Sepsis in Foals

Gram-negative bacteria, particularly Enterobacteriaceae with a predominance of Escherichia coli, remain the most common isolates (60%–70%) from neonatal foals with sepsis. However, the prevalence of gram-positive bacteria has increased over time, and blood culture and sensitivity testing remain important in diagnosis and effective treatment. Common gram-negative pathogens include E coli, Klebsiella spp, Enterobacter spp, Actinobacillus spp, Salmonella spp, and Pseudomonas spp. Approximately 25%–40% of infections also involve gram-positive bacteria, with Streptococcus spp being the predominant isolate. Anaerobic pathogens, especially Clostridium spp, are reported in < 5% of systemic neonatal infections. The routes of entry for these bacteria may include the placenta, umbilicus, and respiratory and GI tracts.

All manifestations of sepsis (eg, sepsis, severe sepsis, septic shock, multiple organ dysfunction) have a common pathogenesis that includes endotoxemia related to gram-negative infections. Endotoxins stimulate macrophages to release an array of cytokines (eg, IL-6, IL-1, TNF-α) and activate pro-inflammatory enzymes (eg, phospholipase A₂). Together, these factors lead to clinical signs of inflammation (fever, vasodilation, myocardial depression), impaired microcirculation, capillary leakage, and coagulation dysfunction. Sepsis initially triggers a procoagulant state, which may lead to disseminated intravascular coagulation and secondary consumptive coagulopathy. A variety of other pathogen-derived molecules can set off similar host responses. Thus, toxic shock syndrome resulting from Streptococcusor Staphylococcus aureus infection is a hyperinflammatory septic syndromes that closely resembles diseases characterized by endotoxemia.

A variety of immunologic and management factors predispose foals to sepsis. Although foals can respond immunologically in utero to bacterial or viral infections, their ability to do so is less developed than that of adult horses. Decreased pathophysiologic response to infectious agents in neonates is related to reduced chemotaxis and killing capacity of neonatal neutrophils, the presence of antigenically naive T cells, and a decreased concentration and function of monocytes. However, the major risk factor for sepsis in foals is failure to receive an adequate quality or quantity of colostral antibodies. If colostrum intake is insufficient and IgG concentration remains low; not only is the foal deprived of specific antibody protection, but neutrophil function is also seriously impaired. Other factors that influence disease incidence include unsanitary environmental conditions, low gestational age of the foal (prematurity or immaturity), poor health and condition of the dam, difficult parturition, and the presence of new pathogens in the environment against which the mare has no antibodies.

The clinical presentation of sepsis depends on the duration of illness, the integrity of the host immune system, the affected body systems, and the severity and route of infection. Frequently affected organ systems include the umbilical remnants, and CNS, respiratory, cardiovascular, musculoskeletal, renal, ophthalmic, hepatobiliary, and GI systems. In the early stages of sepsis, clinical signs are often vague and nonspecific, with affected neonates merely displaying variable signs of depression and lethargy. Owners report that foals appear to lie down more than usual. The mare’s udder is often distended with milk, indicating that the foal is nursing less than expected.

Clinical signs can progress to a complete loss of suckle reflex, hyperemic mucous membranes with a rapid capillary refill time due to peripheral vasodilation, tachycardia; and potentially early petechiae related to capillary leakage. In advanced sepsis, when the infection overwhelms the host’s immune system and compensatory responses, septic shock ensues. Affected foals are severely depressed, recumbent, and hypovolemic, with cold extremities, thready peripheral pulses, and poor capillary refill time. Foals may be hyper- or hypothermic, tachycardic, or bradycardic, when septic. Bacteria can spread hematogenously to various organs, manifesting as respiratory distress, pneumonia, diarrhea, uveitis, meningitis, osteomyelitis, or septic arthritis. Dysfunction of two or more organs is termed multiple organ dysfunction syndrome (MODS).

Hypoglycemia commonly accompanies systemic bacterial infection and is associated with reduced glycogen reserves. Severely hypoglycemic foals may be unable to rise and show signs of depression, convulsions, and eventually death without treatment. Furthermore, clinical signs suggestive of relative adrenal insufficiency have been identified in animals with prolonged untreated sepsis. Primary relative adrenal insufficiency can occur after a direct insult to the adrenal glands (hemorrhage or adrenal ischemia); whereas chronic, illness-induced stress may exhaust the adrenal reserve and decrease the production of cortisol. Septic neonatal foals are often neutropenic with a high ratio of band (immature) to segmented neutrophils. Circulating neutrophils may exhibit toxic changes, which is highly suggestive of sepsis. Fibrinogen concentration > 600 mg/dL in a foal < 24 hours old is indicative of an in-utero infection. Other abnormalities on serum biochemistry testing may include increased serum creatinine concentration due to inadequate renal perfusion, placental insufficiency or perinatal asphyxia (spurious hypercreatinemia), and increased bilirubin concentration secondary to hepatic endotoxin-related damage. A high anion gap (> 20 mEq/L), hyperlactatemia, hypoxemia, hypercapnia, and a mixed respiratory and metabolic acidosis may be present on arterial blood gas analysis.

• History (eg, prematurity), suggestive clinical signs

• Laboratory testing (e.g., CBC, serum chemistry, serum IgG, microbial culture of blood, bodily fluid/tissue samples, lactate/arterial blood gas)

• Relevant advanced diagnostic tests (eg, ultrasonography, CT)

• Response to early treatment

Currently, there is no ideal diagnostic tool to detect early sepsis. However, a scoring system that was originally developed in the 1980s for neonatal foals to establish the likelihood of neonatal infection may still aid the identification of sepsis at a treatable stage. This “sepsis score” incorporates a combination of historical, clinical, and laboratory variables and may also serve as an indicator of whole body insult, SIRS, or multiple organ dysfunction. The specific definition criteria for both SIRS and sepsis are most rigorously validated in humans and have been conceptually applied to equine neonates only recently.

Based on pediatric human and general veterinary guidelines, SIRS may be clinically defined by the presence of at least two of the following five clinical criteria, one of which must be abnormal temperature or leukocyte count:

1. core temperature below or above the normal range for the animal’s age

2. tachycardia, defined as a mean heart rate > 2 standard deviations (SD) above normal for the animal's age in the absence of external stimulus, chronic drugs, or painful stimuli

3. bradycardia, defined as a mean heart rate below the normal range for the animal's age, in the absence of external vagal stimulus, beta-blocker drugs, or congenital heart disease

4. mean respiratory rate > 2 SD above normal for age, or animals undergoing mechanical ventilation for an acute process not related to general anesthesia or underlying neuromuscular disease

5. leukocyte count increased or depressed for age (not secondary to chemotherapy-induced leukopenia) or > 10% immature neutrophils

Infection itself may be suspected or proven (by positive culture, tissue stain, or PCR assay) and caused by any pathogen, or refer to a clinical syndrome associated with a high probability of infection. Evidence of infection includes positive findings from blood culture, clinical examination, imaging, or laboratory tests (eg, WBCs in a normally sterile body fluid, perforated viscus, chest radiograph consistent with pneumonia). Ultimately, sepsis refers to the presence of SIRS with suspected or proven infection.

Depending on the specific organ systems involved, an umbilical, abdominal, and synovial ultrasound examination; arterial blood gas analysis; arthrocentesis; cerebrospinal centesis; and chest, abdominal, and distal limb radiographs are indicated. Advanced diagnostic imaging techniques (eg, CT of the distal limbs in foals with septic arthritis) may also help with prognosis.

Serum IgG levels should be measured in any questionably sick neonate to eliminate inadequate transfer of passive immunity as a risk factor for sepsis. IgG levels < 200 mg/dL indicate complete failure of transfer of passive immunity in the form of maternal antibodies, whereas IgG levels > 800 mg/dL are considered normal.

A positive blood culture confirms the presence of bacteremia in septic foals; however, a negative culture does not exclude the possibility of infection. Differential diagnoses include neonatal encephalopathy, hypoglycemia, hypothermia, neonatal isoerythrolysis ( see Alloimmune Hemolysis), white muscle disease ( see Nutritional Myopathies in Ruminants and Pigs), prematurity or immaturity, neonatal pneumonia, and uroperitoneum.

• Early, goal-directed therapy

• Broad-spectrum antimicrobials (after collection of samples for culture and sensitivity testing)

• IV fluid therapy/resuscitation

• Plasma transfusion

• Supportive care including nutritional support, oxygen therapy, nursing care as indicated

After obtaining relevant blood, tissue and/or fluid samples for culture, foals suspected of being septic should immediately commence treatment with broad-spectrum (typically IV) antimicrobials active against both gram-positive and gram-negative organisms. Ampicillin (15–30 mg/kg, IV, every 6–8 hours) or penicillin (22,000 IU/kg, IV, every 6 hours), in combination with amikacin sulfate (20–25 mg/kg per day, IV) provides good initial coverage until results of culture and sensitivity testing are available. Metronidazole (10–15 mg/kg, PO or IV, every 12 hours) may be necessary if an anaerobic infection (eg, Clostridium) is suspected. A third-generation cephalosporin (eg, ceftiofur, 4.4–6 mg/kg, IV, every 6–12 hours) may also be used as a broad-spectrum agent in foals with renal compromise. Cefpodoxime proxetil (10 mg/kg, PO, every 6–12 hours) has been recommended for treatment of bacterial infections in equine neonates. Cefepime (11 mg/kg, IV, every 8 hours) is a fourth-generation cephalosporin with enhanced antibacterial activity.

Early goal-directed IV fluid therapy is indicated to restore tissue perfusion, attenuate the cytokine response, and reverse cellular injury. Volume expansion should be achieved using a balanced electrolyte solution (crystalloid) with a colloid (plasma) as indicated. Immunologic support in the form of IV plasma transfusion (1–2 L) is also indicated to raise the IgG level to > 800 mg/dL. Fluid resuscitation is aimed at normalizing specific cardiovascular variables (central venous pressure, mean arterial pressure, urine output, and central venous oxygen saturation), while improving clinical parameters. Bolus administration of crystalloid fluids (20–80 mL/kg, IV) may initially be required in foals with septic shock to establish normohydration, followed by maintenance fluid at rates of approximately 100 mL/kg per day, depending on the extent of ongoing losses. Overhydration should be avoided. Because many foals are hypoglycemic, slower continuous infusions of 2.5%–5% dextrose-containing solution should be administered simultaneously with resuscitation fluids.

Treatment with hyperimmune plasma enriched with anti-endotoxin antibodies serum may be considered in foals with endotoxemia. Anti-prostaglandin drugs have been found to counteract several of the clinical and hemodynamic changes associated with endotoxemia and septic shock. Low doses of flunixin meglumine (0.25 mg/kg, IV, every 6–8 hours) may help reduce clinical signs of endotoxemia. In addition, administration of low doses of polymyxin B (6,000 IU/kg, diluted in 300–500 mL of saline, slow IV) is an investigational treatment that may neutralize systemic endotoxin.

Nutritional support is important, because sepsis creates a catabolic state in foals. If the foal is not nursing adequately, it should be fed mare’s milk or a mare milk substitute at a dose of 15%–25% of its body weight throughout each 24-hour period. An indwelling nasogastric tube for enteral feeding should be placed in foals with a decreased suckle reflex. Parenteral nutrition may also be helpful to provide adequate nutrients in the setting of GI dysfunction; although risks versus benefits should be considered. Administration of gastric protectants (eg, cimetidine, omeprazole) has been proposed as an adjunct therapy in sick neonates.

Additional treatment in foals with sepsis may include lavage (at times repeated) of septic joints with sterile crystalloid fluids, regional limb perfusion, and nasal oxygen support (2–10 L/minute) or mechanical ventilation for foals with respiratory failure or central hypoventilation. Corneal ulceration may be treated with low doses of topical atropine (may cause ileus), analgesics (e.g.,IV NSAIDs). Entropion is generally treated with placement of mattress sutures in the lower eyelid. Surgical removal of infected umbilical remnants may also be indicated.

Recovery from neonatal sepsis depends on the severity and specific manifestations of infection. Currently reported survival rates are 50%–81% in foals treated at referral centers, depending on the underlying disease. Severe neonatal pulmonary disease has been associated with higher mortality (35%–50%). Early recognition and intensive treatment of neonatal sepsis improves the outcome, although an average of 1–4 weeks of intensive care should be expected. If the foal survives the initial illness, it has the potential of becoming a healthy adult horse. One report documented that surviving bacteremic Thoroughbred foals were as likely to start races as their siblings, although their earnings were lower.1 The latter retrospective case series (n = 423) further identified that odds of survival were significantly less for foals of older age at admission, with higher band neutrophil count, and increased serum creatinine concentration. Foals that survived had a significantly higher rectal temperature, neutrophil count, and arterial blood pH at admission. In addition, in a more recent prospective multicenter study,2 septic foals had increased odds of death for each 1 mmol/L increase in L-lactate concentration at admission.

• Wong DM, Ruby RE, Dembek KA, et al. Evaluation of updated sepsis scoring systems and systemic inflammatory response syndrome criteria and their association with sepsis in equine neonates. J Vet Intern Med. 2018 May;32(3):1185–1193. doi: 10.1111/jvim.15087. Epub 2018 Mar 26. PMID: 29582480; PMCID: PMC5980351.

• Taylor S. A review of equine sepsis. Equine Vet Educ. 2015 Feb;27(2):99–109. doi: 10.1111/eve.12290. Epub 2015 Jan 14. PMID: 32313390; PMCID: PMC7163761.