Can Vet J Volume 47, June 2006 551

Equine gastrointestinal motility ileus and

pharmacological modification
Judith Koenig, Nathalie Cote
Abstract Colic is a common problem encountered in equine practice. Alteration of gastrointes-
tinal motility is often the underlying cause for abdominal pain. Gastrointestinal motility can be
measured as myoelectric activity, mechanical activity, and transit of intraluminal contents. Regulation
of motility is based on a complex interaction between central innervation, autonomic innervation,
and the enteric nervous system. Various humoral and neurochemical substances are required to inter-
act flawlessly to allow propulsive motility. Ileus is defined as the absence of propulsive aboral move-
ment of gastrointestinal contents, irrespective of its pathophysiology. Potential etiologies for ileus
are described in this review. The prokinetic drugs available for clinical use are discussed. Choosing
the appropriate prokinetic drug requires knowledge about the complex nature of gastrointestinal
motility and its abnormalities.
Rsum Blessures par piquants de porcs-pics chez le chien : rtrospective de 296 cas
(19982002). Le but de cette tude rtrospective tait didentifier les facteurs associs aux blessures
par piquants chez les chiens. Un deuxime objectif tait de dterminer le risque de complications et
tout facteur pouvant aider prvoir le risque de complications. Les dossiers mdicaux de 296 blessures
par piquants de porcs-pics chez le chien ont t tudis entre 1998 et 2002. On a constat une augmen-
tation de lventualit dune rencontre avec les porcs-pics au printemps et en automne; les Huskies
sibriens, Rottweilers et Bergers allemands de races croises taient significativement plus risque
dtre blesss par les piquants. Il ny avait pas dassociation entre le risque de complications et le nom-
bre de piquants ou lutilisation dantimicrobiens. Laugmentation de la priode de temps coule entre
la blessure par piquants et la prsentation tait associe un risque accru de complications. cause de
laugmentation de la frquence des complications relies lallongement de lintervalle entre la blessure
et la prsentation, les clients devraient tre fermement encourags apporter leur chien ds quils
saperoivent de lincident. Les chiens prsents aprs 24 h devraient tre troitement surveills au
cours des 3 semaines suivantes puisque la majorit des complications surviennent ce moment.
(Traduit par Docteur Andr Blouin)
Can Vet J 2006;47:551559
REVIEW ARTICLE COMPTE RENDU
Introduction
G
astrointestinal propulsive motility depends on a
complex interaction between neural, hormonal,
vascular, and neuromuscular pathways. Disruption of this
intricate interaction leads to stasis of aboral movement
of food material, also called ileus. Unfortunately, this is
a common and often fatal problem in the horse. A variety
of prokinetic agents have been used in the horse with
variable success. Choosing the appropriate prokinetic
drug requires knowledge about the physiology and
pathology of equine gastrointestinal motility. Also, one
needs to know the mechanism of action and potential
efficacy of the drug chosen to treat a particular form of
ileus. The purpose of this paper is to review the current
literature and summarize up-to-date information on the
physiology, pathology, and treatment of ileus.
Materials and methods
Literature searches were carried out using the advanced
search options of the new PubMed system of the
National Center for Biotechnology Information (NCBI)
at the National Library of Medicine (NLM), USA
(19662004/06). Further literature searches were
conducted in the Veterinary Science Database (CAB
International, Ovid Technologies, Boston, Massachusetts,
USA) by using search and retrieval software (WinSPIRS,
version 2.0; SilverPlatter International, N.V. [1973
2004/05], Ovid Technologies, Boston, Massachusetts,
USA). Keywords originally used were combinations
of equine or horse with ileus, gastrointestinal
motility, prokinetic, or intestine. Upon evaluation of
articles published relevant to equine motility and related
topics, the literature search was extended to include the
gastrointestinal physiology, pathophysiology, and phar-
macology of other species. Also, textbooks were used
Ontario Veterinary College, University of Guelph, Guelph,
Ontario N1G 2W1.
Address all correspondence to Judith Koenig; e-mail:
jkoenig@ovc.uoguelph.ca
Reprints will not be available from the authors.
552 Can Vet J Volume 47, June 2006
to retrieve information that would help readers to better
understand or elucidate the subject.
Physiology
1. Normal gastrointestinal motility patterns
The net movement of intraluminal contents is defined by
gastrointestinal motility. Assessing gastrointestinal motil-
ity accurately in vivo can be quite challenging. Three
basic parameters of gastrointestinal motility can be mea-
sured: myoelectric activity, mechanical activity, and
transit of intraluminal contents. Myoelectric and mechan-
ical activities are indirect measures of gastrointestinal
motility, but they do not always accurately correlate with
the transit of intraluminal contents (1).
Two types of myoelectric activity have been described
slow waves and spiking activities. Slow waves (basic
electrical rhythm, electrical control activity, pacesetter
potential) are subthreshold electrical potentials that do
not cause smooth-muscle contractions (2). These slow
waves maintain the contractile excitability of smooth
muscle. Spiking activities (intermittent electrical
response activity) are action potentials superimposed on
the slow waves and result in intestinal contractions (2,3).
These spikes assume various patterns, depending on the
species and the area of the gastrointestinal tract.
In most species, the migrating myoelectric complex
(MMC) is a myoelectric pattern found in the stomach
and small intestine many hours after a meal (interdiges-
tive state) or during fasting. In horses, the MMC is
always present (3,4). In most species, there is a differen-
tiation in motility pattern between fasted and fed states.
That, however, does not apply in horses (4). Some authors
believe that the relatively small equine stomach (com-
pared with that of most monogastric animals) and the
greater frequency of food intake are responsible for this
lack of differentiation (4).
The MMC is cyclic with 3 phases: phase 1 is a period
of no spiking activity; in phase 2, there is intermittent
spiking activity; and in phase 3 regular spiking activity
occurs (5). Some authors have described a phase 4 activ-
ity that consists of a bridging irregular phase separating
phase 3 from phase 1 (6,7). Smooth muscle contractions
are correlated with phase 2 and 3 (5,8). In fasted ponies,
the stomach contracted 2 to 3 times per minute during
periods of phase 3 (8). When the stomach was inactive
(phase 1), the duodenum and jejunum were in phase 3
(8,9). As the ileum entered phase 3, its contractions
became longer in duration (mean, 45 min) than those in
the jejunum (mean, 8 min). This is unique in horses and
proposedly aids in maintaining homeostasis and in trans-
ferring ingesta as quickly as possible to the cecum and
colon (4). The intense phase 3 spiking activity in the
ileum, sometimes referred to as the migrating action-
potential complex (MAPC), immediately precedes cecal
myoelectric activity 72% of the time. This myoelectric
coupling of the ileum and cecum is suspected to facilitate
rapid transit of ingesta (10).
In the cecum, as measured with an intraluminal pres-
sure system, frequent low-amplitude peaks were seen in
the cecal base and body, consistent with a haustra-to-
haustra mixing pattern. Once every 22 min, coordinated
pressure peaks originated in the cecal body and pro-
gressed to the cecal base, or vice versa. During this
event, the right ventral colon remained quiet. Once every
3 min, concurrent with a loud rush on auscultation,
aborally-propagating progressive pressure peaks occurred
in the cecal base, cecocolic orifice, and adjacent right
ventral colon. This pattern, which appeared to originate
from a pacemaker in the cecal body, resulted in move-
ment of ingesta from the cecum into the colon at approx-
imately 4 cm/s (4,11). Retropulsive pressure peaks,
originating from a hypothetical pacemaker in the pelvic
flexure and ending at the cecocolic orifice, were also
reported (11). Another group used endoscopy through a
cecal cannula, as well as cinefluoroscopy, to evaluate
motility of the cecum and right ventral colon. They
described movement of cecal contents from the body to
the cupola, followed by simultaneous contraction of the
cupola and elevation and opening of the cecocolic ori-
fice, which allowed outflow of ingesta into the right
ventral colon (12,13). The motility pattern described for
the cecum (cecal myoelectric complex) and colon was
later confirmed in another study in which electrodes
surgically implanted on the ileum, base of the cecum,
and pelvic flexure were used (7,14).
Other groups investigated equine colonic myoelectric
activity by using electrodes surgically fixed to the serosa
in the pelvic-flexure region (15) and the ileum, cecum,
and right ventral colon (14). They reported aborally
migrating long-spike-burst (LSB) complexes that
occurred sporadically for up to 8 min, aborally migrating
LSB and short-spike-burst (SSB) complexes that lasted
up to 5 min (slowly migrating cluster of short and long
SSBs [SMC]), series of propagated spike bursts (termed
colonic migrating myoelectric complex CMMC), and
single sporadic LSBs that traveled both orally and
aborally from the pelvic flexure (15). The presence of a
pacemaker in the pelvic flexure was later confirmed:
Investigators reported an increased neuronal density and
a 10-fold increase in neurons reactive to vasoactive
intestinal peptide (VIP) at the pelvic flexure (16).
However, the pelvic flexure may not be the only pace-
maker site in the large intestine: Throughout the colon,
LSBs were observed traveling orally and aborally (15).
Myenteric-plexus and neuron density was increased not
only in the pelvic flexure but also in the left dorsal and
transverse colon, when compared with the colon as a
whole (17). Coupling of ileal, cecal, and proximal colonic
myoelectric activity has been suggested, since ileal
MAPCs were frequently followed by the so-called cecal
myoelectric complex, which propagated rapidly over the
cecal base and continued into the right ventral colon as
CMMC (11,14). The small colon has also exhibited
motility and myoelectric patterns similar to those
described for the pelvic-flexure region of the large colon
(8). Myoelectric and mechanical activities are closely
related; however, transit of intraluminal contents does
not always correlate with them (3).
2. Regulation of gastrointestinal motility
Visceral smooth muscle is unitary or syncytial smooth
muscle (18). When an action potential is elicited any-
where within the muscle mass, it travels in all directions.
The normal slow-wave or resting potential of visceral
smooth muscle is between -50 and -60 millivolts (mV).
Can Vet J Volume 47, June 2006 553
Smooth-muscle contraction occurs when the cell-membrane
potential rises to threshold at about -40 mV (18).
Contraction results from an increased concentration of
calcium in the cytoplasm (19). Calcium entry into the
muscle fibers is regulated by the protein calmodulin
(18). Two mechanisms are known to cause an increase
of cytoplasmic calcium. Electromechanical coupling
occurs when depolarization of the cell membrane results
in calcium influx in response to acetylcholine (ACh),
and pharmacomechanical coupling occurs secondary to
receptor interaction and is independent of the membrane
potential (19).
In general, regulation of motility occurs as a complex
interaction of central innervation, autonomic innervation,
and the enteric nervous system. However, control of
intestinal contractions by the enteric nervous system is
independent of the central nervous system (18). The
enteric nervous system is a collection of neurons in the
gastrointestinal tract that control motility, exocrine and
endocrine secretions, and microcirculation (20). It con-
sists of the myenteric (Auerbachs) plexus and the sub-
mucosal (Meissners) plexus. The myenteric plexus lies
between the longitudinal and circular layers of smooth
muscle and extends the entire length of the gut. It primar-
ily provides motor innervation to the 2 muscle layers and
secretomotor innervation to the mucosa (17,20). There
are also a substantial number of connections from the
myenteric plexus to submucosal ganglia and sympathetic
ganglia (20). The submucosal plexus, located between
the circular muscle layer and the muscularis mucosa, is
best developed in the small intestine and mainly controls
secretion (18).
The enteric nervous system influences the gastro-
intestinal tract either directly through neurotransmitters
or indirectly through intermediate cells, such as the
interstitial cells of Cajal, cells of the immune system, or
endocrine cells (20). In humans, the interstitial cells of
Cajal are electrically coupled with smooth-muscle cells
and are believed to be responsible for the rhythmicity of
slow-wave activity (5). Similarly, in horses, baseline
myogenic activity appears to be initiated through the cells
of Cajal, independent of sympathetic and parasympa-
thetic input, since baseline myogenic response in the
equine jejunum was minimally affected by adrenergic
and cholinergic blockade (21). In the horse, the location
of the interstitial cells of Cajal varies between segments
of intestine: in the small intestine, they are located pre-
dominantly at the level of the myenteric plexus, whereas
in the large intestine, they are found mainly in the circu-
lar muscle layer. Also, the highest densities of interstitial
cells of Cajal are found in the ileum, pelvic flexure and
cecum (22). When the equine interstitial cells of Cajal
had been damaged, for example, due to grass sickness,
a reduced slow wave frequency of the small intestine was
observed in vitro (23).
The parasympathetic and sympathetic nerves connect
the enteric nervous system to the central nervous system.
In humans, the intensity and frequency of intestinal
contractions is influenced by the parasympathetic (via
vagus and pelvic nerves) and sympathetic (via cranial
and caudal myenteric plexus) nervous systems and by
hormones (18). Acetylcholine (ACh) is the main excit-
atory neurotransmitter in the gut of all species. It pro-
motes contraction through muscarinic type-2 receptors
on the smooth-muscle cell (24). Interestingly, ACh can
also relax circular smooth muscle, when the smooth-
muscle tone is very high. This inhibitory response may
be caused by ACh stimulating the release of nitric oxide
from enteric neurons (25). Sympathetic stimulation
inhibits ACh release from the cholinergic fibers, via
activation of alpha-2 adrenergic receptors located pre-
synaptically on cholinergic neurons in the enteric ganglia
(26). However, alpha-2 agonists have also been reported
to induce contraction in longitudinal smooth-muscle
strips from the equine jejunum (21). Tetrodotoxin, a
neural sodium-channel blocker, prevented this alpha-2
agonist-mediated contraction. Since alpha-2 receptors
are located presynaptically, they are able to regulate not
only the release of ACh, but also the release of other
neurotransmitters. Therefore, apparently a different neu-
rotransmitter was being released by the presynaptic
alpha-2 agonists. Also alpha-1, beta-1, and beta-2 recep-
tor stimulation was shown, in an equine in vitro model,
to decrease jejunal myogenic activity (21). Norepineph-
rine was shown, in an in vitro study, to be another impor-
tant neurotransmitter in the enteric nervous system of
horses, causing relaxation of jejunal smooth muscle
strips. However, it was also shown that high tone circular
or high-intensity stimulated longitudinal muscle strips
from the equine jejunum are able to contract in response
to norepinephrine (21).
The presence of nonadrenergic-noncholinergic neuro-
transmitters in the enteric nervous system was confirmed
by subjecting circular and longitudinal smooth-muscle
strips from the equine jejunum to electric-field stimula-
tion when the adrenergic- and cholinergic-receptors were
blocked (25). Inhibitory nonadrenergic-noncholinergic
neurotransmitters in the gastrointestinal system of horses,
namely adenosine triphosphate (ATP), vasoactive intes-
tinal peptide (VIP), and nitric oxide, have been shown
to be responsible for relaxation of circular and longi-
tudinal smooth muscle strips in vitro (24). In circular
smooth-muscle strips from the equine ventral colon
that were subjected to electric-field stimulation, nitric
oxide and an apamin-sensitive neurotransmitter inhibited
contraction (27). Substance P, another nonadrenergic-
noncholinergic neurotransmitter, was recently shown
in horses to cause relaxation or contraction of jejunal
smooth muscle, depending on the amount of stimula-
tion and orientation of the smooth muscle (28). Possibly,
substance P is also involved in contraction of the large
colon (24).
Ileus
1. Pathophysiology of ileus
Gastrointestinal ileus has been defined as the functional
inhibition of propulsive intestine activity, irrespective
of its pathophysiology (24). The terminology used to
describe the different clinical manifestations of motility
disorders in the horse is confusing, with the terms ileus,
postoperative ileus, endotoxemic ileus, idiopathic ileus,
and adynamic ileus being used inconsistently in the
literature (29). In humans, when using the duration of
clinical signs for classification, ileus can be character-
ized as either adynamic (30), resulting from short-term
554 Can Vet J Volume 47, June 2006
alterations of gastrointestinal motility, or paralytic,
when motility is lost for longer than 72 h (31). Ileus
can develop from diseases directly involving the diges-
tive system, or it can be a consequence of diseases in
other body systems, such as trauma to retroperitoneal
structures or irritation of the peritoneum (32). Shock;
electrolyte imbalances; hypoalbuminemia; peritonitis;
endotoxemia; and distension, ischemia, or inflamma-
tion of the intestinal tract have all been implicated as
contributing to the pathophysiology of ileus in the horse
(8,3335).
Postoperative ileus (POI) has been well documented
as occurring after laparotomy in humans (30) and horses
(36). In one study, 21% (31/148) of horses that underwent
surgical treatment of colic developed POI, which was
fatal in 13% (4/31) of these cases. These horses were
either euthanized due to severe colic or died because of
a ruptured stomach. Horses with evidence of shock (high
pulse rate, hemoconcentration, and high glucose concen-
tration) and small-intestinal obstruction, with or without
intestinal ischemia, were predisposed to the development
of POI (34). In another study, 18% (69/376) of horses
undergoing colic surgery developed POI. Sixteen percent
of the POI cases (11/69) died, compared with 6%
(18/307) fatality in horses without POI. Among horses
undergoing colic surgery, those in which a small-
intestinal resection and anastomosis were performed had
an even greater risk of POI (42% of horses with anasto-
mosis developed POI) (33). In an experimental model of
POI in ponies, using jejunal trauma to create ileus, elec-
trical activity was decreased and the normal synchrony
of gastric and duodenal MMCs was disrupted. Corre-
sponding with the decrease in myoelectric activity, gas-
trointestinal transit time also increased (36).
Many potential etiologic agents have been investigated
to determine a cause for the development of POI. An
imbalance between sympathetic and parasympathetic
nervous-system input to the intestine has been postulated
as an underlying cause. Sympathetic (adrenergic) hyper-
activity results in reduction of propulsive motility, and an
increase in sphincter tone. Parasympathetic (cholinergic)
hypoactivity results in a decrease in gastrointestinal
motility (21,32,36). Following intestinal surgery in
humans, increased circulating levels of epinephrine and
norepinephrine have been observed. In such patients,
dopamine infusions have also been noted to suppress
intestinal activity (32). In a model of POI in rats, where
mechanical trauma to the small intestine and cecum
was used, reserpine (depletes catecholamine stores) and
L-nitroarginine (nitric-oxide synthase inhibitor) com-
pletely reversed the inhibition of ingesta transit. This
finding supported the involvement of adrenergic and
nitrergic neurons in the pathogenesis of POI (37). A
model of POI in horses was used to assess the effects of
specific adrenergic blockade (propanolol, yohimbine),
parasympathetic stimulation (bethanechol), and dopa-
minergic antagonism (metoclopramide) (36). However,
only a small number of horses were used and the protocol
throughout the study was altered, so the results of this
study might have been different with a larger number of
animals. Propanolol did not improve motility. Yohimbine
alone and in combination with bethanechol improved
intestine activity moderately, confirming some adren-
ergic hyperactivity in the development of POI (38). The
best results were achieved with metoclopramide, reveal-
ing dopaminergic involvement as well. It is likely that
abnormalities of the enteric nervous system and damage
to muscle cells generating slow waves also contribute
to the development of ileus, since severance of the
autonomic nervous system does little to alter motility
(3842).
Endotoxemia has been shown to be involved in the
development of POI. In healthy ponies, IV infusion of
endotoxin at 0.1 g/kg body weight (BW) resulted in
inhibition of motility in the stomach, left dorsal colon,
and small colon. However, no nasogastric reflux was
observed. Although motility in the small intestine was
increased, its myoelectric pattern was abnormal. Similar
effects on motility were observed after IV infusion of
prostaglandin E
2
(PGE
2
). These findings led to the con-
clusion that the effects of endotoxin on motility were
partially mediated by PGE
2
(8), possibly stimulating
alpha-2 adrenergic receptors (43). In a later study, it was
shown that a cumulative dose (0.03 mg/kg BW) of endo-
toxin administered over 1 h resulted in cecal and proxi-
mal colonic ileus (44). Intestinal motility was restored
when yohimbine (0.75 g/kg BW) was administered at
the same time as the endotoxin. The authors concluded
that ileus caused by endotoxemia is at least partially
mediated through alpha-2 adrenergic receptors, due to
either increased sympathetic nerve activity or circulating
catecholamines stimulating alpha-2 adrenergic receptors,
modulation of arachidonic acid metabolism to inhibitory
prostaglandins via alpha-2 adrenergic receptors, or pre-
vention of opioid-mediated inhibition of intestinal motil-
ity via alpha-2 adrenergic receptor blockade. Pretreatment
with phenylbutazone, a cyclooxygenase inhibitor, abol-
ished the effects of endotoxin on gastrointestinal motility
in horses (45), further implicating a PGE
2
pathway. A
platelet-activating-factor (PAF) antagonist also sup-
pressed some of the endotoxin-induced inhibition of
motility in horses. Therefore, a PAF may play some role
in the development of POI (46).
Since PGE
2
and PAF are both inflammatory mediators,
ileus may be triggered by endotoxin but actually induced
by inflammation in the intestinal smooth muscle. This
inflammation could also affect the cells of Cajal and thus
alter normal myoelectric patterns. In a recent investiga-
tion in rats, surgical manipulation caused a leukocytic
inflammatory response within the intestinal muscularis
externa, with suppression of smooth muscle contractions.
This suppression of motility was prevented by the admin-
istration of adhesion-molecule antibodies, which
decreased extravasation of leukocytes. The authors con-
cluded that inflammation must contribute significantly
to the development of POI in this model (47). In another
study (48), the investigators concluded that ileus might
actually be triggered by a primary disturbance of the
smooth muscle itself. A portion of equine jejunum was
subjected to ischemia for 60 min: Jejunal segments adja-
cent to the ischemic area had decreased contractility and
relaxation when stimulated with an electrical field or
with norepinephrine, even though histologically there
were no signs of inflammation. When these segments
were stained to determine neurotransmitter content, they
appeared similar to healthy equine jejunum. Since there
Can Vet J Volume 47, June 2006 555
was no evidence of inflammation or altered neurotrans-
mitter release, a possible rationalization is that the
muscles ability to contract may have been affected or
that the number of smooth muscle or neuronal receptors
had changed (48). In smooth-muscle strips from inflamed
rabbit colon, it was demonstrated that a decrease in
motilin-induced contractility was caused by a decrease
in the number of motilin receptors (49). A study on
inflammatory intestine disease in humans showed that
substance-P receptors were increased in neurons of the
myenteric plexus (50). The effects of inflammation on
intestinal smooth muscle or on the enteric nervous sys-
tem may best explain the development of POI or other
forms of ileus common to the horse. Further research to
investigate the role of up- or down-regulation of recep-
tors in the myenteric plexus, as well as changes in the
smooth muscle, is needed to better understand the patho-
physiology of ileus in the horse.
One of the most challenging aspects of POI in horses
is the occurrence of cecal impactions, partly because the
pathophysiology of cecal motility dysfunction is not
known (24,5153). Cecal impaction occurs more com-
monly after orthopedic procedures (54). The effects of
general anesthesia have been thought to initiate cecal
impaction. However, when myoelectric activity was
evaluated in horses using 3 different general-anesthetic
regimens, effects on intestinal motility disappeared com-
pletely within 9 h after anesthesia ended (55). Therefore,
general anesthesia appears to be a less likely primary
cause of cecal motility dysfunction. On the other hand,
horses undergoing orthopedic surgery lasting over 1 h
without the administration of phenylbutazone were at
much higher risk of developing decreased fecal output
(54). Perhaps persistent pain after orthopedic procedures,
resulting in sympathetic overstimulation, is a significant
contributing factor (24). It was demonstrated that
NSAIDs reduced the contractility of equine colonic
muscle strips (56). However, flunixin reportedly had no
effect on the clearance of radiolabeled markers from the
cecum, and induced only an isolated increase in myo-
electric activity in the right ventral colon (26). On the
other hand, flunixin was administered only as a single
dose in this study, and horses developing cecal impac-
tions have usually been treated with NSAIDs for a longer
period of time.
Certain classes of drugs can induce ileus. Activation
of presynaptic alpha-2 adrenergic receptors within the
enteric nervous system inhibited ACh release from cho-
linergic neurons, thereby suppressing intestinal contrac-
tions in normal ponies (26). In horses, IV administration
of xylazine, an alpha-2 adrenergic agonist, resulted in a
significant reduction of duodenal (57), jejunal (58), and
cecal and colonic motility (55,58), and detomidine, a
more-potent alpha-2 adrenergic agonist, was also more
potent in suppressing motility in the duodenum and large
intestine (24,57).
The effect of butorphanol, an opioid agonist-antagonist,
on equine intestinal motility is controversial. In one
study, butorphanol decreased MMC activity in the jeju-
num but did not affect the pelvic flexure (59), whereas
in another study, butorphanol had no effect on either
gastric or duodenal activity (9). Thus, it appears that
there is variability in the response of different intestine
segments to opioids. When xylazine and butorphanol
were given to horses as a combination, duodenal motility
was decreased for up to 1 h (57); however, this decrease
in motility, may have contributed to the xylazine or to a
synergistic effect of the 2 drugs.
Metabolic abnormalities, such as hypokalemia, hypo-
calcemia, and uremia, have been implicated in the patho-
physiology of ileus in humans and other animals, but
little to no information is available on horses (24). In
sheep and cattle, experimentally induced hypocalcemia
depressed intestinal mechanical activity. As calcium
levels progressively dropped, mechanical activity also
decreased, until stasis occurred (3). Analysis of serum
ionized-calcium concentrations in 147 horses with either
nonstrangulating obstruction of the colon or infarction
of the small intestine, cecum, or colon showed that all of
these animals had low calcium levels before and after
surgery (60). The importance of extracellular and intra-
cellular calcium for intestinal smooth-muscle contraction
has been described for other species (18,19,61).
2. Prokinetic drugs for the treatment of ileus
Cholinomimetics Cholinomimetic or parasympatho-
mimetic agents increase ACh either by stimulating ACh
receptors (directly acting parasympathomimetic agents)
or by inhibiting cholinesterase (indirectly acting para-
sympathomimetic agents) (62).
Bethanechol chloride, a directly acting parasympatho-
mimetic agent, is a muscarinic-receptor agonist that
causes contraction of smooth-muscle cells in the gastro-
intestinal and urinary tracts (43). In healthy horses,
bethanechol (0.025 mg/kg BW, IV) significantly hastened
gastric emptying of liquid and solid-phase radiolabeled
markers (63). The only side effect reported in this inves-
tigation was increased salivation. In another study on
normal horses, bethanechol (0.025 mg/kg BW, IV) has-
tened cecal emptying and increased myoelectric activity
in the ileum, cecum, and right ventral colon (26). In these
latter horses, however, side effects included both
increased salivation and mild abdominal pain. In an
equine model of POI, bethanechol accelerated the pas-
sage of orally administered plastic beads being used as
transit markers and improved myoelectric activity in the
stomach, jejunum, ileum, and large and small colon.
However, bethanechol did not improve gastroduodenal
coordination (36). Salivation is the most common side
effect noted, but some animals seem to tolerate it well.
Neostigmine methylsulfate, an indirectly acting para-
sympathomimetic agent, is a cholinesterase inhibitor that
prolongs the activity of ACh by retarding its breakdown
at the synaptic junction (43,62). Neostigmine has been
shown to delay gastric emptying and decrease jejunal
myoelectric activity, but to enhance pelvic flexure activ-
ity in healthy ponies (32,58). In another study, neostig-
mine improved cecal emptying and increased mechanical
and myoelectric activity in the ileum, cecum, and right
ventral colon (26). Although neostigmine has been ben-
eficial in the treatment of reflux esophagitis in humans,
it has also increased gastric secretion, delayed gastric
emptying, and caused abdominal pain. Therefore, it is
not frequently used in humans (62). Based on clinical
impressions, neostigmine can effectively reduce POI in
the horse, especially when the large colon is involved. In
556 Can Vet J Volume 47, June 2006
a survey that evaluated the use of prokinetic therapy,
neostigmine (5 to 10 mg, IM or SC) was the most com-
monly selected prokinetic for treatment of large colon
impactions (64). However, monitoring the patient for any
adverse effects is advised (40).
Adrenergic antagonists Alpha-2 antagonists are
sympatholytic agents that block alpha-2 receptors within
the enteric nervous system and allow release of ACh from
cholinergic neurons (65). Yohimbine increased myoelec-
tric activity in the right ventral colon and cecum of
healthy ponies, but it did not significantly affect cecal
emptying time (26). Although yohimbine was moderately
successful in improving myoelectric and mechanical
activity in an equine model of POI, normal motility was
not restored (36). Based on reports in the literature, little
is known about the effectiveness of yohimbine for treat-
ment of equine POI. Further research is required before
recommending it for use as a prokinetic drug in horses.
Phenoxybenzamine (200 mg diluted in 500 mL sodium
chloride) was administered, IV, and repeated (if no
improvement of clinical signs occurred) to 12 horses
that had developed ileus either after surgery for colic
or secondary to inflammatory intestinal disease. In all
12 horses, the amount of nasogastric reflux decreased in
proportion to increases in the dose of phenoxybenzamine
(66); however, as there were no control animals, it could
not be determined if the improvement was due to the
phenoxybenzamine or from time and other supportive
therapy.
Phenothiazines, a group of peripheral alpha-adrenergic
antagonists, are used in humans for treatment of POI
with variable success (65). Acepromazine was shown to
reduce myoelectric activity in the equine small intestine,
but intestinal transit of fluids became more rapid (67).
Based on clinical impressions, acepromazine was thought
to reduce POI (40), but there was no solid scientific
evidence to support this theory.
Benzamides Benzamides possess 5-hydroxytryptamine
(5-HT, serotonin) antagonist and agonist properties
on 5-HT
3
and 5-HT
4
receptors, respectively (65). Their
prokinetic activity seems to result from neuronal 5-HT
4

agonism, enhancing cholinergic transmission in the
myenteric plexus (37).
Metoclopramide has the 5-HT receptor properties
described above. It also has an antagonistic effect on
dopaminergic DA
2
receptors and obstructs the inhibi-
tory effect of dopamine on gastrointestinal smooth
muscle (68). In a model of POI in the horse, continuous
infusion of metoclopramide restored coordinated gas-
troduodenal activity and gastrointestinal ingesta transit.
However, the presence of dopamine receptors in the
equine gastrointestinal tract has not been documented
(29). Unfortunately, horses showed transient excitement
after the administration of metoclopramide (36). Similar
side effects, such as sweating, excitement, and restless-
ness, have been well documented in humans (65). In a
retrospective study in other horses, the clinical use of
metoclopramide (administered as a continuous infusion
at 0.04 mg/kg BW/h) was evaluated after small-intestinal
resection and anastomosis. Although horses treated with
metoclopramide had decreased total volume, duration,
and rate of gastric reflux, the previously reported side
effects were again noted (69). In another study, metoclo-
pramide increased contractility of smooth-muscle strips
from the equine pyloric antrum, duodenum, and jejunum
(70). When used as a pretreatment, metoclopramide has
also been shown to improve gastric emptying in horses
receiving endotoxin (71). The prokinetic capacity of
metoclopramide appears substantial, but its potential side
effects for clinical use have to be considered.
Cisapride is a substituted benzamide that is devoid of
antidopaminergic properties. Therefore, it is unlikely to
cause the same undesirable side effects as metoclo-
pramide (72). In an experimental model of POI in ponies
and in a clinical trial on horses, cisapride was effective
in reestablishing motility after small-intestinal anasto-
mosis and enterotomy (73). Similar to metoclopramide,
cisapride restored gastric emptying that had been delayed
by endotoxin administration (74). The only side effect
observed in horses after cisapride treatment in a clinical
setting was periodic mild abdominal pain (73). In
humans, cisapride has been shown to have adverse car-
diac effects, including ventricular dysrrhythmias, synco-
pal episodes, and lengthening of the electrocardiographic
QT intervals. These effects have been related to prolon-
gation of the action-potential duration through blockage
of potassium channels, with a resulting delay in cardiac
repolarization (68). No such reports of side effects have
been made for the horse.
Erythromycin Erythromycin estolate is a 14-member
macrolide antibiotic used almost exclusively in equine
practice to treat diseases caused by Rhodococcus equi in
juvenile animals (75). In horses and humans, antimicro-
bial doses of erythromycin occasionally induce severe
colitis and other undesirable side effects (7678). In
healthy horses, low doses of erythromycin lactobionate
(0.1 and 1 mg/kg BW, IV) decreased the emptying time
of radiolabeled markers from the stomach (63). Cecal
emptying in ponies receiving erythromycin lactobionate,
IV, was dose dependent (79). Studies in other species also
demonstrated that the prokinetic effects of erythromycin
were often dose related (80,81). A dose of 0.01 mg/kg
BW, infused over a period of 1 h, had no effect on cecal
emptying, while a similar infusion at a dose of 1 mg/kg
BW maximized equine cecal activity. The onset and rate
of cecal emptying were more rapid when erythromy-
cin, 0.1 mg/kg BW, was administered as a bolus rather
than a slow infusion. The total amount of erythromycin
lactobionate needed to create an increase in ileoceco-
colic myoelectric activity in the horse was as little as
500 g (79). Erythromycin lactobionate increased the
contractility of both circular and longitudinal smooth-
muscle strips from the equine jejunum. In strips from
the pyloric antrum, it increased the contractility of
longitudinal muscle, but inhibited the contractility of
circular muscle. These responses were consistent with
the passage of ingesta from the stomach into the small
intestine (70). Recently, it was shown that erythromycin
lactobionate displaces motilin from motilin receptors in
the equine duodenum, jejunum, cecum, and pelvic flex-
ure (82). When the effect of erythromycin lactobionate,
0.5 mg/kg BW, IV, was evaluated in horses during the
first 24 h after a ventral-midline celiotomy, myoelectric
activity increased in the ileum and pelvic flexure, but not
in the cecum. When reevaluated with the same dose 8 d
after surgery, the cecum was responsive. The prokinetic
Can Vet J Volume 47, June 2006 557
effects of erythromycin reported in healthy horses were
not the same in horses with gastrointestinal disease (83).
A different study showed that distension and subsequent
decompression of a segment of equine jejunum resulted
in inflammation. When testing the response of circular
smooth muscle strips from distended jejunum to eryth-
romycin, contractions were weaker than in control strips
(35). It seems that in several species, the response to
erythromycin in healthy subjects is different from that in
subjects with gastrointestinal disease. Interestingly, the
ability of erythromycin lactobionate to bind to the equine
motilin receptor is not affected by ischemia or distension
of the jejunum (84). Therefore, the decreased response
to erythromycin may be associated with down-regulation
of motilin receptors, which has been reported in rabbits
with chemically induced colitis (49). It has been dem-
onstrated recently, that distension of equine jejunum
results in a decrease of motilin receptors when com-
pared with sham-operated segments of jejunum, which
seems to be partly due to a decrease in motilin receptor
synthesis (84). Prolonged administration of erythro-
mycin can also result in down-regulation of motilin
receptors (85).
The prokinetic activity of erythromycin is very specific
to 14-membered macrolides (86,87). Erythromycin-A
and several erythromycin derivatives were evaluated
in vitro for their antimicrobial properties and their abil-
ity to induce gastrointestinal motility in rabbit duodenal
muscle strips. One derivative, 8,9-anhydroerythromycin-A
6,9-hemiketal propargyl bromide, was 2890 times more
potent in inducing gastrointestinal motility than was
erythromycin-A and had no antimicrobial properties (87).
Clinical use of these derivatives for their prokinetic activ-
ity should prevent the development of antimicrobial
resistance and other undesirable side effects associated
with erythromycin. In the equine patient with ileus,
erythromycin may be a useful prokinetic drug. Currently,
it is most commonly used for treatment of cecal impac-
tions (64). However, before making any assumptions, it
is important to further elucidate the mechanism of action
of erythromycin in the horse. Additional studies, includ-
ing clinical trials, are needed.
Dopamine antagonists Domperidone is a selective
peripheral dopamine (DA
2
receptor) antagonist (24,73).
In a preliminary study in which using an experimental
model of POI in ponies was used, domperidone, given at
0.2 mg/kg BW, IV, was effective in restoring transit time,
electromechanical activity, and coordination of gastric
and intestinal cycles (73). No further information about
domperidone as a prokinetic agent is available at this
time, and further research is needed before it is used
clinically in horses.
Lidocaine Lidocaine may act by inhibiting the
sympathetic response, blocking the effects of endotoxin,
restoring intestinal coordination, or decreasing inflam-
mation (70). However, when comparing the effect of
lidocaine with the use of a placebo in clinical cases with
an intestinal order requiring surgical intervention, no
significant difference was detected between groups (88).
In the treatment of POI, lidocaine, 0.05 mg/kg BW, was
the most common first choice, using a continuous infu-
sion with or without a 1.3 mg/kg BW loading dose (64).
However, the exact mechanism of lidocaines action is
still unknown and further research is required to evaluate
its efficacy.
Conclusion
The complex physiology of equine gastrointestinal motil-
ity has been discussed. The horse always has MMCs,
regardless of whether fed or fasted, in contrast to other
species where a clear differentiation in myoelectric activ-
ity exists. Despite the extensive research that has been
done to measure equine transit of intraluminal contents,
it does not always correlate with myoelectric and
mechanical activity. Consequently, combining all
3 methods seems to provide the most accurate way
to evaluate motility.
Regulation of intestinal motility depends on complex
networking between sympathetic, parasympathetic, and
enteric nervous system. Recently, a lot of research has
been conducted on the neural regulation of equine motil-
ity, especially with a view to understanding the role of
the enteric nervous system. Despite these efforts, much
is still extrapolated from what is known for humans.
Further scientific investigation of the neural regulation
of equine motility is required.
Shock; electrolyte imbalances; hypoalbuminemia;
peritonitis; endotoxemia; and distension, ischemia, or
inflammation of the intestinal tract have all been impli-
cated as contributing to the pathophysiology of ileus in
the horse. Treatment of ileus should consist first of sup-
portive therapy, like IV fluids, anti-inflammatory drugs,
etc, to eliminate as many ileus-contributing factors as
possible, before even considering the use of prokinetic
drugs.
Among the different prokinetic drugs available for use
in horses, bethanechol was shown to promote motility in
both small and large intestine; but, due to loss of gastro-
duodenal coordination, it appears to be safer to use it for
large intestinal problems only. Neostigmine appears to
be most useful for problems of the large intestine, espe-
cially for large colon problems. Erythromycin lactobion-
ate seems to be effective in promoting motility in both
small and large intestine, at least in healthy horses, but
clinically it is used more often for large intestinal prob-
lems. Metoclopramide, used as a continuous infusion,
seems most promising for small intestinal problems, but
the extrapyramidal side effects have to be considered.
Cisapride showed good results for promoting gastric
emptying and small intestinal motility, but it is not sold
anymore in Canada due to potential cardiac side effects
in humans. Lidocaine, as a continuous infusion, is also
used most commonly for small intestinal problems, but
not enough is known about its efficacy. CVJ
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