Sepsis is a clinical syndrome defined by the development of a systemic inflammatory syndrome in response to suspected infection. The condition implies an extensive, whole body insult following invasion of bacteria into tissue or a body fluid or cavity. The presence of viable bacteria in the bloodstream is termed bacteremia. Bacterial infection accounts for nearly one-third of all foal mortality. Sepsis is one of the most common problems of equine neonates, second only to inadequate transfer of maternal antibodies.
Etiology and Pathogenesis
Escherichia coli is the predominant bacteria isolated from foals with sepsis or bacteremia, regardless of isolation technique or geographic location of the patient. Other common gram-negative pathogens include Klebsiella spp, Enterobacter spp, Actinobacillus spp, Salmonella spp, and Pseudomonas spp. Approximately 30–50% of infections also involve gram-positive bacteria, with Streptococcus spp being the predominant isolate. In recent years an increase in the number of gram-positive bacteria has been documented in foals admitted to neonatal intensive care facilities, with a reduction in enteric gram-negative isolates (ie, 63% to 42% over 25 yr). Anaerobic pathogens, especially Clostridia spp, are reported in ~10% 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, hypoglycemia, myocardial depression, procoagulant activity, and eventually DIC). 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), 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.
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, 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 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 leakiness. 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.
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 or multiple organ dysfunction.
Septic 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. Hypoglycemia commonly accompanies systemic infection and is associated with bacterial consumption and reduced glycogen reserves. 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 on arterial blood gas analysis.
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 further serve as a prognostic aid.
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, while IgG levels >800 mg/dL are considered optimal.
A positive blood culture confirms the presence of bacteremia in septic foals, but a negative culture does not rule out the possibility of infection. Differential diagnoses include neonatal encephalopathy (see Hypoxic Ischemic Encephalopathy), hypoglycemia, hypothermia, neonatal isoerythrolysis (see Anemia: Alloimmune Hemolysis), white muscle disease (see Myopathies in Ruminants and Pigs: Nutritional Myopathies in Ruminants and Pigs), prematurity, neonatal pneumonia, and uroperitoneum (see Noninfectious Diseases of the Urinary System in Large Animals: Uroperitoneum in Foals).
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, IV, sid) 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 patients with renal compromise. Cefpodoxime proxetil (10 mg/kg, bid-qid) has been recommended for the treatment of bacterial infections in equine neonates. Cefepime (11 mg/kg, IV, tid) is a new 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 patients 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) 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 the foal. 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 over 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), NSAID, 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%). A minimum of 1–4 wk of intensive care should be expected. Early recognition and intensive treatment of neonatal sepsis improves the outcome. If the foal survives the initial problems, it has the potential of becoming a healthy and useful adult. A recent report documented that surviving bacteremic Thoroughbred foals were as likely to start races as their siblings, although they earned less money.
Last full review/revision March 2012 by Daniela Bedenice, DrVetMed, DACVIM, DACVECC