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Equine Neonatal
KEY FACTS Sepsis: The
■ Although bacteria or their
products may be responsible for
initiation of the inflammatory
Pathophysiology of
response, the response itself
results from the activity of host-
derived proinflammatory
Severe Inflammation
mediators.
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 Compendium July 2001
Normal Foal
Intrauterine infection Postnatal infection
Systemic vasoconstriction
(transient)
Fluid Localized
Impaired cardiac function
extravasation hemostatic
dysfunction
Systemic vasodilatation
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- sponse, the inflammatory process itself results solely
cess, or specific bacterial cell components may be recog- from the production of endogenous mediators.
nized by immune cells (macrophages), which result in Because of the predominance of gram-negative infec-
the production of inflammatory mediators and the ini- tion in foals with sepsis, LPS is commonly involved in
tiation of an inflammatory response.12 The bacterial the molecular mechanisms described. On entering the
cellular components that are recognized by the immune circulation, LPS is avidly bound to the LPS-binding
system include endotoxins (lipopolysaccharide; LPS) protein (LBP); the LPS–LBP complex then binds to a
and exotoxins from gram-negative bacteria as well as receptor present on the surface of the mononuclear
peptidoglycans (PGs), lipoteichoic acids (LTAs), en- phagocyte (mCD14) or in the circulation (sCD14).16,17
terotoxins, and superantigenic exotoxins from gram- CD14 also binds PG and LTA from gram-positive bac-
positive bacteria.7,13–15 Although bacterial infection may teria.7,13,16 This may represent a route of cellular activa-
be responsible for the initiation of an inflammatory re- 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 proinflammatory enzymes (e.g., inducible nitric oxide
for cellular activation of the mononuclear phagocyte via synthase, phospholipase A2, cyclooxygenase-2), and ad-
a toll-like receptor (TLR) that transmits the activation hesion molecules (e.g., selectins, intracellular adhesion
signal across the cell membrane (Figure 4).7 Numerous molecules).18 The transcription of many of the genes
types of TLRs have been identified in mammalian encoded for these mediators or the enzymes that pro-
species; evidence suggests that these different types of duce them is dependent on the transcription activator
TLRs are responsible for recognition of different types nuclear factor–κB; therefore, this molecule may be a
of microbial pathogens.7 potential target for intervention in SIRS (Figure 4).19–21
Cellular activation may also occur because of the de- The initial changes that occur in an inflammatory re-
velopment of a nonspecific oxidative stress reaction sponse are primarily the result of local vasodilation
within the mononuclear phagocyte following stimula- and increased vascular permeability caused by the effects
tion by proinflammatory stimuli such as TNF-α, endo- of vasoactive mediators released by the injured or infect-
toxin, or exotoxins (Figure 4).18 The development of an ed cell (Figures 2 and 3). These factors include his-
inflammatory response is dependent on the produc- tamine, serotonin, kinins, eicosanoids, platelet activat-
tion—primarily by the activated mononuclear phago- ing factor, fibrin degradation products, and the
cyte—of numerous inflammatory mediators, including complement products, C3a and C5a. Changes occur in
proinflammatory cytokines (e.g., TNF-α, IL-1, IL-6), the vascular endothelium under the influence of
Compendium July 2001 Equine 665
boxane A2, leukotrienes), complement components (e.g., cumulation of fibrin and aggregation of platelets and
C3a, C5a), reactive oxygen species (e.g., superoxide an- erythrocytes secondary to activation of the clotting sys-
ion, hydrogen peroxide, hydroxyl radical, singlet oxygen, tem results in occlusion of the vasculature, leading to
hypochloride ion), and vasoactive gases (e.g., NO, car- tissue hypoperfusion. Arteriovenous shunting occurs in
bon monoxide).4,25 As previously described, these media- some tissues, whereas increased vascular permeability
tors all represent components of the normal inflammato- results in extravasation of fluids into the interstitial
ry response to a localized stimulus, but the systemic space, further contributing to hypotension and hypo-
activity of these proinflammatory mediators may result volemia. Progressive alteration of the microcirculation
in an excessive, and often detrimental, response. leading to failure may represent the common final
One of the first effects that occurs with SIRS is pathway of SIRS-related injury contributing to or re-
widespread endothelial activation, resulting in the in- sulting in MODS.30
creased production of vasoactive mediators and alter- Activation of coagulation occurs primarily through
ation of vascular homeostasis. Inflammatory cytokines the extrinsic pathway because of the production and
(e.g., IL-1, TNF-α) are responsible for activation of the surface expression of tissue factor (thromboplastin) on
endothelium, and the activated cells produce inflam- endothelial cells and mononuclear phagocytes under the
matory cytokines as well as increased amounts of NO influence of IL-6, the production of which is increased
(via inducible NO synthase), prostaglandins (via in- by proinflammatory stimuli (e.g., endotoxin, TNF-α,
ducible cyclooxygenase-2), and endothelin-1.26 Activat- IL-1).25,31,32 Endothelial injury secondary to neutrophil
ed endothelial cells retract from one another, increasing degranulation results in decreased production of PGI2
the size of the intercellular pores and allowing for in- and NO, leading to increased platelet adhesion.32 In the
creased vascular permeability. They also increase their normal state, the accumulation of excessive amounts of
production of tissue factor and von Willebrand factor, fibrin would be prevented by the action of plasmin, the
resulting in localized thrombosis and platelet adher- primary mediator of fibrinolysis. In the presence of
ence, respectively.26 SIRS, the fibrinolytic system is suppressed because of
The initial systemic effect of these changes is pul- the increased plasma concentration of plasminogen-acti-
monary vasoconstriction leading to pulmonary hyper- vator inhibitor type 1, the primary inhibitor of fibrinol-
tension 27 likely caused by thromboxane A 2. 28 The ysis.31 The widespread activation of the clotting system,
initial hypertensive phase is followed by systemic hy- combined with impairment of fibrinolysis and depres-
potension caused by decreased arterial tone and results sion of the inhibitors of coagulation, can result in a con-
in decreased left ventricular preload, combined with sumptive coagulopathy potentially leading to dissemi-
venous vasodilation in the large-capacity vessels that nated intravascular coagulation.16,31
decreases venous return. These effects are likely due to
epoprostenal (PGI2; prostacyclin) and NO26 and can Shock
progress to the syndrome of hyperdynamic shock, with The progression of these processes affecting the car-
increases in heart rate and cardiac output developing as diovascular system ultimately results in shock. Shock
compensatory mechanisms to maintain tissue perfu- occurs when cardiovascular function is severely im-
sion.29 This compensatory response is impaired by the paired, such that hypotension cannot be corrected with
reduction in left ventricular preload, combined with intravenous fluid administration and requiring the use
the decreased cardiac contractility resulting from my- of inotropic and/or vasopressor agents.5,11 Shock repre-
ocardial depressants (e.g., NO, TNF-α , IL-1), de- sents severe cardiovascular dysfunction associated with
creased myocardial responsiveness to β-adrenergic SIRS and is a primary component of MODS. Septic
stimulation, and decreased compliance due to myocar- shock is defined as shock associated with infection.
dial edema.15
Changes occurring in the microvasculature further Multiorgan Dysfunction Syndrome
contribute to the impairment of tissue perfusion. Arteri- The development of MODS is likely the result of
olar vasoconstriction develops due to the impairment cardiovascular dysfunction, which leads to tissue hy-
of the normal autoregulatory systems (e.g., NO from poperfusion combined with changes in cellular
endothelial NO synthase, PGI2 from cyclooxygenase-1) metabolism that result in impairment of oxygen deliv-
caused by inflammatory cytokines and endothelin-1 ery and uptake, respectively.11 The presence of tissue
combined with the increased production of vasocon- hypoxia is manifested by metabolic acidosis and de-
strictive substances (e.g., endothelin-1, thromboxane creased oxygen extraction ratios.11 Pulmonary dysfunc-
A2). Adherence of neutrophils to the endothelium and tion is manifested by refractory hypoxemia, potentially
endothelial cell swelling further reduce blood flow. Ac- caused by increased pulmonary vascular permeability,
668 Equine Compendium July 2001
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672 Equine Compendium July 2001
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all of the following except
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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
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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.