Vol. 23, No.
7 July 2001
CE Article #4 (1.5 contact hours)
Refereed Peer Review
KEY FACTS
■ Although bacteria or their
products may be responsible for
initiation of the inflammatory
response, the response itself
results from the activity of host-
derived proinflammatory
mediators.
■ The excessive activity of
antiinflammatory mediators may
result in immunosuppression
during or after a severe
inflammatory response.
■ Because of the difficulty of
definitively identifying neonates
with bacterial infection, it can be
appropriately assumed that any
high-risk neonatal foal that
presents with clinical illness is
septic.
661
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Equine Neonatal
Sepsis: The
Pathophysiology of
Severe Inflammation
and Infection
Marion duPont Scott Equine Medical Center
Leesburg, Virginia
H. C. McKenzie III, DVM, MS, DACVIM
M. O. Furr, DVM, PhD, DACVIM
ABSTRACT: Although the clinical syndrome of sepsis is a major problem in equine neonates,
the pathophysiology of this condition remains incomplete. Because the term sepsis describes
a broad range of disorders with different underlying causes and often different prognoses, the
understanding of this process is further complicated. Continued progress is being made, how-
ever, in defining the syndromes associated with sepsis and in elucidating the mechanisms in-
volved in these processes. Attempts at modulating the septic process by interfering with the
action of bacterial toxins or the production or activity of individual mediators have not been
successful, thereby reinforcing that this is a multifactorial response. Fortunately, the complex
interactions of intra- and extracellular messengers leading to clinical sepsis continue to be de-
fined. An increased understanding of the processes involved in the septic response may aid in
the identification of patients with these syndromes as well as improve the effectiveness of
treatment regimens.
O
ne of the most challenging problems faced by equine veterinarians is the
management of equine neonates with sepsis. Despite the substantial ad-
vances that have been made in the medical management of these foals,
the mortality rate remains high.1 This is due to the fact that sepsis represents a
systemic inflammatory response to infection or injury; therefore, it can rapidly
progress to septic shock and death despite aggressive treatment. Traditionally,
the term septicemia, which is used to refer to this process in equine neonates, de-
scribes a systemic disease process involving the presence of pathogenic microor-
ganisms and/or their toxins in the blood.2 The classic presentation of sepsis was
that of disseminated gram-negative bacterial infections; however, it has become
apparent that an identical syndrome occurs in patients with gram-positive bacte-
662 Equine
Bacteremia
Hypoxia
Viremia
Infection Sepsis SIRS
Fungemia
Parasitemia
Other
Figure 1—Relationships of systemic inflammatory response syndrome (SIRS), sep- of microorganisms. It serves a vital role
sis, and infection. Infection is not always associated with an inflammatory re- because it enhances the movement of
sponse; and SIRS can occur without infection. When SIRS occurs in association phagocytic cells and defensive molecules
with infection, the response may be referred to as sepsis.3
rial infections, viral infections, trauma, hypovolemia,
hemorrhage, and immunologic and drug reactions (Fig-
ure 1).3–6
The abnormalities associated with the clinical syn-
drome of sepsis result from a nonspecific innate inflam-
matory response. This response, which has been termed
the systemic inflammatory response syndrome
(SIRS), is not necessarily associated with the presence
of bacterial infection.7,8 SIRS, which represents a com-
mon terminal phase of the inflammatory response char-
acterized by malignant global activation of multiple
proinflammatory pathways,4 is defined by the presence
of two or more of the following abnormalities: fever or
hypothermia (rectal temperature greater than 39.2˚C or
less than 37.2˚C), tachycardia (heart rate greater than
120 beats/min), tachypnea (respiratory rate greater
than 30 breaths/min) or hypocapnia (partial pressure of
arterial carbon dioxide less than 32 mm Hg), leukocy-
tosis or leukopenia (leukocyte count greater than
12,500 or less than 4000 cells/µl), or increased num-
bers of immature forms of granulocytes (greater than
10% bands).9,10 These manifestations of disease are the
same as those previously used to define sepsis, and the
appreciation that many different stimuli can induce
this response has resulted in sepsis being redefined as
SIRS due to infection (Box 1).8
The changes associated with SIRS can lead to shock,
which is characterized by severe hypotension not re-
sponsive to intravenous fluid therapy (Figure 2). Shock
can result in hypoperfusion and organ dysfunction such
that homeostasis cannot be maintained without inter-
Compendium July 2001
vention, a process termed multiorgan
dysfunction syndrome (MODS). 5,8,9
MODS is a progressive syndrome with
initial dysfunction in the cardiovascular
system, followed by involvement of the
respiratory, hepatic, gastrointestinal, re-
nal, cardiac, and neurologic systems.5,11
These processes result in the development
Trauma of refractory hypotension, lactic acidosis,
and oliguria, often progressing to
death.9,11
Other PATHOPHYSIOLOGY OF SEPSIS
Inflammation
Inflammation represents the response
of tissues to either injury or the presence
(e.g., immunoglobulin, complement)
from the bloodstream to the site of infec-
tion or injury. The first step in this pro-
cess is the recognition of tissue injury or microbial inva-
sion. Injured cells release preformed mediators (e.g.,
histamine) and synthesize proinflammatory substances,
including eicosanoids (e.g., prostaglandins, thrombox-
anes, leukotrienes) and the cytokines (interleukin [IL]-1
and tumor necrosis factor [TNF]–α; Figures 2 and 3).
These mediators are responsible for the initiation of a
nonspecific inflammatory response. Microbial invasion
BOX 1
Terms Used to Describe Clinical Syndromes
Associated with Systemic Inflammation9,10
Infection: Inflammatory response to the presence of
microorganisms or the invasion of normally sterile
host tissue by microorganisms
Bacteremia/septicemia: Presence of viable bacteria in
the bloodstream
Systemic inflammatory response syndrome (SIRS):
Systemic response to an array of severe clinical
insults
Shock: SIRS-induced hypotension refractory to fluid
resuscitation in association with hypoperfusion
Sepsis: SIRS due to infection
Severe sepsis: Sepsis associated with organ
dysfunction, hypoperfusion, or hypotension
Septic shock: Sepsis-induced shock
Multiorgan dysfunction syndrome (MODS):
Altered organ function in an acutely ill patient
requiring intervention to maintain homeostasis
Compendium July 2001 Equine 663

Normal Foal
Intrauterine infection Postnatal infection

Hypoxia Other insults: Trauma, hypovolemia,

hemorrhage, drug or immunologic reactions

Recognition of tissue injury

or presence of microorganisms
(see Figure 4)

Proinflammatory enzymes Proinflammatory cytokines

(inducible nitric oxide synthase, Macrophage activation (interleukin-1, tumor necrosis factor–α,
phospholipase A2, cyclooxygenase-2) (see Figures 3 and 4) interleukin-6, interleukin-12, and
interleukin-18)

Increased vascular Endothelial activation and Neutrophil activation,

permeability local vasodilation chemotaxis, migration

Systemic vasoconstriction
(transient)
Fluid Localized
Impaired cardiac function
extravasation hemostatic
dysfunction
Systemic vasodilatation

Systemic hemostatic Refractory hypotension

dysfunction (shock)

Multiorgan dysfunction Tissue injury/

syndrome cellular dysfunction

Figure 2—Schematic representation of the progression of the inflammatory process and associated pathophysiologic changes in a
foal exposed to infectious organisms or other injurious insults.

may result in tissue injury, thereby initiating this pro-
cess, or specific bacterial cell components may be recog-
nized by immune cells (macrophages), which result in
the production of inflammatory mediators and the ini-
tiation of an inflammatory response.12 The bacterial
cellular components that are recognized by the immune
system include endotoxins (lipopolysaccharide; LPS)
and exotoxins from gram-negative bacteria as well as
peptidoglycans (PGs), lipoteichoic acids (LTAs), en-
terotoxins, and superantigenic exotoxins from gram-
positive bacteria.7,13–15 Although bacterial infection may
be responsible for the initiation of an inflammatory re-
sponse, the inflammatory process itself results solely
from the production of endogenous mediators.
Because of the predominance of gram-negative infec-
tion in foals with sepsis, LPS is commonly involved in
the molecular mechanisms described. On entering the
circulation, LPS is avidly bound to the LPS-binding
protein (LBP); the LPS–LBP complex then binds to a
receptor present on the surface of the mononuclear
phagocyte (mCD14) or in the circulation (sCD14).16,17
CD14 also binds PG and LTA from gram-positive bac-
teria.7,13,16 This may represent a route of cellular activa-
tion in gram-positive infections.7,13,16 The LPS–LBP–
664 Equine Compendium July 2001

Lipopolysaccharide
Trauma Lipopolysaccharide-binding Gram-
Hypoxia protein positive
bacteria
Viruses
Mononuclear
phagocyte
+ –
+
+
PROTEIN MEDIATORS LIPID MEDIATORS REDUCED OXYGEN SPECIES
■ Interleukin-1 ■ Complement ■ Platelet activation factor ■ Singlet oxygen
■ Interleukin-6 system ■ Thromboxane A2 ■ Superoxide anion
■ Interleukin-8 ■ Coagulation ■ Prostaglandins ■ Hydroxyl radical ANTIINFLAMMATORY
■ Interleukin-12 system ■ Leukotrienes ■ Nitric oxide MEDIATORS
■ TNF-α ■ Interferon-γ ■ Hypochloride ion ■ Interleukin-4
■ Elastase/cathepsin B ■ Interleukin-10
■ Kinin/kallikreins ■ Interleukin-13
■ Adrenal corticosteroids
■ Prostaglandin E2
■ Interleukin-1 receptor
antagonist
■ Soluble interleukin-1
Low systemic levels High systemic levels receptor II
of mediators of mediators ■ Soluble TNF receptors

– –
BENEFICIAL EFFECTS DETRIMENTAL EFFECTS
■ Moderate fever ■ SIRS
■ Immune stimulation ■ Disseminated intravascular
■ Microbicidal effects coagulation
■ Septic shock

Figure 3—Interaction of initiating factors and host-derived proinflammatory (+) and antiinflammatory (−) mediators in the reso-
lution of infection and the development of SIRS and septic shock.14

CD14 or PG–LTA–CD14 complex is then responsible
for cellular activation of the mononuclear phagocyte via
a toll-like receptor (TLR) that transmits the activation
signal across the cell membrane (Figure 4).7 Numerous
types of TLRs have been identified in mammalian
species; evidence suggests that these different types of
TLRs are responsible for recognition of different types
of microbial pathogens.7
Cellular activation may also occur because of the de-
velopment of a nonspecific oxidative stress reaction
within the mononuclear phagocyte following stimula-
tion by proinflammatory stimuli such as TNF-α, endo-
toxin, or exotoxins (Figure 4).18 The development of an
inflammatory response is dependent on the produc-
tion—primarily by the activated mononuclear phago-
cyte—of numerous inflammatory mediators, including
proinflammatory cytokines (e.g., TNF-α, IL-1, IL-6),
proinflammatory enzymes (e.g., inducible nitric oxide
synthase, phospholipase A2, cyclooxygenase-2), and ad-
hesion molecules (e.g., selectins, intracellular adhesion
molecules).18 The transcription of many of the genes
encoded for these mediators or the enzymes that pro-
duce them is dependent on the transcription activator
nuclear factor–κB; therefore, this molecule may be a
potential target for intervention in SIRS (Figure 4).19–21
The initial changes that occur in an inflammatory re-
sponse are primarily the result of local vasodilation
and increased vascular permeability caused by the effects
of vasoactive mediators released by the injured or infect-
ed cell (Figures 2 and 3). These factors include his-
tamine, serotonin, kinins, eicosanoids, platelet activat-
ing factor, fibrin degradation products, and the
complement products, C3a and C5a. Changes occur in
the vascular endothelium under the influence of
Compendium July 2001 Equine 665

molecules arising from the injured tis-

CD14
sue (e.g., IL-1, TNF-α, histamine), re- TNF
sulting in neutrophil diapedesis and or IL-1
4,22
receptor
increased vascular permeability. On
TLR
their arrival at the site of tissue injury, +
IκB-α/nuclear factor–κB
complex
neutrophils and macrophages phago- +
cytose foreign material and injured or +
TLR
dead tissue cells and destroy the
Nuclear factor–κB
phagocytosed material by oxidative
mechanisms (neutrophils) or by both
oxidative and nonoxidative mecha-
Phosphorylated
nisms (macrophages). In addition, IκB-α
macrophages release a number of fac-
tors that augment the immune re- Gene +
Proinflammatory transcription Cytoplasm
sponse, including the proinflammato- cytokines Protein
ry cytokines (e.g., IL-1, TNF-α, IL-6, and enzymes synthesis
IL-12, IL-18; Figure 3). The proin- Nucleus
flammatory cytokines signal target
cells, primarily neutrophils, to increase
the production of secondary inflam- Figure 4—The transcription activator nuclear factor (NF)–κB is normally retained in
matory mediators, including phospho- the cytoplasm in an inactivated state, preventing the unregulated production of in-
lipid derivatives (e.g., prostaglandins, flammatory mediators. This inactivation is caused by the binding of NF-κB by the
thromboxane A2, leukotrienes) and re- repressor protein IκB-α.19 Following stimulation of the cell by a proinflammatory
active oxygen species (singlet oxygen, agent, IκB-α is phosphorylated, freeing NF-κB, which is then capable of entering
superoxide anion, hydroxyl radical, the nucleus and activating transcription of genes encoding for inflammatory cy-
hydrogen peroxide, NO, hypochloride tokines (e.g., tumor necrosis factor–α, interleukin-1, interleukin-6), proinflammato-
ion), further increasing the activity of ry enzymes (e.g., inducible nitric oxide synthase, phospholipase A2, cylcooxygenase-18
the inflammatory response.23 The sys- 2), and adhesion molecules (e.g., selectins, intracellular adhesion molecules).
temic manifestations of inflammation
and/or infection (e.g., fever, lethargy,
malaise, loss of appetite, cachexia) are primarily due to flammatory cytokines (e.g., soluble IL-1 receptor type
TNF-α and IL-1. II, soluble TNF receptors).4,21,25 The balance between
these proinflammatory and antiinflammatory compo-
Acute-Phase Response nents is important in determining the characteristics of
Interleukin-6, IL-1, and TNF-α initiate the acute- the inflammatory response because excessive activity of
phase response, whereby the liver increases production the antiinflammatory component may result in im-
of acute-phase proteins. These substances are important munosuppression during or after a severe inflammatory
in many phases of the response to inflammatory stimuli, response, which has been termed compensatory antiin-
including complement activation, coagulation, fibrinol- flammatory response syndrome by Bone and col-
ysis, transport of substances within the blood stream, in- leagues.9
hibition of neutrophil proteases, and modulation of the
inflammatory response (Figure 3).24 The acute-phase re- Systemic Inflammatory Response Syndrome
sponse is critical in inflammation, healing, and adapta- In moderation, the changes associated with an inflam-
tion to noxious stimuli.24 Also included in the acute- matory response are protective, resulting in enhanced
phase response is a counterregulatory antiinflammatory killing of microbes by antigen-specific and nonspecific
component that normally functions to minimize and re- mechanisms, generalized immune stimulation, and in-
solve the inflammatory response to localized stimuli. creased activity of the systems required for the healing of
This counterregulatory response consists of antiinflam- damaged tissue. The excessive, malignant form of the
matory mediators that inhibit macrophage activation inflammatory and acute-phase responses, termed SIRS,
(e.g., IL-4, IL-10, IL-13, adrenal corticosteroids, trans- is characterized by the systemic activity of numerous
forming growth factor-β, prostaglandin-E2), antagonists proinflammatory mediators, including cytokines (e.g.,
to the receptors for proinflammatory cytokines (e.g., IL- IL-1, TNF-α, IL-6, IL-8), phospholipid derivatives
1 receptor antagonist), and soluble receptors of proin- (e.g., platelet activating factor, prostaglandins, throm-
Compendium July 2001
boxane A2, leukotrienes), complement components (e.g.,
C3a, C5a), reactive oxygen species (e.g., superoxide an-
ion, hydrogen peroxide, hydroxyl radical, singlet oxygen,
hypochloride ion), and vasoactive gases (e.g., NO, car-
bon monoxide).4,25 As previously described, these media-
tors all represent components of the normal inflammato-
ry response to a localized stimulus, but the systemic
activity of these proinflammatory mediators may result
in an excessive, and often detrimental, response.
One of the first effects that occurs with SIRS is
widespread endothelial activation, resulting in the in-
creased production of vasoactive mediators and alter-
ation of vascular homeostasis. Inflammatory cytokines
(e.g., IL-1, TNF-α) are responsible for activation of the
endothelium, and the activated cells produce inflam-
matory cytokines as well as increased amounts of NO
(via inducible NO synthase), prostaglandins (via in-
ducible cyclooxygenase-2), and endothelin-1.26 Activat-
ed endothelial cells retract from one another, increasing
the size of the intercellular pores and allowing for in-
creased vascular permeability. They also increase their
production of tissue factor and von Willebrand factor,
resulting in localized thrombosis and platelet adher-
ence, respectively.26
The initial systemic effect of these changes is pul-
monary vasoconstriction leading to pulmonary hyper-
tension 27 likely caused by thromboxane A 2. 28 The
initial hypertensive phase is followed by systemic hy-
potension caused by decreased arterial tone and results
in decreased left ventricular preload, combined with
venous vasodilation in the large-capacity vessels that
decreases venous return. These effects are likely due to
epoprostenal (PGI2; prostacyclin) and NO26 and can
progress to the syndrome of hyperdynamic shock, with
increases in heart rate and cardiac output developing as
compensatory mechanisms to maintain tissue perfu-
sion.29 This compensatory response is impaired by the
reduction in left ventricular preload, combined with
the decreased cardiac contractility resulting from my-
ocardial depressants (e.g., NO, TNF-α , IL-1), de-
creased myocardial responsiveness to β-adrenergic
stimulation, and decreased compliance due to myocar-
dial edema.15
Changes occurring in the microvasculature further
contribute to the impairment of tissue perfusion. Arteri-
olar vasoconstriction develops due to the impairment
of the normal autoregulatory systems (e.g., NO from
endothelial NO synthase, PGI2 from cyclooxygenase-1)
caused by inflammatory cytokines and endothelin-1
combined with the increased production of vasocon-
strictive substances (e.g., endothelin-1, thromboxane
A2). Adherence of neutrophils to the endothelium and
endothelial cell swelling further reduce blood flow. Ac-
Equine 667
cumulation of fibrin and aggregation of platelets and
erythrocytes secondary to activation of the clotting sys-
tem results in occlusion of the vasculature, leading to
tissue hypoperfusion. Arteriovenous shunting occurs in
some tissues, whereas increased vascular permeability
results in extravasation of fluids into the interstitial
space, further contributing to hypotension and hypo-
volemia. Progressive alteration of the microcirculation
leading to failure may represent the common final
pathway of SIRS-related injury contributing to or re-
sulting in MODS.30
Activation of coagulation occurs primarily through
the extrinsic pathway because of the production and
surface expression of tissue factor (thromboplastin) on
endothelial cells and mononuclear phagocytes under the
influence of IL-6, the production of which is increased
by proinflammatory stimuli (e.g., endotoxin, TNF-α,
IL-1).25,31,32 Endothelial injury secondary to neutrophil
degranulation results in decreased production of PGI2
and NO, leading to increased platelet adhesion.32 In the
normal state, the accumulation of excessive amounts of
fibrin would be prevented by the action of plasmin, the
primary mediator of fibrinolysis. In the presence of
SIRS, the fibrinolytic system is suppressed because of
the increased plasma concentration of plasminogen-acti-
vator inhibitor type 1, the primary inhibitor of fibrinol-
ysis.31 The widespread activation of the clotting system,
combined with impairment of fibrinolysis and depres-
sion of the inhibitors of coagulation, can result in a con-
sumptive coagulopathy potentially leading to dissemi-
nated intravascular coagulation.16,31
Shock
The progression of these processes affecting the car-
diovascular system ultimately results in shock. Shock
occurs when cardiovascular function is severely im-
paired, such that hypotension cannot be corrected with
intravenous fluid administration and requiring the use
of inotropic and/or vasopressor agents.5,11 Shock repre-
sents severe cardiovascular dysfunction associated with
SIRS and is a primary component of MODS. Septic
shock is defined as shock associated with infection.
Multiorgan Dysfunction Syndrome
The development of MODS is likely the result of
cardiovascular dysfunction, which leads to tissue hy-
poperfusion combined with changes in cellular
metabolism that result in impairment of oxygen deliv-
ery and uptake, respectively.11 The presence of tissue
hypoxia is manifested by metabolic acidosis and de-
creased oxygen extraction ratios.11 Pulmonary dysfunc-
tion is manifested by refractory hypoxemia, potentially
caused by increased pulmonary vascular permeability,
668 Equine
microthrombi formation, pulmonary epithelial injury,
pulmonary edema, and impairment of surfactant pro-
duction.33 Renal dysfunction is manifested by the de-
velopment of azotemia and oliguria; acute renal failure
is likely caused by alterations in the distribution of in-
trarenal blood flow arising from microvascular alter-
ations with or without systemic hypotension.11
Gastrointestinal dysfunction is primarily manifested
by the presence of ileus but may also result in loss of
the normal barrier function of the gastrointestinal mu-
cosa.34 This loss of the mucosal barrier may further
contribute to the pathogenesis of MODS due to bacte-
rial translocation or endotoxin absorption.34 Hepatic
dysfunction is manifested by the development of hyper-
bilirubinemia and, in some cases, increased serum ac-
tivities of hepatic enzymes (sorbital dehydrogenase, as-
partate aminotransferase). Hepatic dysfunction may
result from hypoperfusion, particularly because of the
high metabolic demands of this tissue, but may be
heightened by the production of inflammatory media-
tors by the hepatic Kupffer’s cells secondary to the ac-
tions of systemic mediators or stimuli derived from the
gastrointestinal tract.35 Dysfunction of the central ner-
vous system, which is frequently present, may manifest
as depression but can progress to septic encephalopathy
with extensive neuronal injury.36 The development of
consumptive coagulopathy (disseminated intravascular
coagulation) could also be considered a component of
MODS rather than merely a pathophysiologic process
contributing to the development of organ failure.
NEONATAL SEPTICEMIA
Risk Factors
A number of factors have been identified that in-
crease the likelihood of septicemia and mortality in
equine neonates. The risk factors for septicemia may
include a history of placentitis, prenatal vulvar dis-
charge, dystocia, maternal illness, premature or delayed
parturition, induced parturition, total failure of passive
transfer, prolonged transport of the pregnant mare, and
the presence of localized disease in the neonate (e.g.,
anterior uveitis, diarrhea, pneumonia, infectious arthri-
tis, open wounds).37,38 Partial failure of passive transfer
(serum IgG concentration 200 to 400 mg/dl) has been
considered a risk factor for septicemia. However, this
may not be the case because one study39 reported no
statistical difference in duration or frequency of illness
or survival when comparing foals with IgG concentra-
tions of less than 400 or greater than 800 mg/dl. Risk
factors for neonatal death may include maternal illness,
premature or delayed parturition, induced parturition,
prolonged duration of clinical signs, and decreased
serum IgG concentration.40,41
Compendium July 2001
Routes of Invasion
Pathogenic organisms can infect equine neonates by
numerous routes. While in the intrauterine environ-
ment, the fetus may be exposed to organisms that have
invaded the placenta or that cross the placental–chorial
barrier, gaining direct access to the foal’s bloodstream.
Bacteria associated with placental disease may enter the
amniotic fluid and gain access to the respiratory and gas-
trointestinal tracts of the fetus. After birth, bacterial in-
fection can be caused by contamination of the umbilical
stump, ingestion or inhalation, or secondary to wounds.2
Organisms Involved in Neonatal Sepsis
Blood culture remains the most definitive test for ante-
mortem identification of septicemia in equine neonates.
Blood culture should be performed—ideally prior to the
administration of antimicrobial therapy—when any
equine neonate presents with a clinical suspicion of sep-
sis. This test has been reported to have variable sensitivi-
ty in many species, including horses, with false-negative
results obtained in up to 37% of cases of fatal
septicemia.42,43 It is interesting to contemplate how much
higher the false-negative rate might be in the less severely
ill neonate that recovers with antimicrobial therapy.44 It
has been recommended that multiple samples be collect-
ed to maximize the sensitivity of this test, but the majori-
ty of isolates have been reported to be present in the first
culture sample. The need for immediate antimicrobial
therapy usually results in only one sample being ob-
tained.2 Because of the low sensitivity of blood culture, it
is important to obtain bacterial cultures from suspected
areas of infection during the course of treatment because
the blood culture may be falsely negative or nosocomial
infection may have developed during the course of treat-
ment. The appropriate samples are dependent on the
system affected but would include transtracheal aspirate;
blood; urine; synovial, peritoneal, and cerebrospinal flu-
id; and umbilical remnants following surgical resection.
Although historically gram-positive organisms were
most commonly associated with neonatal infections,
over the past 20 years the most common bacteria isolat-
ed from infected foals have been gram-negative organ-
isms (Table 1).2,42,43,45 Gram-positive organisms isolated
from infected foals are typically present in mixed infec-
tions with gram-negative organisms; streptococcal
species are most common.2,42,46 Other organisms associ-
ated with severe systemic inflammation in equine
neonates include equine herpesvirus type 1 and Histo-
plasma capsulatum.6,47,48 It is also possible that severe hy-
poxia, which leads to hypoxic ischemic encephalopathy
(also known as neonatal asphyxia, dummy foal syn-
drome), represents a causative factor for induction of
SIRS in equine neonates.49,50
Compendium July 2001 Equine 669

TABLE 1 nents of the clinical situation, it also results in a loss of

Organisms Isolated from Infected Neonatal Foals
information.53 The second limitation arises from the
fact that, as previously discussed, the pathophysiologic
Organism Percentage of Isolates mechanisms operating in equine neonates with SIRS
Gram-negative are consistent, regardless of the primary etiology.
Escherichia coli 42,43,45 30.6–56% Therefore, the manifestations of disease that are subse-
Klebsiella pneumoniae 42,43 3.7–12.9% quently incorporated into a scoring system inherently
Actinobacillus species42,43,45 8–19% lack the precision required to differentiate various types
Enterobacter species42,43,45 3.5–5.7% of primary disease. As a result, no sepsis score can sub-
Pseudomonas aeruginosa 42,43,45 2.8–4.7% stitute for clinical judgment, and these scores should be
Citrobacter species43 4.7% used as a diagnostic aid in the identification of high-
Pasteurella species42 3.7% risk individuals with full consideration given to their
Salmonella species42,45 2.8–3.7% limitations.37,53 Because of the difficulty of definitively
Serratia marcescens 42,45 2.8–3.7%
identifying neonates with bacterial infection, it is ap-
Gram-positive propriate to make the assumption that any high-risk
β-hemolytic streptococci 43,45 1.2–5.6% neonatal foals presenting with clinical illness are sep-
Other streptococci 43 7.1% tic.54 Aggressive therapy that includes antimicrobials is
Staphylococcus species42,45 2.8–3.7% indicated. Although there are some risks associated
Clostridium species42,43,45 2.4–3.7% with antimicrobial therapy, they are greatly outweighed
by the risks associated with withholding antimicrobial
Other therapy from a patient with sepsis secondary to bacteri-
Equine herpesvirus type 16,47 Not available al infection.
Histoplasma capsulatum 48 Not available
CONCLUSION
The development of SIRS in equine neonates is a
Identification of Septic Neonates complex process that involves numerous initiating fac-
Identification of septic neonates is of clinical rele- tors, inflammatory mediators, and variable degrees of
vance in ensuring that appropriate treatment is admin- organ dysfunction. Initially, it may be difficult to deter-
istered and in determining prognosis for survival. The mine the underlying disease process when presented
identification of septic neonates remains problematic, with a neonate with SIRS. Treatment of patients with
however, because neonates that present with clinical ab- SIRS requires the same basic supportive therapies (e.g.,
normalities consistent with sepsis (SIRS) may be nega- intravenous fluids, antimicrobials, antiinflammatories)
tive on blood culture with no evidence of a focal site of regardless of the etiology, but identification of the spe-
infection. Attempts to identify equine neonates with cific etiology will allow for more effective and appropri-
septicemia have included the development of a sepsis ate application of both basic and adjunctive therapies. It
scoring system that combines historical information, is clear that the treatment of SIRS and its sequelae can-
objective data, and subjective measures to derive a nu- not focus solely on any single component of this process
merical representation of the patient’s condition.51 The but must be directed at resolution of the initiating stim-
sensitivity and specificity of this scoring system were re- ulus, modulation of the inflammatory response, and
ported to be 93% and 86%, respectively.51 Unfortu- support and maintenance of organ function.
nately, the specificity and sensitivity may not always be
this high.52 In addition, this scoring system must be REFERENCES
adapted to each intensive care unit in which it is ap- 1. Freeman L, Paradis MR: Evaluating the effectiveness of
plied to achieve reasonably high levels of sensitivity and equine neonatal care. Vet Med 87(9):921–926, 1992.
specificity.52 2. Paradis MR: Update on neonatal septicemia. Vet Clin North
Am Equine Pract 10(1):109–135, 1994.
Attempts to create sepsis scoring systems for human 3. Bone RC, Balk RA, Cerra FB, et al: Definitions for sepsis
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51. Brewer BD, Koterba AM: Development of a scoring system d. systemic antiinflammatory response syndrome.
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6. Blood culture samples
a. are often contaminated with nonpathogenic bacte-
ria.
ARTICLE #4 CE TEST b. are rarely useful in guiding the clinical management

CE
The article you have read qualifies for 1.5 con-
tact hours of Continuing Education Credit from
the Auburn University College of Veterinary
Medicine. Choose the best answer to each of the fol-
lowing questions; then mark your answers on the
postage-paid envelope inserted in Compendium.
of septic foals.
c. must be collected before administration of antimi-
crobial agents.
d. have very high sensitivity and specificity for sep-
ticemia.
e. should be collected in all foals presented with a
clinical suspicion of sepsis.

7. Antimicrobial therapy
1. The clinical condition of sepsis results from the activi- a. should be delayed pending the results of bacterial
ty of culture and sensitivity testing.
a. bacteria. b. should be initiated early in any high-risk clinically
b. viruses. ill neonatal foal.
c. fungi. c. is without major risk.
d. host-derived mediators. d. will prevent the culture of organisms from blood
e. all of the above cultures.
e. should be reserved only for foals with clinically de-
2. SIRS represents tectable infection.
a. the clinical response to infection.
b. the excessive activity of the antiinflammatory re- 8. Abnormalities used to define SIRS include all of the
sponse. following except
c. the result of cardiovascular dysfunction leading to a. fever.
tissue hypoperfusion. b. tachypnea.
d. the excessive, malignant form of the inflammatory c. leukocytosis.
and acute-phase responses. d. central nervous system depression.
e. a systemic disease process involving the presence of e. hypothermia.
pathogenic microorganisms and/or their toxins in
the blood. 9. Sepsis scoring systems are helpful in
a. deciding if a foal should be treated with antimicro-
3. The organisms most commonly involved in equine bials.
neonatal infections are b. monitoring the response to treatment.
a. gram-positive bacteria. c. identification of high-risk individuals.
b. gram-negative bacteria. d. assessment of passive transfer.
c. equine herpesvirus type 1. e. determining the most appropriate antimicrobials
d. mixed bacterial infections. for treatment of sepsis.
e. anaerobic bacteria.
10. Organ dysfunction in equine neonates with sepsis may
4. The excessive activity of endogenous antiinflammatory be manifested by all of the following except
mediators may result in the a. polyuria.
a. MODS. b. hypotension.
b. SIRS. c. hypoxia.
c. compensatory antiinflammatory response syn- d. ileus.
drome. e. hyperbilirubinemia.