You are on page 1of 10

Vol. 22, No.

6 June 2000

CE Refereed Peer Review

FOCAL POINT of Organ Failure
★ Severe acute pancreatitis
(AP) induces systemic immune
system activation, which may
in Severe Acute
lead to organ damage and failure
caused by excessive stimulation
of neutrophils.
Pancreatitis in Dogs
Texas A&M University
Craig G. Ruaux, BVSc, PhD, MACVSc
■ The outcome of a case of
severe AP often does not ABSTRACT: Severe acute pancreatitis (AP) is challenging and associated with a high rate of
reflect the intrinsic severity of mortality and comorbid illness. Assuming initial fluid therapy is adequate, death associated
the pancreatic damage. 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-
■ Adequate therapy of severe AP temic immune system activation. The pathophysiology of organ failure in severe AP is ex-
tremely complex and poorly understood.
requires consideration of colloid
oncotic support, oxygen delivery,

and maintenance of organ iagnosis, assessment, and therapy of spontaneous acute pancreatitis (AP)
function. are all challenging to veterinary clinicians. Severe AP is associated with a
high rate of mortality and comorbid illness in both human and veterinary
■ Immunomodulator therapy may patients. In human medicine, the mortality rate of patients diagnosed with the
hold promise for therapy of condition has been reported as being just under 10%.1 This mortality rate has re-
severe AP in dogs, but the timing mained static over the past 30 years despite advances in intensive care, fluid thera-
of these interventions is likely to py, and diagnostic interventions. In general veterinary medical practice, the mor-
be crucial for success. 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
■ Disease models that focus only dogs are due to fluid volume losses and acid–base disturbances resulting from
on the pancreas are poor models vomiting, a constellation of other complications associated with organ failure
of the clinical disease. 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 Compendium June 2000

failure that accompanies any severe dis-

Comorbid Illness ease process and occurs despite intensive
therapy is referred to as the systemic in-
flammatory response syndrome (SIRS),
• Host response Death multiple organ dysfunction syndrome
Intrinsic Long hospital stay (MODS), or multiple organ failure syn-
Severity • Idiosyncracy
(extent of Short hospital stay
drome (MOFS). These syndromes have
biologic insult) • Level of therapy been extensively defined in the human
Outpatient treatment
• Biologic reserve 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-
Preexisting Illness plied to veterinary medicine and have
also been extensively reviewed.8 An im-
portant distinction must be made be-
OVERALL SEVERITY OUTCOME tween the presence of organ failure or
Figure 1—The relationship between intrinsic severity, overall severity, and outcome in compromise at presentation and the de-
a spontaneous disease process.1 velopment of organ failure despite thera-
py. Failing or compromised organs are
assessed at the time of presentation to
DEFINITION OF SEVERE determine the severity of AP in dogs4 and are an indica-
The severity of disease processes differs among pa- tion of the level of systemic metabolic derangement
tients. A further complication is that individual biolog- before therapy. For example, a dog may have acute re-
ic systems tend to respond differently to the same level spiratory distress syndrome (ARDS) at the time of pres-
of insult (Figure 1). Changes that occur in the pancreas entation or may develop it after therapy is initiated.
may be considered the “intrinsic severity” of the disease Regardless of the inciting cause for SIRS, the host re-
process and represent the magnitude of the insult for sponse tends to be the same and is associated with
that patient. Additional factors, including patient age, marked systemic inflammatory activation. The produc-
previous or comorbid diseases, individual response to tion and release of cytokines control immune system ac-
the insult, and owner willingness to treat the disease, tivation and regulation. Expression of immune system
influence the final outcome and should be considered activation occurs by means of the effector cells of the sys-
part of the “overall severity” of spontaneous AP. tem, such as neutrophils and monocytes or macrophages.
The intrinsic severity of AP is usually described in With an increasing appreciation that the systemic mani-
terms of the histopathologic and gross morphologic festations of severe disease have an immunoinflammato-
characteristics of the gland. Most authors describe the in- ry basis, recent research on severe AP has focused on
trinsic severity of AP as either edematous or hemorrhag- changes in cytokines and other mediators of inflamma-
ic/necrotizing, with the latter form carrying a poorer tion as well as the activity of effector cells in the pancreas
prognosis.3 A histopathologic classification of the severity and their effects on distant organs. The first organ to fail
of AP is certainly valid when samples of pancreatic tissue in most human patients with SIRS, regardless of the pri-
are available. However, it is not helpful in most cases of mary cause, is the lung.5 Pulmonary injury is a common
AP seen in general practice, in which the overall severity early manifestation of pancreatitis and multiple organ
of the disease is more important for the handling of the failure.9 The development of ARDS contributes to the
case. A severity scoring system for spontaneous pancre- morbidity and mortality associated with severe AP in ap-
atitis of dogs has recently been described4 (Table I). This proximately one third of human cases.10
system is a scale of 1 to 4, indicating the number of or-
gans other than the pancreas showing evidence of com- CYTOKINE CHANGES
promise or failure at presentation. A dog with a score of The presence and level of activity of tumor necrosis
3 or 4 is considered to have severe pancreatitis and an ex- factor–α (TNF-α), interleukin (IL)-6, soluble TNF-α
pected mortality rate of 50% or higher. receptors, and C-reactive protein have been assessed in
the circulation of human patients with AP at varying
ORGAN FAILURE IN SEVERE DISEASE levels of severity.11 In a related study, in vitro produc-
In human medicine, severe AP is often associated tion and release of proinflammatory cytokines by iso-
with a characteristic pattern of sequential organ failures lated mononuclear cells from human patients were
despite therapy.5 The phenomenon of multiple organ investigated.12 As the disease progressed, statistically sig-


Compendium June 2000 Small Animal/Exotics

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


Small Animal/Exotics Compendium June 2000

Terminology of Cytokines and Cell Surface Molecules

Cytokines are a group of extremely potent biologic antigens are membrane-bound proteins with various
signaling molecules that are crucial to the regulation of functions. These antigens are usually referred to by
inflammatory processes and immune system function. cluster of differentiation (CD) numbers. In this context,
The cytokines mentioned in this article, their source, differentiation refers to the ability to distinguish
and their target cells are summarized in Table II. between cell types rather than to any role in the
However, this is only a tiny subset of currently known differentiation of cells from their precursor stem cells.
cytokines. For example, CD11b means cluster of differentiation
Most cytokines are predominantly paracrine or antigen number 11b. This receptor protein is found
autocrine in function: They act on the source cell or cells on monocytes, macrophages, and neutrophils and is
in local tissue rather than on distant tissue. Studies of expressed on the cell surface in response to cytokine-
cytokine activity (particularly tumor-necrosis factor–α) mediated stimulation. The antigen CD numbers are
in the peripheral circulation in humans and dogs with assigned to proteins with known functions by
spontaneous acute pancreatitis show a low rate of consensus among researchers in the field according
detection of cytokines, even in severe cases. A very to international conventions.
strong relationship between the detection of cytokine To complicate the issue, cell surface antigens are
activity and the presence of complications or death is commonly known by alternate names. The same
usually observed. This reflects the tight regulation of protein may have different names in different papers.
cytokine production and activity in normal individuals. For example, the neutrophil cell surface adhesion
Detection of tumor-necrosis factor–α activity in molecule CD11b/CD18 (two associated but different
peripheral circulation reflects massive overproduction, proteins) is also known as Mac-1, whereas one of the
or excessive release of cytokines, loss of regulation of receptors for CD11b/CD18, intercellular adhesion
cytokine activity, or a combination of all three factors. molecule–1, is also known as CD54. The cellular
Knowledge of cell surface molecules has recently adhesion molecules mentioned in this article are
become an area of explosive growth. Cell surface summarized in Table III.

tients in the group with mild disease had significantly pancreas and lung is generally believed to be an impor-
higher levels of IL-10. In experimental rodent models, tant event in the early evolution of pancreatitis itself as
treatment with exogenous IL-10 decreased the severity well as that of associated lung injury.3 Histopathologic
of AP.15 Detection of TNF-α activity in dogs presenting analysis of lung tissue from animals with experimental
with spontaneous AP was invariably associated with se- pancreatitis shows an accumulation of neutrophils and
vere disease and a high probability of death.16 thickening of alveolar walls within 3 hours of induction
The tendency of pancreatitis to amplify a local in- of the disease.10 Similar changes may be seen on histo-
flammatory process into a systemic inflammatory re- pathologic examination of lung tissue from dogs that
sponse is unusual among diseases of the gastrointestinal have died of AP (Figure 2). Neutrophils are a source of
tract.17 The reports of increased IL-6, IL-8, and soluble numerous potent proteolytic enzymes and oxidative sub-
TNF-α receptors and decreased IL-10 in human pa- stances, including H2O2 and O2–, the superoxide radi-
tients with severe AP suggest that complex modifica- cal.18 The enzymes and oxidative substances carried by
tions of cytokine regulation and production occur dur- neutrophils are crucial armaments against invading mi-
ing the development of the disease (see Terminology of crobial organisms, but they may also have deleterious
Cytokines and Cell Surface Molecules). effects on host tissues if released inappropriately.
Neutrophil elastase has been measured in the circula-
NEUTROPHIL ACTIVITY tion of human patients with AP of varying severity19; it
Neutrophils are the major effector cells of an acute was significantly increased in patients with severe dis-
inflammatory response. Neutrophil activity is believed ease by the third day of hospitalization. Neutrophil de-
to be central to the pulmonary pathologic characteris- pletion with an antineutrophil antiserum has been
tics of ARDS.3 Sequestration of neutrophils within the 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
chemia–reperfusion injury, Chemokines
and hemorrhagic shock.10 In Endotoxin?
these disease states, as well as
in spontaneous AP, neutrophil B
Local thrombosis
behavior is dramatically modi- CD11b/CD18
fied, which primes them for ICAM-1
damaging host tissues.
Collagen exposure

ENDOTOXIC Activation Margination Degranulation Endothelial damage

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


Small Animal/Exotics Compendium June 2000

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;

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

monocytes, pancreas many somatic cells immune system

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

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

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


Compendium June 2000 Small Animal/Exotics

Your comprehensive
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).

Successful therapy of AP in dogs relies on correct di-
Robert E. Cartee, Editor
agnosis and objective assessment of overall disease sever-
400 pages, hard cover
ity. The therapeutic approach to mild pancreatitis is
quite different from that of potentially fatal cases. Pan- 1597 illustrations
creatitis is a disease that occurs in a continuum of severi-
ty, and the distinctions between mild and severe cases ■ Sonographic diagnosis in dogs and cats,
are necessarily arbitrary. Early assessment of disease including ultrasound, M-mode, pulsed
severity is important, however, to allow a rational deci- and color Doppler echography
sion about how to treat a patient (i.e., whether to treat
on an outpatient or inpatient basis in a general practice ■ Echocardiography, abdominal and pelvic
setting or refer to a secondary care facility). sonography, and fetal ultrasonography
Table I summarizes the prognosis and typical therapeu-
tic interventions that can be used for dogs presenting at ■ Case illustrations using conventional
varying levels of severity. The severity score referred to in radiography, computed microfocal
the table is based on pretreatment clinical biochemistry tomography, specimen photography,
and hematologic characteristics and has been described in
greater depth elsewhere.4 and line drawings
Most of the clinical signs and complications of sponta- ■ Recognition of the disease process and
neous AP in dogs result from dehydration, circulating flu-
id losses, and electrolyte disturbances secondary to vomit-
courses of treatment
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 CALL OR FAX TODAY TO ORDER
therapy in companion animal practice has been reviewed 800-426-9119 • Fax: 800-556-3288
in recent publications.8,25
Price valid only in the US, Canada, Mexico, and
The mainstay of therapy for mild pancreatitis is ade- the Caribbean. Request international pricing.


Small Animal/Exotics Compendium June 2000

Experimental Models of Acute Pancreatitis
Model Species Outcome
Choline-deficient, ethionine-supplemented Rodents Necrotizing pancreatitis; occasional death

Overstimulation of pancreatic secretion Rodents, dogs Edematous pancreatitis; no death;

with cholecystokinin or cerulein few if any clinical signs

Pancreatic duct ligation Dogs Pancreatic necrosis and fibrosis with few
if any clinical signs; no death

Infusion of bile acids and/or trypsins into Rodents, rabbits, dogs Pancreatic necrosis
the pancreatic duct

Overstimulation of pancreatic secretion Rodents, dogs Severe pancreatic necrosis; extremely high
with cholecystokinin plus intraductal mortality rate (up to 100%); acute death
infusion of enterokinase

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

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.

Model studies have elucidated many of the patho- M

ugsy, a four-yea
ined within one
r-old, neutere
d male Beagle,
hour of ingestio
was exam-
n of the rat poison
l placement

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.
vomiting. In l identified as gas-
amount of green-b
lue d charcoa by
mL of activate
nt included 200 neously (SC).
tional treatme 2.5 mg/kg subcuta

cal dilemma takes readers from

and vitamin K1 supply of
tric intubation with a 10-day
ed to his owners

beginning phases of severe AP and the development of ILLUSTRATIO

Mugsy was discharg
vitamin K1 50
mg every 24
hours orally.

for PT determi
nation. All
blood chemist
PT at recheck

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
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
Peer Review

words. 76 Veterinary

The great strength of models is their reproducibility.

The use of a homogenous population of experimental

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

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

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
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

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

In clinical cases, the influence of additional factors tion.

has a much greater importance in determining the MONTH

overall severity and outcome. Clinical cases of pancre- is

Canine Hemipares , D.V.M.


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-
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:

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,

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
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:


Small Animal/Exotics Compendium June 2000

of clinical signs and peak inflammatory cytokine pro- cyte cytokine production in association with systemic com-
duction in humans with AP, it has been suggested that plications in acute pancreatitis. Br J Surg 83:919–923, 1996.
early treatment of these patients with anticytokine ther- 14. Pezzilli R, Billi P, Miniero R, Barakat B: Serum interleukin-
apy may have substantial benefits.17 However, this prop- 10 in human acute pancreatitis. Dig Dis Sci 41:1469–1472,
osition is yet to be tested in clinical trials. 1997.
It is not possible to recommend any specific im- 15. Rongione AJ, Kusske AM, Kwan K, et al: Interleukin-10 re-
duces the severity of acute pancreatitis in rats. Gastroenterology
mune-modulator therapy for routine use on the basis of
112:960–967, 1997.
current knowledge of the mechanisms that underlie or-
16. Ruaux CG, Pennington H, Worrall S, Atwell RB: Tumor
gan failure in dogs with severe AP. Until more objective
necrosis factor-α at presentation in 60 cases of spontaneous
evidence for the usefulness of this approach is available, canine acute pancreatitis. Vet Immun Immunopathol 72:369–
emphasis must remain on the proper fluid repletion 376, 1999.
and supportive care of these challenging medical cases. 17. Norman J: The role of cytokines in the pathogenesis of acute
pancreatitis. Am J Surg 175:76–83, 1998.
REFERENCES 18. Wagner JG, Roth RA: Neutrophil migration during endo-
1. Larvin M: Circulating mediators in acute pancreatitis as pre- toxemia. J Leukocyte Biol 66:10–24, 1999.
dictors of severity. Scand J Gastroenterol 31(Suppl 219):16– 19. Mora A, Pérez-Mateo M, Viedma JA, et al: Activation of cel-
19, 1996. lular immune response in acute pancreatitis. Gut 40:794–
2. Ruaux CG, Atwell RB: General practice attitudes to the 797, 1997.
treatment of spontaneous canine acute pancreatitis. Austr 20. Bhatia M, Saluja A, Hofbauer B, et al: The effects of neu-
Vet Pract 28:67–74, 1998. trophil depletion on a completely noninvasive model of
3. Forward J-L, Salla A, Bhagat L, et al: The role of intercellu- acute pancreatitis-associated lung injury. Int J Pancreatol 24:
lar adhesion molecule 1 and neutrophils in acute pancreatitis 77–83, 1998.
and pancreatitis-associated lung injury. Gastroenterology 21. Exley AR, Leese T, Holiday MP, et al: Endotoxaemia and
116:694–701, 1999. serum tumour necrosis factor as prognostic markers in severe
4. Ruaux CG, Atwell RB: A severity scoring system for canine acute pancreatitis. Gut 33:1126–1128, 1992.
acute pancreatitis. Aust Vet J 76:804–808, 1998. 22. Gerasoli F, McKenna PJ, Rosalia DL, et al: Superoxide an-
5. Bone R: Sepsis, sepsis syndrome, and the systemic inflamma- ion release from blood and bone marrow neutrophils is al-
tory response syndrome (SIRS). JAMA 273:155–156, 1995. tered by endotoxemia. Circ Res 67:154–165, 1990.
6. Bone R: Toward a theory regarding the pathogenesis of the 23. Gukovskaya A, Gukovsky I, Zanizovic V, et al: Pancreatic
systemic inflammatory response syndrome: What we do and acinar cells produce, release and respond to tumor necrosis
do not know about cytokine regulation. Crit Care Med 24: factor-α. J Clin Invest 100:1853–1862, 1997.
163–172, 1996. 24. Norman J, Fink G, Denham W, et al: Tissue specific cy-
7. Bone R: Immunologic dissonance: A continuing evolution tokine production during experimental acute pancreatitis. A
in our understanding of the systemic inflammatory response probable mechanism for distant organ dysfunction. Dig Dis
syndrome (SIRS) and the multiple organ dysfunction syn-
Sci 42:1783–1788, 1997.
drome (MODS). Ann Intern Med 125:680–687, 1996.
25. Mathews KA: The various types of parenteral fluids and
8. Purvis D, Kirby R: Systemic inflammatory response syn-
their indications. Vet Clin North Am Small Anim Pract 28:
drome: Septic shock. Vet Clin North Am Small Anim Pract
483–513, 1998.
24:1225–1247, 1994.
26. Rattner DW: Experimental models of acute pancreatitis and
9. Murakami H, Nakao A, Kishimoto W, et al: Detection of
O2– generation and neutrophil accumulation in rat lungs af- their relevance to human disease. Scand J Gastroenterol 31
ter acute necrotizing pancreatitis. Surgery 118:547–554, (Suppl 219):6–9, 1996.
1995. 27. Hess RS, Kass PH, Shofer FS, et al: Evaluation of risk fac-
10. Closa D, Sabater L, Fernández-Cruz L, et al: Activation of tors for fatal acute pancreatitis in dogs. JAVMA 214:46–51,
alveolar macrophages in lung injury associated with experi- 1999.
mental acute pancreatitis is mediated by the liver. Ann Surg 28. Norman J, Fink G, Messina J, et al: Timing of tumor necro-
229:230–236, 1999. sis factor antagonism is critical in determining outcome in
11. de Beaux AC, Goldie AS, Ross JA, et al: Serum concentra- murine lethal acute pancreatitis. Surgery 120:515–521, 1996.
tions of inflammatory mediators related to organ failure in
patients with acute pancreatitis. Br J Surg 83:349–353,
1996. About the Author
12. de Beaux AC, Ross JA, Maingay JP, et al: Proinflammatory Dr. Ruaux is affiliated with the Gastrointestinal Laborato-
cytokine release by peripheral blood mononuclear cells from ry, Department of Small Animal Medicine and Surgery,
patients with acute pancreatitis. Br J Surg 83:1071–1075, College of Veterinary Medicine, Texas A&M University,
1996. College Station, Texas.
13. McKay CJ, Gallagher G, Brooks B, et al: Increased mono-