Vol. 22, No.
6 June 2000
CE Refereed Peer Review
FOCAL POINT
★ Severe acute pancreatitis
(AP) induces systemic immune
system activation, which may
lead to organ damage and failure
caused by excessive stimulation
of neutrophils.
KEY FACTS
■ The outcome of a case of
severe AP often does not
reflect the intrinsic severity of
the pancreatic damage.
■ Adequate therapy of severe AP
requires consideration of colloid
oncotic support, oxygen delivery,
and maintenance of organ
function.
■ Immunomodulator therapy may
hold promise for therapy of
severe AP in dogs, but the timing
of these interventions is likely to
be crucial for success.
■ Disease models that focus only
on the pancreas are poor models
of the clinical disease.
Pathophysiology
of Organ Failure
in Severe Acute
Pancreatitis in Dogs
Texas A&M University
Craig G. Ruaux, BVSc, PhD, MACVSc
ABSTRACT: Severe acute pancreatitis (AP) is challenging and associated with a high rate of
mortality and comorbid illness. Assuming initial fluid therapy is adequate, death associated
with severe AP usually results from failure of organs other than the pancreas. Severe AP is un-
usual among diseases of the gastrointestinal tract in that it causes a syndrome of marked sys-
temic immune system activation. The pathophysiology of organ failure in severe AP is ex-
tremely complex and poorly understood.
D
iagnosis, assessment, and therapy of spontaneous acute pancreatitis (AP)
are all challenging to veterinary clinicians. Severe AP is associated with a
high rate of mortality and comorbid illness in both human and veterinary
patients. In human medicine, the mortality rate of patients diagnosed with the
condition has been reported as being just under 10%.1 This mortality rate has re-
mained static over the past 30 years despite advances in intensive care, fluid thera-
py, and diagnostic interventions. In general veterinary medical practice, the mor-
tality rate for dogs with spontaneous AP has been reported at approximately 27%.2
Although most of the presenting clinical signs and complications of AP in
dogs are due to fluid volume losses and acid–base disturbances resulting from
vomiting, a constellation of other complications associated with organ failure
may be seen in more severe cases. Dogs presenting to general practitioners with
severe AP are often euthanized or die early in the course of the disease2; euthana-
sia is often done in light of economic concerns of the owner. However, with the
public’s increasing expectations for high-quality animal care and improvements
in the general standards of veterinary critical care, general practitioners are in-
creasingly likely to be called on to handle very severe cases of AP.
The pathophysiology of organ failure in cases of severe AP is extraordinarily
complex. Severe AP may be associated with compromise and failure of organs
that are distant from the pancreas and not immediately related to the gastroin-
testinal tract. This article summarizes current knowledge of the pathophysiologic
mechanisms of the distant organ failure associated with AP.
Small Animal/Exotics
Comorbid Illness
• Host response
Intrinsic
Severity • Idiosyncracy
(extent of
biologic insult) • Level of therapy
• Biologic reserve
Preexisting Illness
OVERALL SEVERITY
Figure 1—The relationship between intrinsic severity, overall severity, and outcome in compromise at presentation and the de-
a spontaneous disease process.1
DEFINITION OF SEVERE
The severity of disease processes differs among pa-
tients. A further complication is that individual biolog-
ic systems tend to respond differently to the same level
of insult (Figure 1). Changes that occur in the pancreas
may be considered the “intrinsic severity” of the disease
process and represent the magnitude of the insult for
that patient. Additional factors, including patient age,
previous or comorbid diseases, individual response to
the insult, and owner willingness to treat the disease,
influence the final outcome and should be considered
part of the “overall severity” of spontaneous AP.
The intrinsic severity of AP is usually described in
terms of the histopathologic and gross morphologic
characteristics of the gland. Most authors describe the in-
trinsic severity of AP as either edematous or hemorrhag-
ic/necrotizing, with the latter form carrying a poorer
prognosis.3 A histopathologic classification of the severity
of AP is certainly valid when samples of pancreatic tissue
are available. However, it is not helpful in most cases of
AP seen in general practice, in which the overall severity
of the disease is more important for the handling of the
case. A severity scoring system for spontaneous pancre-
atitis of dogs has recently been described4 (Table I). This
system is a scale of 1 to 4, indicating the number of or-
gans other than the pancreas showing evidence of com-
promise or failure at presentation. A dog with a score of
3 or 4 is considered to have severe pancreatitis and an ex-
pected mortality rate of 50% or higher.
ORGAN FAILURE IN SEVERE DISEASE
In human medicine, severe AP is often associated
with a characteristic pattern of sequential organ failures
despite therapy.5 The phenomenon of multiple organ
OVERALL SEVERITY ■ SYSTEMIC INFLAMMATORY RESPONSE SYNDROME
Compendium June 2000
failure that accompanies any severe dis-
ease process and occurs despite intensive
therapy is referred to as the systemic in-
flammatory response syndrome (SIRS),
Death multiple organ dysfunction syndrome
Long hospital stay (MODS), or multiple organ failure syn-
Short hospital stay
drome (MOFS). These syndromes have
been extensively defined in the human
Outpatient treatment
medical literature, and several recent re-
Patient not presented views are available.6,7 The concepts and
for treatment
terms SIRS and MODS have been ap-
plied to veterinary medicine and have
also been extensively reviewed.8 An im-
portant distinction must be made be-
OUTCOME tween the presence of organ failure or
velopment of organ failure despite thera-
py. Failing or compromised organs are
assessed at the time of presentation to
determine the severity of AP in dogs4 and are an indica-
tion of the level of systemic metabolic derangement
before therapy. For example, a dog may have acute re-
spiratory distress syndrome (ARDS) at the time of pres-
entation or may develop it after therapy is initiated.
Regardless of the inciting cause for SIRS, the host re-
sponse tends to be the same and is associated with
marked systemic inflammatory activation. The produc-
tion and release of cytokines control immune system ac-
tivation and regulation. Expression of immune system
activation occurs by means of the effector cells of the sys-
tem, such as neutrophils and monocytes or macrophages.
With an increasing appreciation that the systemic mani-
festations of severe disease have an immunoinflammato-
ry basis, recent research on severe AP has focused on
changes in cytokines and other mediators of inflamma-
tion as well as the activity of effector cells in the pancreas
and their effects on distant organs. The first organ to fail
in most human patients with SIRS, regardless of the pri-
mary cause, is the lung.5 Pulmonary injury is a common
early manifestation of pancreatitis and multiple organ
failure.9 The development of ARDS contributes to the
morbidity and mortality associated with severe AP in ap-
proximately one third of human cases.10
CYTOKINE CHANGES
The presence and level of activity of tumor necrosis
factor–α (TNF-α), interleukin (IL)-6, soluble TNF-α
receptors, and C-reactive protein have been assessed in
the circulation of human patients with AP at varying
levels of severity.11 In a related study, in vitro produc-
tion and release of proinflammatory cytokines by iso-
lated mononuclear cells from human patients were
investigated.12 As the disease progressed, statistically sig-
Compendium June 2000 Small Animal/Exotics

TABLE I
Therapeutic Interventions Required for Pancreatitis at Varying Levels of Severity in Dogs
Disease
Severity Score a Prognosis Typical Therapeutic Interventions Required
Mild 0 Excellent Disease often resolves spontaneously, and recovery after therapy is expected to
be uncomplicated. Patients may be treated on an outpatient basis if hydration
status is adequate (confirmed by checking PCV/TP). Treatment consists of
pancreatic rest (i.e., nothing by mouth) and pain control.
1 Good to fair On presentation, patients typically have clinically significant dehydration. The
renal system is the most commonly compromised system, evidenced by prerenal
azotemia. Treatment consists of crystalloid fluids at twice the maintenance rate
to correct fluid deficits, nothing by mouth, and pain control. Recovery usually
occurs without complications, but adequate rehydration is essential. Crystalloid
fluids and nothing by mouth should be maintained until vomiting has stopped
for a minimum of 24 hours. If patients are hospitalized for more than 2 days,
nasogastric trickle feeding should be considered.
2 Fair to guarded Patients are dehydrated and hypovolemic on presentation and commonly
exhibit prerenal azotemia or acute renal failure and leukocytosis with
degenerative left shift. Initial therapy consists of shock-rate crystalloid fluids (90
ml/kg/hr) for 1 to 2 hours, then reassessment. Urine output, lung sounds, and
blood urea nitrogen/creatinine levels should be monitored. Colloid support is
useful, as are synthetics (hetastarch or dextrans) or plasma products. Pain should
be controlled and nasogastric intubation and trickle feeding considered.
PCV/TP and coagulation status should be monitored frequently. Deterioration
in coagulation status is a poor prognostic sign; early therapy with fresh-frozen
plasma and heparin may be warranted. Many patients recover; death is usually
by euthanasia because of economic constraints. Nasal oxygen delivery may be
helpful (empiric observation). The decision of whether to treat the patient in a
general practice setting or refer it to an emergency/critical care facility depends
on response to therapy.

Severe 3 Poor Patients require extensive therapy and life-support interventions. Adequate
therapy often cannot be provided in most general practice settings because these
4 Grave patients typically require constant monitoring. Early referral to emergency/
critical care facilities is recommended. Patients may be candidates for surgical
intervention, peritoneal lavage, and open peritoneal drainage. Ventilatory
support, central venous pressure monitoring, and high-volume fluid therapy
(which can potentially worsen pulmonary edema) may be required. Patients
often also require insulin therapy to maintain normoglycemia and nutritional
support by means of jejunostomy tube feeding. Most patients die.
a The severity scoring system is based on the number of organ systems other than the pancreas showing evidence of failure or

compromise at initial presentation. Further details on this scoring system and its application to general practice cases can be found
elsewhere in the literature.4
PCV/TP = packed cell volume/total protein.

nificant increases in the median concentrations of solu-
ble TNF-α receptors and IL-6 were seen in the circula-
tion of patients with severe disease. Significant increases
in mononuclear cell production of cytokines at the
time of presentation were associated with severe disease.
Studies of monocytes isolated from human patients
over several days of hospitalization showed a signifi-
cantly increased peak secretion rate of TNF-α, IL-6,
and IL-8 that was associated with severe disease.13
Levels and function of antiinflammatory cytokines
have been investigated in cases of spontaneous AP of
human patients14 and in experimental rodent models.15
In the human patients, IL-10 was detectable in mild
and severe cases but not in healthy controls. The pa-

MONONUCLEAR CELLS ■ INFLAMMATORY CYTOKINES

Small Animal/Exotics
Terminology of Cytokines and Cell Surface Molecules
Cytokines are a group of extremely potent biologic
signaling molecules that are crucial to the regulation of
inflammatory processes and immune system function.
The cytokines mentioned in this article, their source,
and their target cells are summarized in Table II.
However, this is only a tiny subset of currently known
cytokines.
Most cytokines are predominantly paracrine or
autocrine in function: They act on the source cell or cells
in local tissue rather than on distant tissue. Studies of
cytokine activity (particularly tumor-necrosis factor–α)
in the peripheral circulation in humans and dogs with
spontaneous acute pancreatitis show a low rate of
detection of cytokines, even in severe cases. A very
strong relationship between the detection of cytokine
activity and the presence of complications or death is
usually observed. This reflects the tight regulation of
cytokine production and activity in normal individuals.
Detection of tumor-necrosis factor–α activity in
peripheral circulation reflects massive overproduction,
or excessive release of cytokines, loss of regulation of
cytokine activity, or a combination of all three factors.
Knowledge of cell surface molecules has recently
become an area of explosive growth. Cell surface
tients in the group with mild disease had significantly
higher levels of IL-10. In experimental rodent models,
treatment with exogenous IL-10 decreased the severity
of AP.15 Detection of TNF-α activity in dogs presenting
with spontaneous AP was invariably associated with se-
vere disease and a high probability of death.16
The tendency of pancreatitis to amplify a local in-
flammatory process into a systemic inflammatory re-
sponse is unusual among diseases of the gastrointestinal
tract.17 The reports of increased IL-6, IL-8, and soluble
TNF-α receptors and decreased IL-10 in human pa-
tients with severe AP suggest that complex modifica-
tions of cytokine regulation and production occur dur-
ing the development of the disease (see Terminology of
Cytokines and Cell Surface Molecules).
NEUTROPHIL ACTIVITY
Neutrophils are the major effector cells of an acute
inflammatory response. Neutrophil activity is believed
to be central to the pulmonary pathologic characteris-
tics of ARDS.3 Sequestration of neutrophils within the
EFFECTOR CELLS ■ HISTOPATHOLOGY ■ PROTEOLYTIC ENZYMES ■ OXIDATIVE SUBSTANCES
Compendium June 2000
antigens are membrane-bound proteins with various
functions. These antigens are usually referred to by
cluster of differentiation (CD) numbers. In this context,
differentiation refers to the ability to distinguish
between cell types rather than to any role in the
differentiation of cells from their precursor stem cells.
For example, CD11b means cluster of differentiation
antigen number 11b. This receptor protein is found
on monocytes, macrophages, and neutrophils and is
expressed on the cell surface in response to cytokine-
mediated stimulation. The antigen CD numbers are
assigned to proteins with known functions by
consensus among researchers in the field according
to international conventions.
To complicate the issue, cell surface antigens are
commonly known by alternate names. The same
protein may have different names in different papers.
For example, the neutrophil cell surface adhesion
molecule CD11b/CD18 (two associated but different
proteins) is also known as Mac-1, whereas one of the
receptors for CD11b/CD18, intercellular adhesion
molecule–1, is also known as CD54. The cellular
adhesion molecules mentioned in this article are
summarized in Table III.
pancreas and lung is generally believed to be an impor-
tant event in the early evolution of pancreatitis itself as
well as that of associated lung injury.3 Histopathologic
analysis of lung tissue from animals with experimental
pancreatitis shows an accumulation of neutrophils and
thickening of alveolar walls within 3 hours of induction
of the disease.10 Similar changes may be seen on histo-
pathologic examination of lung tissue from dogs that
have died of AP (Figure 2). Neutrophils are a source of
numerous potent proteolytic enzymes and oxidative sub-
stances, including H2O2 and O2–, the superoxide radi-
cal.18 The enzymes and oxidative substances carried by
neutrophils are crucial armaments against invading mi-
crobial organisms, but they may also have deleterious
effects on host tissues if released inappropriately.
Neutrophil elastase has been measured in the circula-
tion of human patients with AP of varying severity19; it
was significantly increased in patients with severe dis-
ease by the third day of hospitalization. Neutrophil de-
pletion with an antineutrophil antiserum has been
shown to attenuate the severity of experimental AP and
Compendium June 2000 Small Animal/Exotics

Figure 2A Figure 2B
Figure 2—Histologic changes in the lung of a dog after spontaneous severe acute pancreatitis. (A) Note the thickening of alveolar
septa, presence of neutrophilic infiltrate, and interstitial edema compared with (B) the lung of a normal dog. (Original magnifica-
tion, ×10; courtesy of Dr. J. Edwards, Texas A&M University, College Station, Texas)

can completely block development of pancreatitis-asso- with severe AP strongly suggests that circulating endotoxin
ciated lung injury in a rodent model.20 plays a role in the development of lethal complications.21
Neutrophil margination and degranulation is a com- Circulating endotoxin was detected in more than 50% of
plex receptor-mediated process. A simplified model of severe cases and more than 90% of fatal cases in one study
some major cell surface receptors, cytokines, and neu- of human patients.21
trophilic enzymes is illustrated in Figure 3. ARDS in- During endotoxemia, neutrophils exhibit marked up-
duced by pancreatitis is clinically and histopathological- regulation in cellular oxidant production.22 Endotoxic
ly indistinguishable from that
induced by circulating lipo-
polysaccharide endotoxin, is- A TNF-α
IL-6
chemia–reperfusion injury, Chemokines
and hemorrhagic shock.10 In Endotoxin?
DIC
these disease states, as well as
in spontaneous AP, neutrophil B
Local thrombosis
behavior is dramatically modi- CD11b/CD18
C
fied, which primes them for ICAM-1
damaging host tissues.
Collagen exposure

ENDOTOXIC Activation Margination Degranulation Endothelial damage

NEUTROPHILS
The status and behavior of
neutrophils in bacterial sepsis
with an obvious source of en-
dotoxin is very similar to that
seen in other conditions with-
out an obvious source of en-
dotoxin.18 It has become in-
creasingly obvious that these
conditions have an endogenous
endotoxemia, which originates
from the release of gut-derived
endotoxin into the circulation.
Assessment of endotoxemia as
a prognostic marker in humans
Positive
feedback Loss of Fluid losses, Increased endothelial
organ function swelling permeability
Local cytokine
production
Figure 3—Diagram of cellular events leading to neutrophil-induced distant organ dysfunction
in severe acute pancreatitis. Circulating, quiescent neutrophils (A) are activated by locally pro-
duced or circulating cytokines. Expression of CD11b/CD18 is increased, allowing margina-
tion (B) to occur. Excessive activation, or bacterial endotoxin, blocks migration from the cir-
culation. Degranulation releases damaging proteases and reactive oxygen species onto the
endothelium (C), leading to cellular dysfunction. Loss of endothelial integrity promotes coag-
ulopathy, compromises organ function, and leads to further local cytokine release. (CD =
cluster of differentiation; DIC = disseminated intravascular coagulation; ICAM = intracellular
adhesion molecule; IL = interleukin; TNF = tumor necrosis factor)

NEUTROPHIL MARGINATION AND DEGRANULATION ■ ENDOTOXEMIA

Small Animal/Exotics Compendium June 2000

TABLE II
Sources, Example Target Cells, and Effects of Cytokines
Cytokines Sources Example Target Cells Effects
Tumor necrosis factor–α Monocytes, macrophages, Neutrophils, monocytes, Immune system
pancreas, lung, damaged bone marrow, many upregulation; neutrophil
tissue somatic cells activation; fever;
tachycardia

Interleukin-1 Macrophages, peripheral Neutrophils, bone marrow, Neutrophil activation;

monocytes, pancreas many somatic cells immune system
upregulation

Interleukin-6 Peripheral T cells, pancreas Bone marrow, liver, B cells, Increased production of
many somatic cells acute-phase proteins and
immunoglobulins

Interleukin-8 Monocytes, macrophages, Neutrophils, macrophages, Increased neutrophil

neutrophils monocytes activation and
degranulation; monocyte
and macrophage activation

Interleukin-10 T and B lymphocytes Macrophages Decreased production of

other cytokines; immune
system downregulation

TABLE III
Cell Types and Function of Cellular Adhesion Molecules
Cellular Adhesion Types of Cell Carrying
Molecules Adhesion Molecule Function
CD11b/CD18 Neutrophils, macrophages,
Cellular adhesion molecules—the CD11b/CD18 complex—
monocytes
interact with ICAM-1 during neutrophil margination. This is
an essential prerequisite before neutrophils migrate from the
ICAM-1 Endothelial cells, many
circulation into the tissue.
immune system cells
CD = cluster of differentiation; ICAM = intercellular adhesion molecule.

neutrophils are also chemotactically depressed and may
be less able to extravasate in response to IL-8 or platelet-
activating factor.18 These changes result in migratorially
depressed but oxidatively hyperactive neutrophils that
are marginated in vascular beds and closely primed to
injure endothelial cells.18
Neutrophil-mediated damage to vascular endotheli-
um results in increased vascular permeability.9 Increas-
ing vascular permeability of the pulmonary circulation
is likely to lead to interstitial edema, thereby compro-
mising gaseous transfer. Vascular endothelial cells and
alveolar macrophages increase their production of cellu-
lar adhesion molecules and proinflammatory cytokines
(Tables II and III), perpetuating damage to the pul-
monary vascular endothelium and helping to establish
a condition of ventilation–perfusion mismatch. If not
arrested by homeostatic mechanisms of the host, this pro-
cess eventually leads to ARDS and acute onset of pul-
monary edema.
Endothelial cell damage resulting from exposure to
neutrophilic proteases and oxidants tends to result in
changes of cellular anatomy, revealing basement mem-
brane collagen. Exposed collagen is a potent trigger of
the extrinsic coagulation pathway; thus extensive en-
dothelial dysfunction may rapidly lead to disseminated
intravascular coagulation and consumptive coagulopathy.
Local embolic processes exacerbate end-organ hypoxia
and ischemia–reperfusion injury.

INTERSTITIAL EDEMA ■ VENTILATION–PERFUSION MISMATCH

Compendium June 2000 Small Animal/Exotics

Your comprehensive
SOURCES OF CYTOKINES
Many of the systemic manifestations of severe AP are guide to diagnostic
inflammatory in origin and cytokine mediated. The
source of the cytokines in spontaneous AP is an area of ultrasonography
interest in research. The exocrine pancreas itself has
been shown to produce, release, and respond to TNF- Nautrup and Tobias
α.23 TNF-α production, combined with increased pro-
duction of intercellular adhesion molecule 1, is likely to
mediate the initial neutrophil accumulation in the in-
flamed pancreas. Monocytes and macrophages are also
a significant source of TNF-α production in cases of se-
vere AP, and the presence of a large number of alveolar
macrophages may explain the early development of
neutrophil accumulation and margination in the pul-
monary circulation.
Studies of mRNA production in the pancreas and
distant organs during experimental pancreatitis indicate
that proinflammatory cytokines (TNF-α, IL-1, and IL-
6) are produced in the pancreas and, after an apprecia-
ble delay, in the lungs, liver, and spleen.24 Cytokine
production was not detected in the kidney, cardiac New
muscle, or skeletal muscle at any stage. Thus the organs
that have failed as a result of immunoinflammatory
processes during AP themselves seem to be significant
sources of cytokines (Table II).

THERAPY
Successful therapy of AP in dogs relies on correct di-
agnosis and objective assessment of overall disease sever-
ity. The therapeutic approach to mild pancreatitis is
quite different from that of potentially fatal cases. Pan-
creatitis is a disease that occurs in a continuum of severi-
ty, and the distinctions between mild and severe cases
are necessarily arbitrary. Early assessment of disease
severity is important, however, to allow a rational deci-
sion about how to treat a patient (i.e., whether to treat
on an outpatient or inpatient basis in a general practice
setting or refer to a secondary care facility).
Table I summarizes the prognosis and typical therapeu-
tic interventions that can be used for dogs presenting at
varying levels of severity. The severity score referred to in
the table is based on pretreatment clinical biochemistry
and hematologic characteristics and has been described in
greater depth elsewhere.4
Most of the clinical signs and complications of sponta-
neous AP in dogs result from dehydration, circulating flu-
id losses, and electrolyte disturbances secondary to vomit-
ing.4 In the majority of less severe cases, attention to
adequate fluid replacement, pain control, and pancreatic
rest are sufficient to allow uncomplicated recovery. Fluid
therapy in companion animal practice has been reviewed
in recent publications.8,25
The mainstay of therapy for mild pancreatitis is ade-
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■ Recognition of the disease process and
courses of treatment
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TUMOR NECROSIS FACTOR ■ ASSESSMENT

Small Animal/Exotics
TABLE IV
Experimental Models of Acute Pancreatitis
Model Species
Choline-deficient, ethionine-supplemented Rodents
diet
Overstimulation of pancreatic secretion Rodents, dogs
with cholecystokinin or cerulein
Pancreatic duct ligation Dogs
Infusion of bile acids and/or trypsins into Rodents, rabbits, dogs
the pancreatic duct
Overstimulation of pancreatic secretion Rodents, dogs
with cholecystokinin plus intraductal
infusion of enterokinase
quate attention to the dehydration and ionic depletion
that result from vomiting and, in some cases, fluid pool-
ing in the intestines secondary to ileus. Hospitalization
may not be necessary for patients with very mild disease
(i.e., a history of vomiting once or twice within 12
hours and adequate hydration). These patients are not
often presented to veterinarians, and those that are can
be adequately treated by a short period of gastric and
pancreatic rest and pain control. I have found buprenor-
phine to be useful for analgesia in these cases and com-
bine it with a minimum of 12 hours of pancreatic rest
(i.e., nothing by mouth). These dogs often have a histo-
ry of repeated minor episodes, which is suggestive of re-
lapsing disease.
Dogs presenting with clinically appreciable dehydra-
tion, as indicated by changes in skin turgor, ocular po-
sitioning, packed cell volume, and total protein, require
correction of fluid deficits and maintenance of ade-
quate hydration during a period of gastric and pancre-
atic rest. In the overall severity scoring system, these pa-
tients commonly have a score of 1 or 2, which describes
an animal with prerenal or renal azotemia and/or
marked leukocytosis with a left shift. For these cases,
the use of a polyionic crystalloid fluid (i.e., lactated
Ringer’s solution) for initial fluid replacement com-
bined with pancreatic rest is usually adequate.
Dogs presenting with a score of 1 typically respond well
to replacement of fluid deficits over 12 hours at a fluid
rate twice that of regular maintenance rates. Patients re-
quiring fluid therapy beyond 24 hours of hospitalization
benefit from transition to a maintenance fluid (e.g., lac-
tated Ringer’s solution with supplemental potassium). Af-
ter fluid deficits are corrected, I typically use a mainte-
FLUID THERAPY ■ PANCREATIC REST ■ MULTIPLE ORGAN FAILURE
Compendium June 2000
Outcome
Necrotizing pancreatitis; occasional death
Edematous pancreatitis; no death;
few if any clinical signs
Pancreatic necrosis and fibrosis with few
if any clinical signs; no death
Pancreatic necrosis
Severe pancreatic necrosis; extremely high
mortality rate (up to 100%); acute death
nance rate that is 1.5 to 2 times the calculated rate.
Animals presenting with a score of 2 are treated with
more aggressive initial fluid therapy. I usually adminis-
ter crystalloid fluids at shock rates (90 ml/kg/hour) for
1 to 2 hours while monitoring packed cell volume/total
protein and levels of blood urea and creatinine. After
the initial crystalloid dose, colloid fluids are adminis-
tered. Colloid fluids may be synthetic (hetastarch or
dextran-70) or plasma products. They are typically ad-
ministered as a bolus of 5 ml/kg during a period of 1
hour followed by an equal amount administered in the
subsequent 24 hours in combination with crystalloid
fluids. Although these patients require close monitoring
for the development of complications, thereby repre-
senting a significant challenge to clinicians, most recov-
er if therapy is adequate.
Therapy for dogs with a score of 3 or 4 has a dramat-
ically different emphasis. The patient is no longer sim-
ply being treated for pancreatitis but for severe shock
and multiple organ failure. The fact that pancreatitis—
not some other extremely severe disease process—is the
source of these disorders does not alter the therapeutic
plan. Details of the therapy for these animals are be-
yond the scope of this article and have been reviewed
elsewhere.8 The prognosis for these patients is poor to
grave, and most of them die or are euthanized within a
relatively short period after presentation.2,4 Treatment of
dogs with pancreatitis-related organ failure is frequently
unrealistic in general practice. These cases are generally
best handled by referral services, if available.
IMMUNE-MODULATOR THERAPY
Clinical research investigating the pathophysiology of
Compendium June 2000 Small Animal/Exotics

spontaneous severe AP in dogs (as opposed to con-

Share Your
trolled induction of AP) is sparse. The effect of current
therapeutic methods on cytokine production and cellu-
Knowledge
lar immune system function is an area of current re-
search interest. In the absence of specific data relating We invite you to impart your clinical knowledge
to dogs, however, it is necessary to extrapolate from
clinical experience with human patients and models of
by discussing your interesting cases, unusual
pancreatitis. However, the applicability of these model- presentations, or procedures for clinical solutions
based studies to actual clinical cases is often question-
able. Most studies that are based on induced models of for the following features:
the disease focus on the intrinsic severity of the disease
process. Model systems that have been used to induce
E
IC CHALLENG
DIAGNOST

isoning
rn on a Rat Po
Unexpected Tu
pancreatitis are summarized in Table IV. DIAGNOSTIC CHALLENGE By Marjory
Brooks, D.V.M
and Jeff Jacobs
on, D.V.M
.
., Dipl. A.C.V.
I.M.,

Model studies have elucidated many of the patho- M

ugsy, a four-yea
ined within one
r-old, neutere
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hour of ingestio
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n of the rat poison
Con-
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A detailed account of a clini- trac® . Initial

treatment consiste
and 30 mL of
d of subconjunctiva
oral hydrogen
peroxide to induce
vomited a large

physiologic changes that occur in the pancreas in the

of apomorphine therapy, Mugsy
response to this the rat bait.
Addi-
vomiting. In l identified as gas-
materia
amount of green-b
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cal dilemma takes readers from

and vitamin K1 supply of
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beginning phases of severe AP and the development of ILLUSTRATIO

NS BY LES
SEALING
Mugsy was discharg
vitamin K1 50
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for PT determi
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specific patient presentation

hours later limits. The
d for 48 hours within normal because cor-

systemic complications. Unfortunately, clinical trials on tion was schedule values were ted finding
A recheck examina vitamin K regimen to
confirm , an unexpec K deficiency
was 65.9 seconds al PT due to vitamin
ion of the owners report- initiating an
after complet Although his rection of abnorm 48 hours of
coagulopathy. and Mugsy within 24 to
resolution of K1 as directed should resolve K1. of
had given vitamin re to rat poison, clotting appropriate
dose of vitamin persistent prolongation
ed that they y the cause of
nity for reexposu was markedl To determine al vitamin
had no opportu time (PT) assay whether addition for more
prothrombin finding in the PT and

therapy for spontaneous cases of severe AP in humans

the ). This time was sent

through the steps leading to the

time in : 9.5-12.5 clotting a sample
57 seconds (normal d that his early pre- was needed, was drawn
prolonged at it appeare K therapy . Whole blood
unexpec ted because g had prevented coagulat ion analyses
(one part 3.8 percent
was vomitin detailed ulant
productive Contrac, how- citrate anticoag ged, and the
sentation with of rodenticide. directly into and centrifu
on of a toxic dose ing poison. to nine parts blood) cold packs to a vet-
absorpti a long-act citrate shipped on
s bromadiolone, at the same vitamin K1 plasma was Coagulation
ever, contain supernatant (Comparative
therefore resumed e laboratory University,

based on these models have almost invariably failed to

Treatment was two weeks.
erinary referenc
tic Laborat
ory, Cornell
completion
dosage for another recheck, 48 hours after Section, Diagnos

ultimate diagnosis in 1000-1500

ed and d
At Mugsy’s next was still markedly prolong York). d of activate
Ithaca, New ion panel consiste
, the PT sample. A thrombin
of vitamin K1 from the previous The initial coagulattime (aPTT), PT, and g
unchanged al vita- plastin TCT screenin
essentially submitted, parenter were partial thrombo aPTT and
ry profile was owners (TCT). The
blood chemist SC, and the clotting time
given 50 mg 48

show benefit.26
min K1 was K and recheck
vitamin 1
August 2000
resume oral
instructed to
ed
Peer Review

words. 76 Veterinary
Forum

The great strength of models is their reproducibility.

The use of a homogenous population of experimental
THERAPEUTIC
CHALLENGE

animals, with standardized levels of insult, allows the THERAPEUTIC CHALLENGE

KAREN WILSON
Intussuscep
effects of treatment to be detected with a much greater While the course of therapy is of- tio
In a Yearlin n
g
level of statistical confidence. In model studies, the in- ten clear-cut, some patients pre-
By Linnea Lentz,
D.V.M.

trinsic severity of the disease has the greatest influence B eau, a 15-mont
when the owners
h-old colt, had been
colicky for about

sent true challenges to medical

called the referring four hours
veterinarian. The and no other
described as mild, colic was
abnormali-
and Beau was treated ties. An initial
IV injection
nixine) administe with 10 cc Banamin ®

on outcome because other factors, such as comorbid

red intravenously e (flu- of xylazine appeared
(IV), 10 cc of control the pain to
approximately 1 dipyrone IV, and for only 20
⁄2 gallon of mineral minutes before
tube. Within the oil administered a second
hour, Beau was via nasogastric dose was necessary.
University of Minneso again colicky and Rectal
was referred to the palpation revealed

skills. In 1000-1500 words, these

ta. many
distended loops
of small
testine. After placemen in-

and preexisting illnesses and host responsiveness, are

Initial Treatme t of
nt on Referra a nasogastric
Clinical signs l reflux were obtained. tube, 6-7 L of
on presentation Abdominocen-
included profuse tesis results were
sweating, numerous normal.
attempts to lie Because of the
down, and a distended severity of the
abdomen. Physical colic, the small
examination re- intestinal distention

cases describe the steps that

vealed a pulse and nasogastr ,
of 84 beats per

controlled by the homogeneity of the experimental ani-

minute, ic reflux, we
decreased gastrointe mended explorato recom-
stinal motility ry laparotomy
all four quadrants in diagnose the cause to
, slightly toxic of the colt’s colic.
cous membran mu- The owners quickly
es, a capillary agreed, and pre-
time of 2.5 seconds refill operative antibiotic
(normal: 1-2),
and a normal
temperature. potassium penicillin s, including
work revealed Blood 22,000 units/kg
a packed cell IV and Gentocin

mals.
volume (gentamicin) 6.6

eventually lead to case resolu-

of 48 percent mg/kg IV, were
(normal: 32-48), administered before
protein of 7.2 g/dL total preparing the colt
(normal: 5.7-7.9), for surgery. During
surgery, a jejunocec
August 2000 al intussuscep-➔
Peer Reviewed
Veterinary Forum
73

In clinical cases, the influence of additional factors tion.

has a much greater importance in determining the MONTH
CASE OF THE

overall severity and outcome. Clinical cases of pancre- is

Canine Hemipares , D.V.M.

CASE OF THE MONTH

By Donivan Hudgins

atitis in dogs are most commonly seen in middle-aged

to elderly patients.2 Age and the presence of preexisting Some case presentations are so J asmine, a four-year-
kg, spayed Golden
old, 29-
Retriev-
activity levels
and vaccinations
for distemper,
had been normal,
were current
hepatitis, lep-
nza, par-
to the clinic

disease are both risk factors for death in dogs with

er, was presented tosporosis, parainflue
of lameness. irus, Lyme
for sudden onset vovirus, coronoav

confounding that both diagnosis

found a stray
The owner had and sus- disease, and rabies.
given Solu
goat in the backyard The patient was
that the goat may have Cortef
® (prednisolone)
pected Delta
On presenta- usly (IV) and
butted Jasmine. ry 100 mg intraveno cc in-
was ambulato in injectable 2.5

spontaneous AP.27
tion, the dog amoxicill
uncoordinated, The owner was
but obviously tramuscularly.
n revealed the provide cage rest
and observatio instructed to

and therapy are perplexing. Often,

deficit was in and return
primary walking over the weekend
dog’s condition
the right rear leg. ion re- Monday if the
Physical examinat .
had not improved Jas-
re of 101.6˚F, following week,

Very few experimental studies demonstrate effective-

vealed a temperatu The
es, capil- to improve, and
pink mucous membran (normal:
CORBIS

mine appeared
of 1 sec she did have
lary refill time whatever problems
heart and Over the next
1-2 sec), normal seemed subtle.

a patient may return again and

sign of pain. The weeks, her prob-
lungs, and no two to three
did knuckle over, but not as pro-
right rear foot proprio- lems recurred the
indicating decreased indicat- before, and

ness of therapeutic agents given after the start of dis-

nounced as
pinch that the dog
ception, but toe owner reported
were intact. to her deficits.
ed sensory nerves seemed to adjust
of the affected next few weeks,
Temperatures Then, over the
no different of coördination
foot and leg were Jasmine’s lack

again with continuously changing

other three feet
than that of the seemed to worsen.
and flexion October 21,
Jasmine

ease.26 In nearly all cases, early or preemptive therapy

and legs. Extension On
hip joints were for examina-
of the stifle and reflex on was re-presented
on a leash
normal, but patellar tion. When followed appeared
exaggerated,
the right was in the lawn, Jasmine
upper motor ated, with
which suggested to be very uncoördin
Appetite and
neuron disease.

shows the greatest benefit. However, early intervention signs. Word count: 1000-2000. 66 Veterinary Forum
Peer Reviewed
August 2000

is very difficult to achieve in clinical cases because the

disease process is often relatively advanced before the
patient is admitted.
The observation that TNF-α activity is closely linked
to development of systemic complications has prompted SEND YOUR ARTICLES TO:
investigation of anti–TNF-α therapy in rodent models
of AP.28 Anti–TNF-α therapy, using soluble TNF-α re- Editor, Veterinary Forum
ceptors to bind to circulating active TNF-α, attenuated 275 Phillips Blvd.
the severity of the disease process. In marked contrast to Trenton, NJ 08618
other experimental therapies, most benefit was seen
when treatment was applied after the disease had start- Fax: (609) 882-6357
ed. Because of the appreciable delay between the onset E-mail: lmiller.vls@medimedia.com

DISEASE MODELS ■ RISK FACTORS FOR DEATH

Small Animal/Exotics
of clinical signs and peak inflammatory cytokine pro-
duction in humans with AP, it has been suggested that
early treatment of these patients with anticytokine ther-
apy may have substantial benefits.17 However, this prop-
osition is yet to be tested in clinical trials.
It is not possible to recommend any specific im-
mune-modulator therapy for routine use on the basis of
current knowledge of the mechanisms that underlie or-
gan failure in dogs with severe AP. Until more objective
evidence for the usefulness of this approach is available,
emphasis must remain on the proper fluid repletion
and supportive care of these challenging medical cases.
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About the Author
Dr. Ruaux is affiliated with the Gastrointestinal Laborato-
ry, Department of Small Animal Medicine and Surgery,
College of Veterinary Medicine, Texas A&M University,
College Station, Texas.