Sepsis is a clinical syndrome defined by the development of a systemic inflammatory response syndrome (SIRS) in response to proven or suspected infection. The condition implies an extensive, whole body insult after invasion of bacteria into tissue or a body fluid or cavity. The presence of viable bacteria in the bloodstream is termed bacteremia. Sepsis and SIRS are two of the most common problems of equine neonates, while bacterial infection accounts for nearly one-third of all foal mortality.
Etiology and Pathogenesis:
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 throughout time, and blood cultures remain important in diagnosis and 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 sepsis syndromes (eg, sepsis, severe sepsis, septic shock, multiple organ dysfunction) have a common pathogenesis that also 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 signs of inflammation (fever, vasodilation, myocardial depression), impaired microcirculation, capillary leak, and intravascular coagulation. 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 syndromes resulting from streptococcal or Staphylococcus aureus infection are hyperinflammatory septic syndromes that closely resemble 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 than that of adults. Deficits in the physiologic response to infectious agents in neonates relate to reduced chemotaxis and killing capacity of neonatal neutrophils, the presence of antigenically naive T cells, and a decreased concentration and impaired 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 levels remain low, the foal is not only 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, difficulty of parturition, and the presence of new pathogens in the environment against which the mare has no antibodies.
Clinical Findings and Lesions:
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 organs. In the early stages of sepsis, clinical signs are often vague and nonspecific, with affected neonates merely displaying some degree 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 not nursing at a normal frequency.
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 leak. In the advanced stage of illness, when the infection overwhelms the host’s immune system and compensatory responses, septic shock ensues. Affected foals are severely depressed, recumbent, and hypovolemic, which manifests as cold extremities, thready pulse, and poor capillary refill time. Foals may be hyper- or hypothermic, tachycardic, or bradycardic. In the face of sepsis, bacteria 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.
Hypoglycemia commonly accompanies systemic infection and is associated with bacterial consumption and reduced glycogen reserves. Severely hypoglycemic foals may be unable to rise and show depression, convulsions, and eventually death. Furthermore, clinical signs suggestive of relative adrenal insufficiency have been identified in animals with prolonged 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 deplete the production of cortisol. Septic neonatal foals are often neutropenic with a high ratio of band (immature) to segmented neutrophils. The neutrophils may exhibit toxic changes, which are highly suggestive of sepsis. Fibrinogen levels >600 mg/dL in a foal <24 hr old are indicative of an in-utero infection. Other chemistry abnormalities may include azotemia due to inadequate renal perfusion or perinatal asphyxia, and increased bilirubin secondary to endotoxin damage to the liver. A high anion gap (>20 mEq/L), hyperlactatemia, hypoxemia, hypercapnia, and a mixed respiratory and metabolic acidosis may be present with arterial blood gas analysis.
Currently, there is no ideal diagnostic tool to detect early sepsis. However, a scoring system has been developed for neonatal foals to establish the likelihood of neonatal infection and 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. However, the specific definition criteria for both SIRS and sepsis are most rigorously validated in people 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, β-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) 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 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 passive transfer of maternal antibodies, whereas IgG levels >800 mg/dL are considered normal.
A positive blood culture confirms the presence of bacteremia in septic foals, but a negative culture does not exclude the possibility of infection. Differential diagnoses include neonatal encephalopathy ( see Neonatal Encephalopathy Neonatal Encephalopathy Neonatal encephalopathy (NE) is a common, noninfectious CNS disorder of neonatal foals, resulting in clinical signs such as lethargy, inappropriate behavior, seizures, and other neurologic deficits... read more ), hypoglycemia, hypothermia, neonatal isoerythrolysis ( see Alloimmune Hemolysis Alloimmune Hemolysis Hemolytic anemia results from loss of RBCs. Immune-mediated destruction is the most common cause in dogs, although infections, tumors, and other causes also occur. Immune-mediated hemolytic... read more ), white muscle disease ( see Nutritional Myopathies in Ruminants and Pigs Nutritional Myopathies in Ruminants and Pigs Young Boer goat kid with white muscle disease. The patient can move its legs normally but is too weak to stand. CK and AST concentrations were elevated on serum biochemical evaluation. The goat... read more ), prematurity or immaturity, neonatal pneumonia, and uroperitoneum ( see Uroperitoneum in Foals Uroperitoneum in Foals Uroperitoneum is leakage of urine into the peritoneal space and is caused most often by rupture of the urinary bladder or urachus. Signs, including lethargy, tachycardia, frequent attempts to... read more ).
Treatment, Control, and Prevention:
Foals suspected of being septic should be placed on broad-spectrum antibiotics active against both gram-positive and gram-negative organisms. Penicillin (22,000 IU/kg, IV, qid) in combination with amikacin sulfate (20–25 mg/kg/day, IV) provides good initial coverage until culture results are available. Metronidazole (10–15 mg/kg, PO or IV, tid) may be necessary if an anaerobic infection (eg, Clostridium) is suspected. A third-generation cephalosporin (eg, ceftiofur, 4.4–6 mg/kg, IV, bid-qid) may also be used as a broad-spectrum agent in foals with renal compromise. Cefpodoxime proxetil (10 mg/kg, bid-qid) has been recommended for treatment of bacterial infections in equine neonates. Cefepime (11 mg/kg, IV, tid) is a fourth-generation cephalosporin with enhanced antibacterial activity.
Early goal-directed IV fluid therapy is needed to restore tissue perfusion, attenuate the cytokine response, and reverse cellular injury. Volume expansion should be achieved using a balanced electrolyte solution (crystalloid) or plasma (colloid). 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. Severe septic shock may require initial fluid rates of 40–80 mL/kg/hr. Because many foals are hypoglycemic, slower continuous infusions of 2.5%–5% dextrose-containing solution should be administered simultaneously with rehydration fluids.
Treatment with hyperimmune antiendotoxin serum may be considered in foals with endotoxemia. Antiprostaglandin 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, tid-qid) may help reduce signs of endotoxemia. Additionally, administration of low doses of polymyxin B (6,000 IU/kg, diluted in 300–500 mL of saline, slowly IV) is an investigational treatment used to 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 15%–25% of its body weight throughout each 24-hr period. An indwelling nasogastric tube should be placed in foals with a decreased suckle reflex. Parenteral nutrition may also be helpful to provide adequate nutrients in the face of GI dysfunction. Administration of gastric protectants (eg, ranitidine, cimetidine, omeprazole) has been proposed as an adjunct therapy in sick neonates.
System-specific therapy includes lavage of septic joints with sterile fluids, regional limb perfusion, and nasal oxygen support (2–10 L/min) or ventilation for foals with respiratory failure or central hypoventilation. Corneal ulceration may be treated with low doses of topical atropine (although it may cause ileus), NSAIDs, and broad-spectrum topical antimicrobials. Entropion generally requires mattress sutures of the lower eyelid. Surgical removal of infected umbilical remnants may be indicated.
Recovery from neonatal sepsis depends on the severity and manifestation of the infection. Currently reported survival rates are 50%–81% in referral centers, depending on the underlying disease. Severe neonatal pulmonary disease has been associated with a higher mortality (35%–50%). Early recognition and intensive treatment of neonatal sepsis improves the outcome, although an average of 1–4 wk of intensive care should be expected. If the foal survives the initial problems, it has the potential of becoming a healthy and useful adult. One report documented that surviving bacteremic Thoroughbred foals were as likely to start races as their siblings, although their earnings were lower. The latter retrospective case series (n=423) further identified that odds of survival were negatively associated with age at admission, band neutrophil count, and serum creatinine concentration, and positively associated with rectal temperature, neutrophil count, and arterial blood pH. Additionally, in a recent prospective multicenter study, septic foals had increased odds of nonsurvival for each 1 mmol/L increase in L-lactate concentration at admission.