will ever be definitively identified.

Clinical Signs and Differential Diagnosis

The major differential diagnoses for DPJ include simple or strangulating small intestinal obstructions. Differentiation can be extremely difficult in some cases and may delay surgical intervention in cases of small intestinal obstruction, to the detriment of the patient. The criteria used to discriminate between DPJ and obstructive lesions include degree of pain, presence of fever, and changes in hematologic parameters and abdominal fluid.

Horses with DPJ have a history of an acute onset of moderate to severe abdominal pain that often is followed by varying degrees of depression. Nasogastric intubation yields a large volume of enterogastric reflux, which is frequently orange-brown in color, with a fetid odor. Palpation per rectum reveals multiple loops of mild to moderately distended small intestine. The initial volume of reflux may range from as little as 4 to 5 L to up to 32 L. The duration of the reflux may be as short as 24 to 48 hours, but it usually lasts 3 to 7 days. Horses are often febrile (rectal temperature greater than 38° C [101° F]) and dehydrated and have injected mucous membranes, prolonged capillary refill time, diminished intestinal sounds, tachycardia (>60 beats/min), and tachypnea.^{490-493,502,503} Although abdominal pain usually abates after gastric decompression, most horses remain depressed, which perhaps is the most consistent and characteristic clinical sign of the disease. If the fluid that accumulates in the proximal intestinal tract is not removed periodically, signs of abdominal pain recur.

Assessment of the degree of small intestinal distention and the thickness of the intestinal wall can be useful indicators. Often, horses with DPJ have generalized distention of small intestine, but when palpated per rectum the intestine does not feel taut. In many cases of small intestinal obstruction the bowel will feel tightly distended, but this is not universally true. Ultrasonography can be used, both transrectal and transabdominal, to determine the diameter of the small intestine, evaluate contractions, and measure the thickness of the wall of the intestine. With acute obstruction one can see several segments of small intestine that are 6 to 10 cm in diameter, have no contraction, and have a wall diameter of 3 to 5 mm. With DPJ small intestinal diameter may be less, and the thickness of the intestinal wall may exceed 6 mm.

Culture of the reflux for Clostridium and Salmonella species can be attempted. This can be difficult, however, given the special conditions required for anaerobic cultures, as well as the intermittent shedding of Salmonella species into the gastrointestinal tract of normal horses. Also, the large volume of reflux in these cases may dilute the bacterial population to the point where isolating low numbers of bacteria is difficult.

Clinicopathologic Findings

Clinical laboratory findings include increased PCV and total plasma proteins (hemoconcentration) and a metabolic acidosis in longstanding or severe cases. Abdominocentesis often reveals an elevated peritoneal fluid total protein concentration and a mild to moderate increase in the peritoneal WBC count (>5000 cells/μL).⁵⁰² The peritoneal fluid is usually yellow and turbid, but in severe cases diapedesis occurs, resulting in a serosanguineous color. An abdominal fluid total protein concentration ≥3.5 g/dL is associated with a poorer prognosis.⁵⁰² The WBC count in the peripheral blood may be normal or increased.^491,492 In addition, hypocalcemia, hyponatremia, hypochloremia, hypokalemia, and acid-base alterations have been reported in horses with DPJ.⁴⁹³ An elevated anion gap may be present, secondary to decreased calcium and magnesium or increased lactate or albumin concentrations.⁵⁰² Increases in the anion gap to ≥15 mEq/L have also been associated with a poor prognosis.

Elevations in liver enzymes, particularly GGT, may be seen in horses with DPJ and may be a useful way to help differentiate between DPJ and strangulating lesions of the small intestine.^494,495 A study examining a large series of DPJ cases retrospectively to determine the prevalence of hepatic damage in horses with small intestinal inflammation showed that horses with DPJ had significantly higher hepatic enzyme activities than the control group of horses with small intestinal strangulating obstruction (SISO).⁴⁹⁵ Over 50% of horses with PE had biochemical evidence of hepatic disease (high GGT, aspartate aminotransferase [AST], or ALP activity). Horses with DPJ had a 12.1-fold higher risk of having a high GGT activity and a 1.8-fold risk of having a high AST activity than horses with SISO. AST activity in horses with PE ranged from 133 to 2994 IU/L (reference range 215.8 to 365 IU/L), GGT ranged from 7 to 117 IU/L (reference range 6.2 to 19.1 IU/L), and ALP ranged from 86 to 1103 IU/L (reference range 69.4 to 293.7 IU/L). Bile acid concentrations were rarely abnormal, indicating that hepatic failure was uncommon. Histopathologic evidence of liver pathology was a common feature in the horses with PE that had either biopsies or necropsies performed. Centrilobular necrosis and inflammation were noted in some cases.

Treatment

Because the causative agent(s) of DPJ are unknown, treatment remains empiric and consists of aggressive supportive therapy. The continuous production of enterogastric reflux requires gastric decompression every 1 to 2 hours to relieve pain and to prevent gastric rupture. Approximately 4 to 8 L of malodorous gastric fluid can be collected during decompression. The stomach should be decompressed frequently, regardless of whether or not the horse is showing signs of abdominal pain, as these signs may be masked by severe depression or the administration of analgesic or antiinflammatory medications. Horses should receive nothing by mouth until small intestinal function has returned, recognized clinically by cessation or reduction of the nasogastric reflux to 1 to 2 L over a 4-hour period and increased frequency of borborygmi. The time necessary for gastric decompression varies with each individual patient. Repeated rectal examinations after the first day of therapy will inconsistently reveal distended loops of small intestine, depending on the frequency of removal of the reflux and the severity of the initial lesion. Ultrasonography may reveal fluid-filled small intestine when such bowel is not discernible by rectal palpation. Loops of small intestine are most frequently visualized in the ventral flank area, near the udder or prepuce; therefore this area should be examined in all cases of suspected small intestinal distention.

Intravenous administration of a balanced electrolyte solution is necessary to maintain intravascular fluid volume and cardiovascular performance. In some horses even rapid administration of fluid fails to adequately restore and maintain intravascular volume because of enteric fluid losses that can be as great as 8 L hour. In addition, the very large volume of isotonic crystalloid fluid that must be given IV to keep pace with enteric fluid losses with DPJ may accelerate the flux of fluid from the vasculature into the intestinal lumen because of reduced intravascular oncotic pressure, increased capillary perfusion pressure, and increased capillary permeability in the inflamed intestine. Consequently the balance between adequate hydration and the volume of enterogastric reflux obtained requires careful and frequent monitoring.

Administration of colloid solutions may be of benefit in preserving intravascular volume without promoting enterogastric reflux. The most frequently used colloids in the horse include hyperimmune plasma, and hydroxyethyl starch solutions. Plasma products require a large volume of administration to exert a colloidal effect, which is cost prohibitive in many cases. Smaller doses, however, may have a beneficial effect in horses with DPJ, particularly in animals showing signs of sepsis or endotoxemia. Hydroxyethyl starch solutions have been shown to significantly increase plasma oncotic pressure in ponies administered 10 mL/kg⁵⁰⁴ and represent a reasonably priced alternative to plasma. These solutions have been associated with changes in the hemostatic profile in normal ponies at higher doses of 20 mL/kg⁵⁰⁵ and should be used only with caution in horses already at risk for coagulopathies.

During the initial hours of therapy, even aggressive intravenous fluid administration may result in only moderate clinical improvement. A positive clinical response, as evidenced by improved hydration status, decreased heart rate, decreased enterogastric reflux, improved attitude, and improvement in parameters reflecting kidney function (decreased blood urea nitrogen [BUN] and serum creatinine), correlates with resolving intestinal inflammation.

NSAIDs should be used judiciously to avoid masking the clinical signs of a potential surgical lesion. Flunixin meglumine can be used at a dose of 0.25 to 0.5 mg/kg every 6 hours to reduce the untoward effects of arachidonic acid metabolites.

Antimicrobial agents are typically administered to horses with DPJ, although the necessity for antimicrobial treatment in horses with DPJ is uncertain. Given the association of DPJ with C. difficile, administration of intravenous penicillin (22,000 to 44,000 IU/kg q6h) is warranted. Metronidazole also has excellent activity against C. difficile; however, administration is difficult because nothing can be administered per os. Rectal administration of metronidazole has been studied⁵⁰⁶ and can be used in these cases. The dose and frequency of administration should be increased because bioavailability after rectal administration is much less than after oral administration (30% vs. 74%, respectively). Broad-spectrum antimicrobial treatment may be indicated in horses with low WBC counts, but care must be taken in selecting an antimicrobial to avoid potential adverse effects, particularly nephrotoxicosis with aminoglycosides in a dehydrated patient with compromised renal function.

Horses with DPJ may have to be kept from eating for several days and are often in a hypermetabolic state; therefore they rapidly develop a negative energy and nitrogen balance. In these horses parenteral nutritional support should be considered. Parenterally administered solutions containing glucose, balanced amino acid solutions, lipid emulsions, balanced electrolyte and trace minerals, and vitamins have been administered to adult horses with a variety of intestinal disorders, including DPJ. Providing for part of the horse’s nutritional requirements (8000 to 12,000 kcal/day) is possible with glucose—amino acid solutions that are of moderate cost. The rationale for this treatment is that through provision of nutritional support to an anorectic, severely ill horse, the healing process will be facilitated, complications will be reduced, and the duration of hospitalization may be shortened. Thus the overall cost of providing nutritional supplementation, enteral or parenteral, to horses with DPJ may well be offset by quicker recoveries and diminished requirements for other costly treatments.

Prokinetic agents may also be useful in cases of DPJ. Of the available prokinetics, lidocaine is used most frequently.⁵⁰⁷ A loading dose of 1.3 mg/kg slow intravenous bolus followed by a continuous infusion of 0.05 mg/kg/hr has been shown to shorten the time of reflux and decrease the hospital stay in horses with DPJ.⁵⁰⁸ It may do this by decreasing sympathetic tone, acting as an analgesic agent, or decreasing granulocyte infiltration in the intestinal wall. Its use should be reserved for horses in which a surgical lesion has been ruled out, as it can very effectively mask intestinal pain. Horses should be refluxed frequently during the infusion and checked for other signs of complications, such as laminitis, routinely. Metoclopramide, erythromycin lactobionate, and cisapride are also used in cases of DPJ.⁵⁰⁷ The efficacy of prokinetics in this disease is debated, mainly because they require a healthy intestine in order to exert an effect. A more in-depth discussion of prokinetic agents can be found in the section on gastrointestinal ileus in this chapter.

Medical therapy is sufficient in most cases of DPJ. In patients with prolonged nasogastric reflux (>7 days), excessive fluid losses that cannot be corrected with conventional fluid therapy, or clinical and laboratory findings strongly suggestive of an intestinal obstruction, surgery should be considered. Animals with severe cases of DPJ may develop infarction of a segment of the small intestine that requires surgical removal. Surgery is used to make the diagnosis and potentially to alleviate enterogastric reflux by providing an alternative route for fluid that accumulates in the small intestine. On entrance into the abdominal cavity, dilated small intestine is immediately apparent. After the extent of the diseased intestine is determined, a segment of normal distal jejunum is laid side to side to the proximal diseased intestine in an isoperistaltic fashion, as far proximal on the affected bowel as possible without extending to bowel that cannot be removed from the abdominal cavity. A small 1- to 1.5-cm hand-sewn anastomosis can then be made between the two segments of intestine.⁵⁰⁹ This provides an adequate stoma for direct intestinal decompression while minimally compromising the digestive and absorptive capacity of the small intestine. Potential complications of this procedure include development of an intestinal incarceration through the loop that is formed and the development of small intestinal adhesions.

Complications

Complications of DPJ include septic peritonitis, myocardial and renal infarction, aspiration pneumonia, adhesions of the proximal small intestine, and laminitis. The prognosis for surviving the initial intestinal insult is good in cases of DPJ. The death and function losses from this disease are more commonly related to the secondary complications such as laminitis and intraabdominal adhesions. In one report, laminitis occurred in 28% of horses with DPJ, and associated factors were high body weight and hemorrhagic gastric reflux.⁵¹⁰ Laminitis prophylaxis is routinely incorporated into the medical therapy and can consist of a variety of treatments, none of which is proven to be effective. These include NSAIDs, topical glyceryl trinitrate, and DMSO (200 mg/kg given as a 10% solution in normal saline). Horses that received heparin as a prophylactic treatment for laminitis were less likely to develop clinical laminitis than horses that did not receive heparin in one study.⁵¹⁰

Pathophysiology

The mechanism of enteritis after infection with L. intracellularis involves invasion of the proliferating crypt cells in the ileum, causing excessive mitotic division and severe hyperplasia.⁵¹⁶ The hyperplastic mucosa becomes grossly thickened and develops a corrugated appearance. As would be expected, this thickening of the mucosa, along with the proliferation of immature crypt cells rather than mature villous cells, leads to a limited brush border development and a decreased absorptive capacity, which results in the weight loss and hypoproteinemia present in these cases. The organism can divide within the infected cells and migrate up to the mucosal layers as the cells proliferate and advance. The main differential diagnosis in these cases is R. equi enteritis, which can also cause ulceration in the areas of Peyer’s patches throughout the small intestine, cecum, and colon.

A genetic predisposition to L. intracellularis infection has been proposed. A recent study showed that polymorphisms in several important immune response genes in foals were related to the fecal shedding of L. intracellularis organisms.⁵¹⁷ None of these foals had clinical disease consistent with PE, however, and the significance of these gene polymorphisms is still unknown.

Clinical and Laboratory Findings

PE is a chronic, progressive disorder, and therefore affected animals are typically not presented until the disease is advanced. Horses with PE have a variety of clinical problems, most notably chronic weight loss, intermittent abdominal discomfort, or diarrhea. Some affected animals are erroneously treated for primary gastric ulceration, and indeed there may appear to be temporary improvement in attitude and appetite. This may reflect successful treatment of gastric ulcers that develop as a secondary problem. Many affected animals are diminished in stature, reflecting retarded growth resulting from a chronic intestinal disorder that probably affects absorption of nutrients. Affected animals typically appear lethargic with a rough haircoat and may have concurrent respiratory infection, dermatitis, and intestinal parasitism.

Ventral edema often is present as a result of hypoproteinemia. Some animals have tachycardia and tachypnea. Fever is an inconsistent finding. Abdominal ultrasonography is often useful to identify thickened small intestine. The entire ventral abdomen should be examined, but the affected intestine is most often in the distal jejunum and ileum, which can be most commonly seen along the midline caudally. If transrectal ultrasonography is possible, better detail of the intestinal wall will be appreciated. In affected animals the intestinal wall diameter will be 6 to 12 mm. More normal surrounding small intestine may be seen, and in contrast the affected segment of bowel will appear rigid with a corrugated appearance to the mucosa, and the diameter of the lumen will be decreased in size because of mucosal proliferation (Fig. 32-48).

Fig. 32-48 Cross-section of ileum from a 6-month-old horse with proliferative enteropathy.

Courtesy of Dr. M.J. Murray.

CBC findings in horses with PE vary. Leukocytosis is a frequent finding, and this may be characterized by a lymphocytosis. Profound hypoproteinemia (serum protein <3 g/dL, albumin <1.5 g/dL) is a consistent finding. A foal in one report had mildly decreased total serum protein with markedly low albumin (0.6 g/dL) and polyclonal gammopathy (4.6 g/dL). Hyperfibrinogenemia occurs in some cases. Other clinicopathologic findings are variable and depend on the chronicity and whether there are excessive fluid and electrolyte losses through diarrhea.

For definitive diagnosis of PE caused by L. intracellularis, isolation of the organism is considered the gold standard. However, culture of this organism is difficult and requires specialized culture media; therefore the sensitivity of this test is questionable. Specific tests for L. intracellularis infections in foals have been developed. A PCR can be performed on tissues or feces of PE-suspect foals. Use of this test in tissues is sensitive and specific; however, fecal PCR has a higher incidence of false-negative results.⁵¹⁵ A more useful antemortem test is the indirect fluorescent antibody (IFA) test that detects antibodies against L. intracellularis in serum.⁵¹⁵ Titers ≥1:30 were found to be diagnostic of infection in foals.

Pathologic Findings

Lesions are most frequently found in the distal jejunum and ileum, although diffuse thickening of the small intestine may occur. Classically there is pronounced mucosal thickening with varying severity of ulceration and transmural edema. The affected bowel appears to be stiff, and the mucosal surface has a corrugated appearance. Mucosal pleocytosis is a common feature, but in different cases the predominating inflammatory cell type will differ. A lymphocytic or plasmacytic cellular infiltration may be present. There is crypt proliferation, accompanied by crypt elongation and epithelial hyperplasia. The villi are blunted and may become fused. Silver staining with Warthin-Starry stain reveals elongated, curved bacilli in the apical zone of the crypt epithelial cells.⁵¹⁴

Treatment

Treatment objectives are to eliminate the infection, reduce intestinal inflammation, and maintain hydration and plasma colloid oncotic pressure. Several antibiotics have been reported to be useful for the treatment of L. intracellularis infection. Lipophilic drugs with high intracellular penetration are most effective because the bacterium resides within the cells. Ampicillin has good activity against the bacterium in vitro, but because it does not penetrate intracellularly, it is unlikely to be effective in vivo. The most common antibiotic used in PE is erythromycin with or without rifampin for approximately 6 weeks.⁵¹⁵ Other drugs in this class, including azithromycin, may be useful for treatment of this disease owing to their high intracellular concentrations.⁵¹⁸ Chloramphenicol has also been reported to be effective and is a good alternative in foals that develop a worsening of the diarrhea while on erythromycin. The tetracyclines, particularly oral doxycycline, are a cheap and effective alternative to other antibiotics. A recent report looked at 11 cases of PE in foals treated with tetracycline therapy.⁵¹⁹ In this report, 9 of the 11 survived to discharge. The average time to resolution of the diarrhea was 3.5 days after initiation of therapy, and the average treatment time was 3 weeks. The most common administration schedule used was oxytetracycline 6.6 mg/kg IV q12h for 3 to 7 days followed by oral doxycycline 10 mg/kg PO q12h for up to 17 days.⁵¹⁷

Supportive therapy with crystalloid fluids to correct dehydration, electrolyte imbalances, and azotemia secondary to fluid losses from profuse diarrhea is warranted. Colloidal support with plasma or hydroxyethyl starch solutions can help correct the edema and decreased colloid oncotic pressure. NSAIDs should be used with caution in foals showing signs of dehydration.

Prognosis in these cases is generally good with early and correct diagnosis of the problem. Therapy can be prolonged and should be continued until the diarrhea and hypoproteinemia have resolved and there is no longer evidence of thickened small intestine on ultrasound.

Pathophysiology

Intestinal infection with R. equi can occur through either fecal-oral transmission or swallowing of infected sputum. The organism invades and reproduces within the macrophages, causing a pyogranulomatous disease. In a survey of normal foals on two different farms, R. equi was shed in the feces of 16 of 17 and 19 of 26 foals, respectively.⁵²¹ Only two foals developed clinical signs of intestinal disease, and the shedding of bacteria in the feces increased threefold to fourfold during those times. Such foals, as well as adults, are likely the source of repeated contamination on endemic farms. Whether or not the organism causes disease is based on the presence of virulence factors, particularly VapA, which has been most commonly associated with disease in pneumonic foals.

Clinical and Laboratory Findings

Foals diagnosed with R. equi enteritis typically manifest the signs of pneumonia first, although foals in which the enteric form is the major pathology have been reported.⁵²² With the enteric form of the disease, diarrhea, weight loss, and colic are present. Foals are often febrile, anorectic, and depressed. Typical clinicopathologic findings include leukocytosis with neutrophilia and severe hyperfibrinogenemia. Ultrasound of the abdomen may reveal pyogranulomatous abscesses in the lymph nodes.

A diagnosis of R. equi enteritis can be presumed in pneumonic foals showing signs of gastrointestinal disease that culture positive for R. equi in transtracheal wash fluid. R. equi can also be cultured from the feces, small intestinal luminal contents, or occasionally the peritoneal fluid of affected animals. A PCR based on the vapA gene has been developed and can be used as an adjunct diagnostic in these cases.⁵²³

Pathologic Findings

The most common small intestinal lesion is multifocal ulcerative enteritis in the area of the Peyer’s patches of the ileum. Other parts of the small intestine may be affected, with lesions present throughout the entire small intestine.⁵²³ These lesions frequently extend into the cecum and colon as well. A suppurative exudate is also present, along with pyogranulomatous inflammation of the mesenteric lymph nodes.

Treatment

Treatment of R. equi enteritis is similar to treatment of R. equi pneumonia. Erythromycin estolate (25 mg/kg PO q6-8h) or erythromycin phosphate (37.5 mg/kg PO q12h) combined with rifampin (5 to 7.5 mg/kg PO q12h) has been the traditional treatment for these foals, and it is still effective but requires a long duration of treatment and is difficult for owners to administer because of the frequency of the treatments. Alternative treatments include azithromycin (10 mg/kg PO q24h for 5 days, followed by q48h) and clarithromycin (7.5 mg/kg PO q12h). It is very important to continue treatment until the hematologic abnormalities and radiographic examinations have returned to normal, in order to prevent relapses.

Complications

Complications associated with R. equi enteritis include septic peritonitis and the development of intestinal adhesions. These may lead to death of the animal, or chronic abdominal problems in those that survive. Therapy is often prolonged in these cases, and owners should be warned that foals with extrapulmonary disorders associated with R. equi pneumonia have a more guarded prognosis.

Pathophysiology

Pythium species are presumed to be transmitted via contact with contaminated water. Once ingested the organisms are thought to penetrate the intestinal mucosa through an existing lesion, because necrotic tissue is considered chemotactic.⁵²⁴Pythium species may be able to penetrate healthy tissue, however, because some cases in dogs have been reported to have mesenteric lymph node involvement without any mucosal lesions.⁵²⁵

Clinical and Laboratory Findings

Four reports of enteric pythiosis can be found in the literature.^526-529 In all cases, masses occurred in the mid to distal jejunum. One horse died suddenly, one was euthanized during surgery, and two were successfully treated with a jejunal resection. Organic iodide therapy was instituted in one horse postoperatively for 30 days. In three cases clinical signs of intestinal disease had been present for several months before diagnosis. Chronic colic, weight loss, inappetence, and ill thrift have all been reported and could be related to the intestinal lesion. None of the reported animals had skin lesions. Hematologic evaluation was nondiagnostic in the three cases in which it was performed.

Grossly, lesions are caseous with discrete yellow foci (“kunkers”), and the intestinal wall is thickened because of a pyogranulomatous inflammation. Microscopically, a diffuse, mixed inflammatory infiltrate, along with granulation tissue, is found in the submucosa, tunica muscularis, and mesenteric attachments. Culture of the organism is difficult in these lesions; however, an indirect immunoperoxidase technique to stain for Pythium-positive hyphae is available in some laboratories.⁵²⁸

Treatment

Treatment of phycomycetes is often difficult. They are not true fungi; therefore they are resistant to many antifungal drugs. Systemic amphotericin B is only rarely effective in treating the cutaneous disorder. Organic iodides are inexpensive and safe when administered orally, but the mechanism of action as an antimicrobial drug is not understood, and the efficacy of this compound has not been proven when treating this disease. A vaccine can be formulated against the organism, and this has been shown to shrink the lesions in horses with cutaneous disease. Whether or not it would work in enteric disease is unknown at this time. In addition, premortem or presurgical diagnosis of the disease is extremely difficult, making surgical resection and biopsy the most effective treatment.

Clinical and Laboratory Findings

Horses with IBD typically have progressive weight loss despite a good appetite and have intermittent abdominal discomfort. If the disease predominates in the small intestine, diarrhea will not be a feature. In some cases there will be associated dermatitis.⁵³⁸ Horses often present with peripheral edema secondary to hypoproteinemia from enteric protein losses. Ultrasonography may reveal thickened small intestine (>5 mm wall diameter).

Clinicopathologic abnormalities may include anemia, hypoalbuminemia, hypoproteinemia, and malabsorption of glucose and D-xylose. Hypoalbuminemia in the absence of proteinuria or severe liver dysfunction is consistent with protein-losing enteropathy. Some horses may have a relative gammopathy. Serum electrolyte concentrations and total CO₂ are usually normal. Subclinical disseminated intravascular coagulation with thrombocytopenia and increased fibrinogen degradation products have been identified in horses with chronic enteritis.^533,539

In many horses inflammatory cells infiltrate throughout the intestinal tract. Therefore rectal mucosal biopsy may be useful to identify cases of IBD in horses.⁵⁴⁰ A definitive diagnosis often requires biopsy of the small and/or large intestine. With appropriate instruments this can be done by laparoscopy, although an exploration via a ventral midline approach permits a more thorough evaluation of the abdomen. In most horses cellular infiltration can be found to varying degrees throughout the intestinal tract.

Histopathologic evaluation of biopsy specimens can be used to differentiate among the various IBDs reported in horses, based on the following criteria.⁵³⁴ A diagnosis of granulomatous enteritis is made when aggregates of macrophages and epithelioid cells are found in the mucosa and/or submucosa, along with villous atrophy. In lymphocytic-plasmacytic enterocolitis, lymphocytes and plasmacytes are present in the lamina propria, and villous atrophy usually occurs. For multisystemic eosinophilic epitheliotropic disease, eosinophils, lymphocytes, and macrophages are found in the mucosa and submucosa. Rarely basophils have also been reported.

A new syndrome has recently been discovered involving focal areas of eosinophilic inflammatory infiltrates within the small intestine, termed idiopathic focal eosinophilic enteritis (IFEE).^536,541-544 Affected horses typically are presented not because of chronic weight loss or diarrhea, but rather as acute colic cases. Hypoproteinemia and malabsorption are not present. The lesions are intramural masses or circumferential mural bands. Eosinophils with or without lymphocytes are seen infiltrating all layers of the intestine, with varying degrees of fibrosis.⁵³⁴ No underlying cause of the disease has been found, although food allergy, parasitism, and Pythium species have all been suggested.⁵⁴⁴ The incidence, or at least the diagnosis, of this disease appears to be increasing.

Treatment and Prognosis

Because the specific diseases included under the general category of IBD are quite different, a generalized treatment recommendation cannot be made. Most reported cases of IBD in horses have been fatal, even with aggressive treatment with corticosteroids. Classically reported cases of eosinophilic, lymphocytic, and basophilic enteritis have failed to respond to treatment. If treatment is attempted, immunosuppressive doses of dexamethasone, up to 0.2 mg/kg, once daily are recommended. Successful remission of granulomatous enteritis was reported in one patient that was treated with dexamethasone⁵⁴⁵; however, in the vast majority of cases treatment is unsuccessful. Cases of IFEE should be differentiated from other causes of IBD with regard to treatment and prognosis. These cases frequently respond to surgical decompression without resection if circumferential mural bands are the only lesion present.⁵⁴⁴ In cases of intramural masses, surgical resection of the lesions usually resolves the problem.⁵⁴³

Ascarid Impactions

Impactions caused by Parascaris equorum typically occur in weanling foals (median age, 5 months; range, 4 to 24 months) that have been on a poor deworming program and that are administered an anthelmintic when they have a heavy parasite burden.⁵⁶⁴ Products that cause sudden ascarid paralysis or death, including piperazine, organophosphates, and pyrantel pamoate, have been incriminated.⁵⁶⁵ However, it is likely that any effective broad-spectrum anthelmintic, such as the avermectins, will have the same effect. Clinical signs include variable onset of colic after administration of an anthelmintic (usually within 1 to 5 days) and signs compatible with small intestinal obstruction, including nasogastric reflux.⁵⁶⁴ The onset of the disease varies according to the degree of obstruction.⁵⁶⁵ Diagnosis may be tentatively based on the history in a foal that appears unthrifty, has been recently dewormed, and has signs referable to small intestinal obstruction. The presence of dead ascarids in nasogastric reflux would raise the index of suspicion of this particular form of obstruction.⁵⁶⁴ Abdominal radiographs or ultrasound will likely indicate the presence of multiple loops of distended small intestine but are not needed if clinical signs indicate the need for immediate surgery. Surgical treatment typically involves an enterotomy made over the intraluminal impaction and removal of ascarids.

Although simple intestinal obstruction tends to carry a favorable prognosis for survival, ascarid impaction is a notable exception. The mortality rate in these cases is high (up to 92% in one study) as a result of severe intestinal compromise, peritonitis, and development of adhesions. The severe intestinal compromise is almost entirely attributable to the duration of impaction, which for unknown reasons is not as readily recognized in foals as it is in adults. Reasons for this could include failure of the owner or farm manager to recognize colic in foals, or failure on the part of the owner or veterinarian to recognize the implications of colic in foals. Although foals readily display signs of colic, other medical causes of colic such as gastric ulcer disease or enteritis might be higher on the list of differential diagnoses than for adults. Second, the size of a foal may make episodes of colic appear more manageable than in adults, in which colic-induced trauma, especially to the head, may force the issue of referral and surgery at an earlier stage. This is speculative, but early intervention in foals with ascarid impaction would likely result in dramatic reductions in the reported mortality rate.⁵⁶⁴

Ileal Impaction

Ileal impactions occur most commonly in adult horses in the southeastern United States. Although feeding of coastal Bermuda hay has been implicated in the regional distribution of this disease, it has been difficult to separate geographic location from regional hay sources as risk factors.⁵⁶⁶ However, a recent study from the Southeastern United States showed that feeding coastal Bermuda hay and failing to deworm with an anthelmintic with efficacy against tapeworms are significant risk factors for ileal impaction.⁵⁶⁷ Furthermore, in a study performed in the United Kingdom, horses with evidence of tapeworm infection were at risk for developing ileal impaction.⁵⁶⁸ Signs are typical for an adult horse with small intestinal obstruction, including onset of moderate to severe colic and palpable loops of distended small intestine per rectum as the condition progresses. Because the ileum is the distalmost aspect of the small intestinal tract, nasogastric reflux may take a considerable time to develop and is found in only approximately 50% of horses requiring surgical correction of ileal impaction.^569,570 The diagnosis is usually made at surgery, although an impacted ileum may be palpated per rectum.⁵⁷¹ However, multiple loops of distended small intestine frequently make the impaction difficult to palpate. Nonetheless, clinicians working in the southeastern United States who evaluate horses with cases of mild or moderate colic that have a history of eating coastal Bermuda hay, and in which distended loops of small intestine can be detected adjacent to the cecum, should have ileal impaction high on the list of differential diagnoses. Ileal impactions may resolve with medical treatment. In particular, horses that have clinical signs compatible with obstruction of the small intestine but also have normal abdominal fluid should be treated medically unless pain is unmanageable or subsequent abdominal fluid samples indicate intestinal compromise. In those cases in which surgery becomes necessary, fluids (2 to 3 L) can be directly infused into the mass, allowing the surgeon to breakdown the impaction. However, extensive small intestinal distention and intraoperative manipulation of the ileum frequently leads to POI.⁵⁷² Therefore some surgeons now elect to perform an enterotomy and to flush the contents from the intestinal lumen with minimal manipulation. Although early studies indicated a guarded prognosis,⁵⁷⁰ more recent studies indicate that the prognosis is good.^569,571

Ileal Hypertrophy

Ileal hypertrophy is a disorder in which the muscular layers (both circular and longitudinal) of the ileum hypertrophy for unknown reasons. Parasitism has been implicated, particularly for those parasites that tend to localize to the ileum (such as tapeworms), but this has never been proven. In some cases the jejunum may also be hypertrophied, either alone or in combination with the ileum.⁵⁷³ It is clear from these findings that initial functional obstruction initiates this syndrome, causing the musculature of the intestine to hypertrophy in order to push intestinal contents aborally, but there is no evidence as to the mechanisms of this disease. Clinical signs include chronic intermittent colic as the ileum hypertrophies and gradually occludes the lumen. In one study partial anorexia and chronic weight loss (1 to 6 months) were documented in 45% of the horses.⁵⁷³ The diagnosis is usually made at surgery, although in some cases the hypertrophied ileum may be palpated per rectum or seen on ultrasonographic evaluation of the abdomen. For treatment, an ileocecal or jejunocecal anastomosis to bypass the hypertrophied ileum is performed. Without surgical bypass, intermittent colic persists, and the thickened ileum may ultimately rupture. According to one recent report of 11 horses with hypertrophy of the ileum, only one horse survived, indicating a poor prognosis. The most common reason for euthanasia was spontaneous ileal rupture.⁵⁷³

Meckel’s Diverticulum

Meckel’s diverticulum is an embryonic remnant that may become impacted. The diverticulum arises from the vitelloumbilical duct, which fails to completely atrophy, and becomes a blind pouch projecting from the antimesenteric border of the ileum.^574,575 Occasionally an associated mesodiverticular band may extend from the diverticulum to the umbilical remnant and serve as a point around which small intestine may become strangulated. Mesodiverticular bands may also originate from the embryonic ventral mesentery and attach to the antimesenteric surface of the bowel, thereby forming a potential space within which intestine may become entrapped (Fig. 32-50).⁵⁷⁶ Clinical signs range from chronic colic for an impacted Meckel’s diverticulum to acute severe colic if a mesodiverticular band strangulates intestine. The diagnosis is made at surgery, and treatment requires resection of the diverticulum and any associated bands.

Fig. 32-50 Jejunal mesodiverticular band. This anomaly was discovered in this horse as an incidental finding during exploration of the abdomen. Intestine may become entrapped within the mesenteric pocket formed by the attachment of the ventral to the dorsal mesentery (arrows).

Epiploic Foramen Entrapment

The epiploic foramen is a potential opening (because the walls of the foramen are usually in contact) to the omental bursa located within the right cranial quadrant of the abdomen. It is bounded dorsally by the caudate process of the liver and caudal vena cava and ventrally by the pancreas, the hepatoduodenal ligament, and the portal vein.^588,589 Clinical signs include acute onset of severe colic with examination findings compatible with small intestinal obstruction. Although the condition was reportedly more prevalent in older horses, recent studies have not detected an age predilection.⁵⁹⁰ However, studies have detected a seasonal pattern for this disease. Specifically, more horses appear to suffer from epiploic foramen entrapment during the fall and winter months.⁵⁹¹ An additional factor associated with epiploic foramen entrapment is crib-biting. One potential reason for this association is the development of negative intrathoracic pressure during cribbing, which might then result in cranial movement of intestine into the vicinity of the epiploic foramen. The association between crib-biting and epiploic foramen entrapment has now been shown in separate studies performed in the United Kingdom and the United States.⁵⁹²

The diagnosis is definitively made at surgery, although ultrasonographic findings of distended loops of edematous small intestine adjacent to the right middle body wall are suggestive of epiploic foramen entrapment.⁵⁸⁸ Entrapped small intestine may enter the foramen from the visceral surface of the liver toward the right body wall or in the opposite direction. Reports differ as to which is the more common form. Entrapped small intestine may be limited to a portion of the intestinal wall (parietal hernia).⁵⁹³ In addition, the large colon may become entrapped within the epiploic foramen.⁵⁹⁴ In treating epiploic foramen entrapment, the epiploic foramen must not be enlarged either by blunt force or with a sharp instrument, because rupture of the vena cava or portal vein and fatal hemorrhage may occur. In addition, excessive force used to extract entrapped bowel during surgery may also result in rupture of a mesenteric branch of the cranial mesenteric artery. The finding of intraabdominal hemorrhage in some cases of epiploic foramen entrapment before surgery may result from compromise of the mesenteric blood supply rather than the major blood vessels that border the epiploic foramen. Prognosis has substantially improved over the last decade, with current short-term survival rates (discharge from the hospital) ranging from 74% to 79%.^588,595

Strangulation by Mesenteric Pedunculated Lipoma

Lipomas form between the leaves of the mesentery as horses age, and mesenteric stalks develop as the weight of the lipoma tugs on the mesentery. The stalk of the lipoma and a loop of small intestine or small colon may become intertwined, causing strangulation (Fig. 32-53). Strangulating lipomas should be suspected in mature horses (>10 years old) with acute colic referable to the small intestinal tract.⁵⁹⁶ In addition, geldings and ponies appear to be at risk for developing strangulating lipomas,⁵⁹⁷ possibly because of differences in fat metabolism. One recent study documented a case of strangulating lipoma in a much younger patient, indicating that although the aging process is associated with development of lipomas, this disease cannot be ruled out preoperatively purely on the basis of age.^598,599 The diagnosis is usually made at surgery, although on rare occasions a lipoma can be palpated per rectum.⁶⁰⁰

Fig. 32-53 Strangulating lipoma of the ileum. A lipoma, together with its mesenteric stalk (arrows), has become intertwined with a loop of the ileum, resulting in a hemorrhagic strangulating obstruction.

Treatment involves surgical resection of the lipoma and strangulated bowel, although strangulated intestine is on occasion viable. Studies indicate that approximately 50% to 78% of horses are discharged from the hospital after surgical treatment.⁵⁸⁵

Small Intestinal Volvulus

A volvulus is a twist along the axis of the mesentery, whereas torsion is a twist along the longitudinal axis of the intestine. Small intestinal volvulus is theoretically initiated by a change in local peristalsis, but the mechanisms of this disease are unclear.⁶⁰¹ It is reportedly one of the most commonly diagnosed causes of small intestinal obstruction in foals.^602,603 It has been theorized that young foals may be at risk for small intestinal volvulus because of changing feed habits as they adapt to a forage-based adult diet. Onset of acute, severe colic, a distended abdomen, and radiographic or ultrasonographic evidence of multiple loops of distended small intestine in a young foal would be suggestive of small intestinal volvulus. However, volvulus is not possible to differentiate from other causes of small intestinal obstruction preoperatively.

In adult horses, volvulus frequently occurs in association with another disease process, during which small intestinal obstruction results in distention and subsequent rotation of the small intestinal around the root of the mesentery (e.g., in horses that have strangulation caused initially by a pedunculated lipoma). Although any segment of the small intestine may be involved, the distal jejunum and ileum are most frequently affected, most likely because the mesentery is longer in the more distal bowel. The diagnosis is made by palpating a twist at the origin of the cranial mesenteric artery during surgical exploration. Treatment includes resection of devitalized bowel, which may not be an option because of the extent of small intestinal involvement. For example, if complete volvulus of the small intestinal tract occurs, the only option would be to untwist the intestine and hope that the bowel was sufficiently viable to survive the disease process. This would in turn depend on the duration of disease and the extent of intestinal ischemia (i.e., how tightly the intestine twisted as the volvulus developed). Prognosis is based on the extent of small intestine involved and its appearance after surgical correction of the lesion.⁶⁰⁴ For example, the degree of sepsis may relate to the surface area of devitalized tissue. In addition, the length of the time it takes to complete the surgery can become problematic, particularly in patients with sepsis, in which it is difficult to maintain adequate arterial blood pressure. Nonetheless, survival in patients with extensive small intestinal resection may not relate to the absolute length of intestine resected.⁶⁰⁵ A recent study indicated that the prognosis for survival is good (80% of horses recovered from surgery and were discharged).⁶⁰⁶

Inguinal Hernia

Inguinal hernias are more common in standardbred and Tennessee Walking horses, which tend to have congenitally large inguinal canals. Inguinal hernias may also occur in neonatal foals, but they differ from hernias in mature horses in that they are typically nonstrangulating. Typical historical findings in mature horses with inguinal hernias include acute onset of colic in a stallion that has recently been used for breeding. A cardinal sign of inguinal herniation is a cool, enlarged testicle on one side of the scrotum.^607,608 This is attributable to occlusion of the testicular blood supply in most cases rather than strangulated intestine within the scrotum itself. Inguinal hernias can also be detected on rectal palpation, and ultrasound of the testicle is very helpful in determining the diagnosis, particularly considering the differential diagnosis of testicular torsion. The nature of the hernia (direct versus indirect) is determined by the integrity of the parietal vaginal tunic. In horses in which the bowel remains within the parietal vaginal tunic, the hernia is said to be indirect, because strictly speaking the bowel remains within the peritoneal cavity. Direct hernias are those in which bowel ruptures through the parietal vaginal tunic and occupies a subcutaneous location, followed by strangulation. Direct hernias most commonly occur in foals and should be suspected when a congenital inguinal hernia is associated with colic, swelling that extends from the inguinal region of the prepuce, and intestine that may be palpated subcutaneously.^609,610 Although most congenital indirect inguinal hernias resolve with repeated manual reduction and/or application of a diaper, surgical intervention is recommended in foals with congenital direct hernias in order to reduce the hernia as well as repair the parietal vaginal tunic.

In stallions with indirect inguinal hernias, manipulation of herniated bowel per rectum can be used to reduce a hernia but is not generally recommended because of the risk of a rectal tear. In addition, the inability to visually assess the integrity of the bowel may well be problematic. However, in many cases taken to surgery, the short segment of herniated intestine will markedly improve in appearance once it has been surgically reduced, and in some cases the affected intestine can be left unresected. The affected testicle will be congested because of vascular compromise within the spermatic cord, and although it may remain viable, it is recommended that it be resected. Furthermore, the inguinal canal should be partially closed at surgery to prevent recurrence, and the risk that this procedure will reduce spermatic cord vasculature is a further problem. The prognosis in adult horses is good, with up to 75% of horses surviving to 6 months of age.⁶⁰⁸ Horses that have been treated for inguinal hernias may be used for breeding. In these horses, the remaining testicle will have increased sperm production, although an increased number of sperm abnormalities will be noticed after surgery because of edema and increased temperature of the scrotum.

Strangulating Umbilical Hernias

Although umbilical hernias are common in foals, strangulation of herniated bowel is rare. In one study, 6 of 147 horses with umbilical hernias (4%) had incarcerated intestine.⁶¹¹ Clinical signs include a warm, swollen, firm, and painful hernia sac associated with signs of colic. The affected segment of bowel is usually small intestine, but herniation of cecum or large colon has also been reported.⁶¹² In rare cases a hernia that involves only part of the intestinal wall may be found and is referred to as Richter’s hernia. In foals that have Richter’s hernia, an enterocutaneous fistula may develop. In one study, 13 of 13 foals with strangulating umbilical hernias survived to discharge, although at least three horses died because of long-term complications.⁶¹²

Diaphragmatic Hernias

Herniation of intestine through a rent in the diaphragm is uncommon in the horse, accounting for 0.3% of all cases of colic in a large multicenter study.⁵⁸⁴ Any segment of bowel may be involved, although small intestine is most frequently herniated.⁶¹³ Diaphragmatic rents may be congenital or acquired, but acquired hernias are more common. Congenital rents may result from incomplete fusion of any of the four embryonic components of the diaphragm: pleuroperitoneal membranes, transverse septum, and esophageal mesentery. In addition, abdominal compression of the foal at parturition may result in a congenital hernia. Acquired hernias are presumed to result from trauma to the chest or a sudden increase in intraabdominal pressure such as might occur during parturition, distention of the abdomen, a sudden fall, or strenuous exercise.⁶¹⁴ In one study, 19 of 40 horses diagnosed with diaphragmatic hernia (48%) had a history of recent trauma.⁶¹⁵ Hernias have been located in a number of different locations, although large congenital hernias are typically present at the most ventral aspect of the diaphragm and most acquired hernias are located at the junction of the muscular and tendinous portions of the diaphragm. In addition, a peritoneal-pericardial hernia has been documented in at least one horse.⁶¹⁶

The clinical signs are usually associated with intestinal obstruction rather than respiratory embarrassment. However, careful auscultation may reveal an area of decreased lung sounds associated with obstructed intestine and increased fluid within the chest cavity. Such signs may prompt thoracic radiography or ultrasound, both of which can be used to make a diagnosis. In one review, 7 of 40 horses reported in the literature with diaphragmatic hernia (18%) had dyspnea.⁶¹⁵ Auscultation may also reveal thoracic intestinal sounds, but it is typically not possible to differentiate these from sounds referred from the abdomen. In one report, two of three horses diagnosed with small intestinal strangulation by diaphragmatic hernia had respiratory acidemia, attributable to decreased ventilation.⁶¹⁷

Intussusceptions

An intussusception involves a segment of bowel (intussusceptum) that invaginates into an adjacent aboral segment of bowel (intussuscipiens). The reason for such invagination is not clear, but it may involve a lesion at the leading edge of the intussusception, including small masses, foreign bodies, or parasites. In particular, tapeworms (Anoplocephala perfoliata) have been implicated.⁶¹⁸ Ileocecal intussusceptions are the most common intestinal intussusceptions in the horse and typically affect young animals. For example, in one study evaluating 26 cases of ileocecal intussusception, the median age of the horses was 1 year old.⁶¹⁹ Acute ileocecal intussusceptions are those in which the horse has a duration of colic of less than 24 hours and involve variable lengths of intestine that ranged in one study from 6 cm to 457 cm long. In acute cases the involved segment of ileum typically has a compromised blood supply. Chronic ileocecal intussusceptions typically involve short segments of ileum (up to 10 cm long), and the ileal blood supply is frequently intact. Abdominocentesis results are variable because strangulated bowel is contained within the adjacent bowel. There is often evidence of obstruction of the small intestine, including nasogastric reflux and multiple distended loops of small intestine on rectal palpation. Horses with chronic ileocecal intussusceptions have mild, intermittent colic, often without evidence of small intestinal obstruction. A mass may be palpated in the region of the cecal base in approximately 50% of cases. Transabdominal ultrasound may be helpful in discerning the nature of the mass. The intussusception has a characteristic target appearance on cross-section.⁶²⁰

Other segments of the small intestine may also be intussuscepted, including the jejunum. In one study on 11 jejunojejunal intussusceptions, the length of bowel involved ranged from 0.4 to 9.1 m.⁶²¹ Attempts at reducing intussusceptions at surgery are usually futile because of intramural swelling of affected bowel. Jejunojejunal intussusceptions should be resected. For acute ileocecal intussusceptions the small intestine should be transected as far distally as possible, and a jejunocecal anastomosis performed. In cases with particularly long intussusceptions (length up to 10 m has been reported), an intracecal resection may be attempted. For horses with chronic ileocecal intussusceptions, a jejunocecal by-pass without small intestinal transection should be performed.

In one study that evaluated the survival of horses with ileocecal intussusceptions, seven of seven horses with chronic intussusceptions survived long term (>4 months), whereas only 5 of 12 horses with acute intussusceptions (42%) survived long term.⁶¹⁹ In a separate study that evaluated survival in horses with jejunojejunal intussusceptions, 6 of 11 horses (54%) were discharged from the hospital after surgery, and 4 of 11 horses (36%) survived long term (>16 months).⁶²¹

Other Small Intestinal Strangulations

Entrapment of the small intestine may occur through rents in the mesentery, internal ligaments such as the gastrosplenic ligament,⁶²² the broad ligament, and the proximal aspect of the cecocolic ligament.⁶²³ Entrapments may also occur through trauma-induced body wall hernias. For all of these conditions it is often necessary to enlarge the rent or hernia to allow reduction of entrapped small intestine. In the case of body wall hernias, the defect should be closed with suture, or patched using mesh. Entrapment of small intestine within mesenteric rents appears to be particularly problematic because they are difficult to reduce and have an unfavorable prognosis. The latter may be a result of the fact that large lengths of intestine may become strangulated, and because the mesenteric vasculature is frequently compromised to the extent that intraabdominal hemorrhage has been noted in some cases.⁶²⁴

Physiology

The control of intestinal motility is complex and involves a combination of central innervation, autonomic innervation, and the enteric nervous system (Fig. 32-54). Intestinal contractions are primarily controlled by the enteric nervous system and do not require extrinsic neural input. The inherent rhythmicity of electrical activity in the intestine is controlled by the interstitial cells of Cajal (ICCs). These are highly specialized cells that are electrically coupled to the smooth muscle syncytium via gap junctions.⁶³⁵ ICCs are responsible not only for generation of slow waves (cyclical electrical activity), but also for coordination of pacemaker activity and propagation of slow waves along the intestine. ICCs appear to be critically involved in a range of motility disorders in humans, including gastroparesis, pseudoobstruction, and chronic constipation.⁶³⁶ In horses a reduction in ICC density was demonstrated with equine dysautonomia (grass sickness) and in horses with large intestinal disease.^637,638

Fig. 32-54 Schematic representation of some neural and hormonal influences on intestinal motility. ACh, Acetylcholine; ATP, adenosine triphosphate; DA2, dopamine type 2 receptors; +5-HT1, 5-hydroxytryptamine type 1 receptors; M2, muscarinic type 2 receptors; NANC, noncholinergic, nonadrenergic pathway; NE, norepinephrine; NK-1, neurokinin-1 receptors, NO, nitric oxide; +ve, excitatory; +ve, inhibitory; VIP, vasoactive intestinal peptide.

The inherent “excitability” of smooth muscle cells in response to stimuli varies among regions of the gastrointestinal tract and among species. This variability in cell excitability is dependent on the magnitude of the membrane potential, which in turn is regulated by the number and subtype of potassium channels.⁶³⁵

The enteric nervous system plays an important role in control and coordination of intestinal contraction. Contractile events are influenced by central and autonomic innervation, but external neural input is not required for contraction. The parasympathetic supply to the gastrointestinal tract is via the vagus and pelvic nerves, and the sympathetic supply is through postganglionic fibers of the cranial and caudal mesenteric plexuses. A complex network of interneurones within each plexus integrates and amplifies neural input, and the intensity and frequency of resultant smooth muscle contractions are proportional to sympathetic and parasympathetic input. Additional binding sites for a number of other endogenous chemicals, including dopamine, motilin, and serotonin, can be found within the enteric nervous system and on smooth muscle cells.⁶³⁹ It is important to appreciate that mechanisms to slow progressive intestinal motility are also critical in order to retain feed for adequate digestion and absorption of nutrients. The terms jejunal and ileal brake have been used to describe the slowing of transit caused by mediators such as peptide YY, noradrenergic nerves, and opioid, serotonergic, and chemosensitive afferent neurons.⁶⁴⁰

Acetylcholine (ACh) is the dominant excitatory neurotransmitter in the gastrointestinal tract and exerts its action through muscarinic type 2 (M₂) and M₃ receptors. Sympathetic fibers innervating the gastrointestinal trace are adrenergic, postganglionic fibers with cell bodies located in the prevertebral ganglia. Activation of α₂-adrenergic receptors on cholinergic neurons within enteric ganglia inhibits the release of ACh and therefore reduces intestinal contraction. The β₁-, β₂- and β-atypical receptors are directly inhibitory to the intestinal smooth muscle.⁶⁴¹ Inhibitory nonadrenergic, noncholinergic (NANC) neurotransmiters include ATP, vasoactive intestinal peptide (VIP), and nitric oxide (NO).^642,643 These neurotransmitters are critical for mediating descending inhibition during peristalsis and receptive relaxation. Substance P is a NANC neurotransmitter that may be involved in contraction of the small intestine and large colon.^644-646 The rate and force of intestinal contractions along the small intestine and large colon of the horse are key determinants of intestinal motility. Of even greater importance to the net propulsion of digesta are the cyclical patterns of contractile activity. These patterns are known as the small intestinal and colonic migrating motility complexes (MMC).⁶⁴⁷ The colonic complex usually originates in the right ventral colon and variably traverses the ascending and descending colons. Many of these complexes are temporally related to a specialized motility event of the ileum known as the migrating action potential complex.

Diagnosis

The diagnosis of ileus is based on history and physical examination findings. Important tests include determination of pulse rate and rhythm, auscultation and percussion of the abdomen, rectal palpation, and passage of a nasogastric tube. A CBC with fibrinogen estimation and cytologic analysis of peritoneal fluid may improve the accuracy of diagnosis. Affected animals may be colicky because of accumulation of fluid in the upper gastrointestinal tract (classical POI) or cecal contents (cecal emptying defect). Decompression of the stomach is important diagnostically and therapeutically in horses with POI after small intestinal surgery. Failure to relieve pain with gastric decompression could point toward mechanical obstruction, severe inflammation of the intestine, or peritonitis. Most animals with ileus are depressed and have reduced fecal output and intestinal borborygmi. Intestinal sounds should, however, be interpreted with caution, because the presence of borborygmi does not always equate to progressive intestinal motility and may merely reflect local, nonpropagated contractions. Rectal palpation findings in cases of persistent POI or DPJ are usually nonspecific but may reveal dilated, fluid-filled loops of small intestine. Roughened peritoneal surfaces can occasionally be palpated if there is peritonitis. Cecal distention with digesta can be palpated in horses with advanced cecal dysfunction.

It is important to distinguish functional ileus from mechanical obstruction. This can be extremely difficult, but horses with mechanical obstruction typically have sustained high volumes of gastric reflux that vary little over time.

Treatment

The management of gastrointestinal ileus is dependent on the segment of gastrointestinal tract involved. Therapy for ileus of the proximal gastrointestinal tract typically involves a combination of gastric decompression, fluid and electrolyte therapy, and antiinflammatory drugs. Nasogastric decompression is the mainstay of management to prevent overdistention of the stomach and small intestine. This often necessitates placement of an indwelling nasogastric tube, a procedure that some have speculated may in itself delay gastric emptying. The placement of an indwelling tube for 18 hours did not adversely affect the emptying of liquids, but in a recent study a delay was noted when the tube was left in place for 72 hours.^673,674 Both studies used apparently healthy animals.

Electrolyte balance is important, particularly with respect to maintaining adequate extracellular concentrations of potassium, calcium, and magnesium. Calculation of the volume of fluid to be administered should include maintenance requirements (40 to 60 mL/kg/day) plus an estimate of losses, especially those lost through gastric decompression. Overhydration should be avoided in horses with small intestinal ileus. Fluid therapy is the key component in the management of cecal emptying defect, usually in combination with lubricants or laxatives, such as mineral oil or magnesium sulfate, and with careful use of antiinflammatory drugs. Horses with primary cecal impaction or impaction secondary to an emptying defect may require surgery in order to prevent rupture. The surgical management of these cases is controversial and may include typhlotomy alone, typhlotomy with a bypass procedure such as ileocolic or jejunocolic anastomosis, or a bypass without typhlotomy.⁶⁷⁵ Most horses that undergo simple typhlotomy have an uneventful recovery, although a small number will reimpact and require a second laparotomy.⁶³³

A significant clinical or economic benefit of parenteral nutrition in adult horses with gastrointestinal disease has also yet to be demonstrated.^676-678 Parenteral nutrition should be considered when feed has been withheld for more than 96 hours, particularly in the horse with a surgical wound. Limited exercise, in the form of hand-walking, may provide some benefit to these animals, although there is no evidence that exercise has a direct impact on intestinal motility in either horses or humans with POI.⁶⁷⁹

Drugs that may retard normal intestinal motility should be avoided in horses with gastrointestinal ileus. These include the anticholinergics, such as atropine, and opiate receptor agonists, such as morphine and meperidine.^680,681 Butorphanol appears to have little or no adverse effect on either small or large intestinal motility.^682,683 α2-Adrenergic agonists should be used sparingly because of their inhibitory effects on large intestinal motility.

The pivotal role of intestinal inflammation provides a strong rationale for the use of antiinflammatory drugs in affected animals. Flunixin meglumine is widely used in equine practice as an analgesic and antiinflammatory agent, and it also ameliorates many of the adverse systemic effects of endotoxin. A potential negative effect of NSAIDs on large intestinal contractility has been suggested on the basis of in vitro studies⁶⁶⁰; however, a similar response has not been reported in whole animal studies.^663,665,684 There may be a role for novel agents in the future. Carbon monoxide (CO) has prevented POI in experimental animals, a benefit not only when CO was inhaled but also when CO was dissolved in a peritoneal lavage solution, making potential administration considerably easier and safer.⁶⁸⁵ CO has potent intestinal antiinflammatory properties and is derived from the degradation of heme by the enzyme heme oxygenase. Expression of a heme oxygenase isoform (HO-1) can be induced by a variety of stimuli.

Broad-spectrum antimicrobial drugs are indicated when sepsis is suspected or if the immune system is compromised, as in cases with moderate to severe endotoxemia. Theoretic concerns have been raised regarding the use of aminoglycoside antibiotics in animals with ileus. Inhibition of intestinal contractions occurred when sections of intestine were exposed to high concentrations of aminoglycoside antimicrobial drugs, but this inhibitory effect is unlikely to occur at clinically relevant doses.⁶⁸⁶ The administration of benzyl penicillin and/or ceftiofur was associated with an increased risk of colic in the week after anesthesia for diagnostic imaging or nonabdominal surgical procedures.⁶⁸⁷

Motility-modifying drugs could play an important role in the prevention and treatment of gastrointestinal ileus. An effective prokinetic agent could shorten the length of hospitalization, thereby reducing the cost of treatment and the number of potential complications such as weight loss, thrombophlebitis, and laminitis. There is also evidence that the development of abdominal adhesions could be minimized with the use of an effective prokinetic drug.^688,689 A potential negative impact of prokinetic use in the postoperative period after anastomosis is increased predisposition to dehiscence.⁶⁹⁰

Most motility-modifying drugs require a healthy intestinal wall in order to enhance intestinal contraction. There are several examples in horses in which the expected contractile response to certain drugs is blunted in the face of disease. It is reasonable to assume that many putative prokinetic drugs would be partially or totally ineffective in horses with abdominal disease. This would include intestine that has undergone prolonged or excessive distention or that is in any inflammatory condition, such as after intestinal manipulation or associated with primary inflammatory diseases such as DPJ or Salmonella enteritis. Numerous drugs have been investigated in humans with POI, but currently there is no prokinetic agent that has been found to be safe and effective.⁶⁹¹ The financial pressures associated with equine patient management often compel attending veterinarians to “experiment” with a range of putative prokinetic drugs.

Bethanechol is a methyl derivate of carbachol and is an ACh receptor agonist. The drug acts both at the level of the myenteric plexus and directly on intestinal smooth cells through muscarinic receptors. The actions are primarily mediated through activation of M₃ receptors, although M₂ receptors are also involved to a lesser extent.⁶⁹² There is evidence in other species that activation of M₂ receptors not only facilitates intestinal contraction but also may lead to antinociception.⁶⁹³ Bethanechol is not degraded by the enzyme anticholinesterase. As anticipated the drug has a range of cholinergic side effects, including abdominal discomfort, sweating, and salivation, although these are minimal when the drug is administered at 0.025 to 0.05 mg/kg of body weight SC. Bethanechol is one of the most useful prokinetic agents in equine practice, as it exerts effects throughout the gastrointestinal tract; however, it does not appear to be commonly used.⁶⁹⁴ It is most commonly used in the management of delayed gastric emptying and slowed small intestinal transit. Experimentally the drug has been shown to significantly increase gastric contractility and hasten the emptying of liquid and solid phase markers from the stomach of normal horses.^695,696 The drug has potent effects in the hindgut as well. Bethanechol increases both the relative strength and duration of wall contractions in the cecum and right ventral colon and consequently speeds up cecal emptying.⁶⁶⁵ When given to ponies at a dose of 0.05 mg/kg SC, the drug increased electrical activity in the large colon for approximately 80 minutes.⁶⁸⁴ There are wide ranges in reported dose rates of bethanechol, with doses up to 0.25 mg/kg recommended for oral administration in the management of delayed gastric emptying.

Neostigmine increases receptor levels of ACh by inhibiting cholinesterase. The drug (0.022 to 0.025 mg/kg IV) promotes cecal and colonic contractile activity and enhances cecal emptying in normal ponies.⁶⁶⁵ Neostigmine has been used in the management of small intestinal ileus but significantly delayed the emptying of 6-mm beads from the stomach of normal adult horses.⁶⁹⁷ A survey of prokinetic use indicated that neostigmine was more commonly used in the management of large intestinal disease.⁶⁹⁴

Metoclopramide is a moderate partial 5-hydroxytryptamine 4 (5HT-4)–receptor agonist, a moderate 5HT-3–receptor antagonist, and an antagonist of both dopamine 1 (DA₁) and 2 (DA₂) receptors. It has been suggested that the 5HT-4 agonist properties are primarily responsible for the prokinetic effects of metoclopramide. Antagonism of prejunctional DA₂ receptors facilitates ACh release and smooth muscle contraction. The effect on dopamine receptor antagonism is absent in newer benzamides. Metoclopramide crosses the blood brain barrier, where its antagonist properties on central DA₂ receptors can result in extrapyramidal signs, including seizure. These have been observed when the original reported dose of 0.25 mg/kg, given by intravenous infusion over 30 minutes, was used in practice.⁶⁹⁸ These signs were responsible for poor acceptance of the drug in equine practice. An experimental bolus of endotoxin caused a delay in gastric emptying, as assessed using the acetaminophen absorption test; this delay was partially ameliorated through pretreatment with metoclopramide (0.125 mg/kg in 1 L infused over 15 minutes), but again the investigators reported adverse side effects.⁶⁹⁹ Most investigators have failed to demonstrate significant effects of metoclopramide in experimental animals, but constant intravenous infusion (0.04 mg/kg/hr) in a population of postoperative horses significantly decreased the volume and duration of gastric reflux over control and intermittent drug infusion groups.⁷⁰⁰ Infusion was well tolerated and was superior to intermittent infusion or no treatment at all.

Cisapride is a second-generation benzamide that is commonly reported to act as a primary 5HT-4 agonist and 5HT-3–receptor antagonist. Furthermore, stimulation of 5HT-4 receptors within the enteric nervous system enhances release of ACh from the myenteric plexus, thereby promoting intestinal contraction. In vitro studies of equine jejunum concluded that the contractile actions of cisapride in the species were primarily mediated through 5HT-2 and not 5HT-4 receptors and that the response was noncholinergic.⁷⁰¹ Several reports suggest efficacy of cisapride in the management of intestinal disease in horses, including the resolution of persistent large colon impaction, treatment of equine grass sickness, and prevention of POI in horses after small intestinal surgery (0.1 mg/kg body weight IM during postoperative period).^702-705 Cisapride has the potential to cause adverse cardiac side effects mediated through blockage of the rapid component of the delayed rectifier potassium current that include lengthening of the QT interval and development of torsades de pointes, a potentially fatal arrhythmia. These adverse effects have resulted in drug withdrawal in the United States and in many other countries. Another benzamide, mosapride, resulted in increased myoelectric activity of the small intestine and cecum of horses after oral administration. The authors reported that mosapride is a selective 5HT-4 agonist; consequently the reported effects are surprising given that the actions of 5-HT on the equine jejunum were reported to be primarily mediated through activation of 5HT-2 and 5HT-3 receptors.⁷⁰¹ Mosapride is marketed in several Asian countries and is not available in the United States.

Domperidone acts as a competitive antagonist at peripheral DA₂ receptors; these receptors are inhibitory. The drug has been used to manage gastroparesis in humans for many years.⁷⁰⁶ The primary use in equine practice is in the management of mares grazing endophyte-infected tall fescue (1.1 mg/kg/day PO), principally because of drug-enhanced prolactin release from the anterior pituitary. The potential prokinetic effects of domperidone have not been extensively studied in horses, but a modest efficacy of domperidone (0.2 mg/kg IV) was demonstrated in a model of experimental ileus in two ponies.⁷⁰²

Erythromycin is a direct motilin receptor agonist acting directly on smooth muscle cells as well as within the enteric nervous system to facilitate the release of ACh and motilin. Erythromycin enhances gastric emptying in normal horses but in contrast to most other species has a more pronounced effect on the hindgut.^695,707 This is somewhat surprising given that a higher density of motilin receptors was reported in the duodenum than in either the cecum or pelvic flexure of adult horse.⁷⁰⁸ Erythromycin lactobionate (1 mg/kg IV) hastens cecal emptying in normal animals and induces propagating colonic MMC-like activity across the colon. Administration is often associated with defecation and abdominal discomfort.

Several problems limit use of erythromycin as a prokinetic agent in equine practice. The principal use in human medicine has been restricted to management of acute exacerbations of diabetic gastroparesis, facilitation of feeding tube placement, and upper gastrointestinal endoscopy.⁷⁰⁹ Although it has been shown to enhance emptying in normal horses, it was not as effective as bethanechol.⁶⁹⁵ Given its potent prokinetic effects in the cecum, erythromycin may be helpful at preventing cecal impaction in horses after anesthesia. However, its effectiveness on cecal motility appears to be markedly reduced in the immediate postoperative period.⁶⁵⁹ High doses, constant infusion, or prolonged use of erythromycin also induces receptor tachyphylaxis and therefore reduced efficacy. There is also evidence that as little as 2 hours of intraluminal distention leads to a reduction in the total number of motilin receptors and in the amount of motilin receptor mRNA, although erythromycin binding to remaining motilin receptors is not affected.⁷¹⁰ Erythromycin can induce diarrhea in adults; therefore administration over many days should be avoided. The diarrhea induced by erythromycin is most likely mediated by C. difficile overgrowth and toxin elaboration.⁷¹¹

Given that opiates have an inhibitory effect on normal intestinal motility, it is not unreasonable to assume that antagonists may have the potential for prokinetic activity. Naloxone (0.05 mg/kg IV) have been shown to induce contractile activity in the cecum and left colon.⁷¹² The administration of naloxone was often followed by defecation within 15 to 20 minutes. Naloxone has not been beneficial in preventing POI in human beings.⁷¹³ An in vitro study reported a direct contractile effect of the peripherally acting opioid antagonist N-methylnaltrexone on the circular muscle layer of the jejunum and large colon.⁷¹⁴ The authors suggested a potential role for the drug in preventing intestinal complications associated with the use of morphine for pain relief.

α₂-Adrenoreceptor antagonists, such as yohimbine and telazoline, counteract increased sympathetic outflow in response to nociceptive stimulation. Yohimbine (75 μg/kg by slow intravenous infusion) hastens cecal motility and emptying in normal ponies and also attenuates the negative effects of endotoxin on motility.^655,665

Lidocaine (also referred to as lignocaine in some countries) appears to be the most commonly used putative prokinetic agent in the management and prevention of POI.⁶⁹⁴ Intravenous infusion of lidocaine may suppress primary afferent neurons, thereby limiting reflex efferent inhibition of motility. It is also possible that lidocaine may block the inhibitory effect of NANC neurotransmitters on smooth muscle.⁷¹⁵ Any positive effect of lidocaine could also be related to the drug’s significant antiinflammatory properties. These include amelioration of the cytokine response to endotoxemia, reduced neutrophil free-radical production, impaired leukocyte phagocytic function, and inhibition of leukocyte migration through suppression of chemokines.⁷¹⁶ As discussed earlier, inflammation may be the most important initiator of intestinal stasis in the postoperative period.

A combination of intraoperative and postoperative lidocaine infusion is commonly used as a preventative strategy against POI. Postanesthetic treatment typically involves a slow intravenous bolus of 2% lidocaine (1.3 mg/kg) followed by a constant infusion at 0.05 mg/kg/min for 24 hours. The recommended target range for serum concentration of lidocaine is 1 to 2 mg/dL. In a prospective study of horses undergoing laparotomy for colic, the authors failed to demonstrate any difference between lidocaine and saline infusion with respect to return of borborygmi, time to first feces, or gastric reflux.⁷¹⁷ The authors did, however, report some positive differences in several ultrasound parameters, including jejunal diameter and the apparent volume of peritoneal fluid. Unfortunately only several of the horses in the study had a small intestinal lesion that required resection and anastomosis, and only two animals developed significant POI, one in each group. Lidocaine infusion was also contrasted with saline infusion in a group of horses with DPJ or POI.⁷¹⁵ Criteria for inclusion in that study included animals with net gastric reflux of more than 2 L/hr for 24 hours or a cumulative reflux volume of more than 20 L in less than 24 hours. Significant benefits of lidocaine infusion included a reduction in the duration of refluxing, hastened passage of feces, and a shorter total period of hospitalization for survivors. There were horses that did not improve in response to lidocaine infusion, and animals that continued to produce net gastric reflux throughout the 24-hour infusion period had a poorer outcome.

The rate of lidocaine infusion requires close monitoring, because infusion can be associated with reversible side effects that include muscle fasciculations, ataxia, and seizure. The drug is highly protein-bound, so hypoproteinemic horses may be more susceptible to signs of toxicity.

Salmonellosis

Salmonella bacteria possess an array of virulence factors that confer attributes of mucosal adhesion and invasion, produce enterotoxins that stimulate intestinal fluid secretion, activate local inflammation, including recruitment of inflammatory cells and the release of their mediators, cause local cytotoxic effects, and initiate systemic responses attributable to LPS.

Epidemiology

Numerous Salmonella serotypes have been associated with equine colitis, and overall more than 2500 serotypes of Salmonella have been described. Salmonella Typhimurium is the most frequently isolated serotype in horses, with dozens of other serotypes isolated sporadically. There are many reports describing clusters of cases of equine salmonellosis in which specific Salmonella serovars predominate. Nosocomial infections associated with Salmonella Krefeld,^718-720Salmonella Typhimurium,⁷¹⁹Salmonella Anatum,⁷²¹ and Salmonella Infantis⁷²² have been reported in recent years. Pertinent features of these bacteria are the ability to withstand a wide range of environmental conditions, the ability to rapidly invade and spread within the host (and thus be shed into the environment through the feces), and the range of severity of illness that results from infection.

Other key elements that influence whether clusters of cases will occur given the presence of a particular Salmonella serovar in the environment are availability and population density of susceptible hosts and the size of infective dose of the pathogen. It is for these reasons that veterinary hospitals, breeding farms, and other facilities that may have a high density of horses are most vulnerable to the development of Salmonella outbreaks. In one study at a veterinary teaching hospital, horses that were at greatest risk for developing salmonellosis were those treated with antimicrobial drugs or admitted for treatment of colic.⁷²³ Such horses will include the majority of patients in any equine referral hospital. Breeding farms are susceptible to Salmonella outbreaks (or other enteric infections) because of the concentration of large numbers of immunologically immature newborn animals. In either case the particular Salmonella organism involved in disease outbreaks may not have to be especially virulent, because the inherent susceptibility of the host provides the microbe the opportunity to colonize and invade the host. Also of importance is the ability of the organism (inherent or acquired) to persist in the environment, lying in wait for both susceptible hosts and environmental conditions that favor its propagation and dissemination.

Serovars or strains of Salmonella that have newly acquired virulence plasmids can rapidly become established and spread among farms, sales areas, veterinary clinics, and veterinary teaching hospitals. Often the origin of these “new” bacteria is undetermined, but in some cases the organism can be traced to contaminated feed,⁷²⁴ a specific shedder introduced into the environment, domestic or feral animals (barn cats), birds, and wildlife.

Salmonellae are ubiquitous in the environment, and the prevalence of fecal shedding varies by the group of horses sampled and the method of detection. Prevalence of fecal shedding, based on fecal culture, in asymptomatic horses admitted to teaching hospitals varied from 1% to 5%.^725,726 In a nationwide survey of prevalence of Salmonella in fecal samples from horses on farms and ranches. Salmonella bacteria were cultured from less than 1% of horses.⁷²⁷ Use of PCR to detect Salmonella DNA in horse feces resulted in a prevalence rate of 17% in horses admitted to a teaching hospital for lameness examination and greater than 60% in hospitalized horses with gastrointestinal disease.⁷²⁸ In that report the PCR technique was determined to be specific for Salmonella DNA, but the test cannot differentiate between shedding of live bacteria and DNA from dead organisms.

Horses are not considered to be carriers per se of Salmonella, because no host-adapted Salmonella species have been identified in horses. Salmonella Abortus equi has now disappeared in the United States. Horses that shed Salmonella species in the feces usually do so transiently for several days to weeks; infrequently horses may shed salmonella bacteria for several months.

In acutely affected horses, large numbers of highly infective salmonellae can be shed in the diarrheic feces. Susceptible animals such as young foals, hospitalized horses receiving antimicrobial drugs, and horses under stress can become ill after becoming infected by numbers of salmonellae 100 to 1000 times less than those required to infect immunocompetent normal horses. Thus particular care should be taken in the management of horses and foals with diarrhea in environments in which there are animals at risk (e.g., hospitals, breeding farms, racetracks). Asymptomatic shedders generally pass relatively small numbers of salmonellae in the feces and do not appear to pose an important threat to healthy horses, although asymptomatic shedders have been responsible for outbreaks of salmonellosis in hospitals and on breeding farms.

Clinical Findings

Salmonellosis typically is characterized by an acute colitis that results in profuse diarrhea and occasionally abdominal pain. Horses with salmonellosis often have signs of sepsis associated with endotoxemia and suffer from cardiovascular shock, vascular leak syndrome, and coagulopathies. Horses are usually febrile, tachycardic, moderately to severely obtunded, and dehydrated. With other clinical syndromes of salmonella infection, diarrhea is not a feature. These syndromes include fever and leukopenia, colic, and proximal enteritis with gastric reflux.

Diagnosis

Confirmation of salmonellosis requires bacteriologic culture of Salmonella bacteria. Multiple fecal cultures for Salmonella species should be performed on all horses with diarrhea. It is recommended that at least three to five fecal samples collected 12 to 24 hours apart be submitted to increase the sensitivity of culture.⁷²⁹ Samples with little solid matter often yield negative culture results, even when the horse is infected with Salmonella. Formed fecal samples are more likely to result in a positive culture result from infected horses. A 5- to 10-g amount of feces should be submitted for culture in selective media such as tetrathionate broth or selenite broth and brilliant green agar or XLD agar. Culture of a rectal mucosa biopsy may be a useful adjunctive test for Salmonellosis. PCR is a sensitive screening tool for detection of fecal Salmonella DNA and is important for environmental monitoring and biocontrol measures in hospitals.

Treatment and Prevention

In most cases of salmonellosis, aggressive treatment facilitates resolution of the severe diarrhea and associated metabolic disorders within 7 to 10 days of the onset of illness. Intravenous administration of polyionic fluids is required to replace fluid and electrolyte losses and to augment preload in horses with poor venous return (see the Fluid Therapy for Horses with Gastrointestinal Diseases section [p. 767] and Chapter 44 for more comprehensive information about fluid therapy in horses with diarrhea). Plasma may be required to replace lost plasma proteins and increase plasma colloidal pressure. Alternative colloidal fluids, such as hetastarch, may be quite useful and more cost-effective than plasma in horses with vascular leak syndrome and hypoproteinemia. Flunixin meglumine is often used to treat inflammation in horses with signs of sepsis. Flunixin and other NSAIDs should be used with caution and at the lowest dose possible to prevent worsening of colonic mucosal damage or inhibition of mucosal repair. Other antiinflammatory strategies may be used to treat sepsis associated with salmonellosis. Total or partial parenteral nutritional support is often indicated to provide adequate calories and amino acids during the most debilitating period of the illness. Antimicrobial administration to horses with suspected or known salmonellosis is not universally practiced. Antimicrobial administration may decrease the spread of salmonella bacteria to other organs and may have some direct effect on salmonella bacteria in the colon. Traditionally, use of antimicrobial drugs such as chloramphenicol, trimethoprim-sulfa (TMS), gentamicin, and cephalosporins has not appeared to accelerate resolution of signs of colitis. Fluoroquinolones, such as enrofloxacin, although potentially arthropathic in young horses, may be more effective because of high lipid solubility and bactericidal activity against Salmonella bacteria.

Horses that have severe diarrhea and sepsis for 10 days or longer are unlikely to survive, even with intensive therapy, because they often have extensive ulceration of colonic mucosa and chronic, severe inflammation within the wall of the colon. Ulceration may be exacerbated by administration of NSAIDs. Complications such as catheter-associated thrombophlebitis, colonic infarction (Fig. 32-55), colonization of other organs by salmonellae or other enteric bacteria, and laminitis can occur.

Fig. 32-55 Colonic infarction in a horse with salmonellosis. Tenesmus and rectal prolapse were early clinical signs of colonic infarction.

Courtesy of Dr. M.J. Murray.

Measures designed to prevent the spread of Salmonella in an environment with potentially susceptible hosts need not be excessively laborious or expensive. The goal is to minimize the size of the infective dose of an enteric pathogen to which a susceptible host may be exposed. Thorough cleaning of areas where fecal contamination is likely and prevention of mechanical distribution of contaminated material are the most important measures that should be taken. Extensive use of disinfectants may not be necessary if cleaning measures are adequate. Cleaning must include removal of organic debris, which can be accomplished with several products designed for that task. Areas that require particular attention are stalls, including water buckets or automatic watering systems, drains, and cracks in the floors and wall; stall implements; surgical areas, including drains; and nasogastric tubes and pumps.

If a diarrheic horse is in the environment, it should be isolated to the degree possible. Bedding material should be removed frequently to minimize accumulation of potential enteropathogens. Personnel entering the stall should be restricted to the professional staff, and they should wear disposable plastic boots. Footbaths with disinfectant often are not effective because they quickly accumulate organic material that interferes with the disinfectant activity of the footbath. Once a horse vacates a stall, the stall should be thoroughly cleaned, allowed to dry, disinfected, and determined to be negative for Salmonella by culturing selected sites in the stall (floor, drain, waterer). Personnel should use common sense when dealing with diarrheic animals. If bedding is being blown about by wind or if mechanical blowers are used to clean aisles, then potential enteric pathogens may be readily spread to other horses.

Potomac Horse Fever

PHF is an infectious enterocolonic disorder caused by N. risticii (formerly Ehrlichia risticii).^730,731 The organism is an obligate intracellular parasite, infecting peripheral monocytes and macrophages, colonic and small intestinal epithelial cells, and colon mast cells.⁷³² The pathophysiology of the disease is incompletely understood, although horses infected with N. risticii often have clinical signs and complications similar to those in horses with salmonellosis. After experimental inoculation with N. risticii horses had a mild, transient fever 2 to 4 days after infection.⁷³³ By 10 to 14 days after experimental infection horses became febrile, had a poor appetite, and exhibited mild to severe gastrointestinal signs ranging from mild colic and soft stool to profuse diarrhea.

In clinical cases of PHF, there are signs of sepsis, including fever, leukopenia, congested mucous membranes, and hypercoagulability. The early fever observed in experimental cases is usually not detected by owners, and when clinical signs are seen it is presumed that the horse was infected 10 to 14 days previously. Hypoproteinemia is a frequent finding in horses with clinical cases of PHF, which reflects loss of serum prote in through inflamed intestinal mucosa. It is interesting to note, however, that the magnitude of intestinal inflammation is typically much less than with salmonellosis, yet the magnitude of hypoproteinemia (total protein <3 g/dL) can be as severe.

Laminitis is a frequent sequela and may occur in 30% in horses with PHF. N. risticii has also been associated with abortion in mares, although this is an unusual occurrence.⁷³⁴ In some horses that show significant seroconversion to N. risticii, laminitis is the only clinical sign.

Mode of Transmission

Although originally described as a disease of horses living near the Potomac River in Maryland and Virginia, horses with serologic evidence of exposure to N. risticii have been reported in most states. Because early research on PHF demonstrated that infection was readily transmitted through blood,⁷³³ it was presumed that the natural mode of transmission involved an insect or arthropod vector. However, several studies have failed to demonstrate any such vectors.^735,736

The association between an affected horse and proximity to a river (within 5 miles) remains strong. Recently investigators have found a possible link between this association and how the disease may be transmitted. N. risticii and Neorickettsia helmintheca were found to share a high degree of DNA homology.⁷³⁷N. helmintheca is transmitted to mammals via a trematode that parasitizes fish and aquatic snails.⁷³⁷ This prompted investigators to search for evidence that N. risticii might reside in trematodes and their hosts found in riverine inhabitants. N. risticii DNA was detected in operculate snails (Pleuroceridae: Juga species) collected from stream water in a northern California pasture in which PHF is enzootic.⁷³⁸ Moreover, N. risticii was detected in trematode stages found in the secretions of freshwater snails and in aquatic insects.^739,740 The sequences of these genes were virtually identical to those of the genes of an equine N. risticii strain isolated from horses located on a property near the snail collection site. Further work demonstrated N. risticii DNA in two trematodes. Acanthatrium species and Lecithodendrium species, found in bats and swallows, suggesting that these animals may serve as a reservoir for the organism.⁷⁴¹ Oral transmission of N. risticii with infected cell cultures has been produced experimentally,⁷⁴² supporting a role for ingestion of N. risticii, rather than blood transmission, as the route of natural infection. Oral transmission and clinical signs of PHF were demonstrated in horses fed infected aquatic insects (caddis flies), suggesting that ingestion of infected aquatic insects may be the natural route of infection.^743,744 Ingestion of water containing infected trematode stages released from aquatic snails may also be a route of infection.