Sepsis in neonates (Proceedings)

Sepsis or septicemia in the equine neonate is a common cause of mortality in the foal. Septicemia is defined as bacteremia with associated with a whole body inflammatory state. It is difficult to estimate the morbidity associated with sepsis but more is known about the mortality.  A study in Kentucky cited the one third of the deaths of the periparturient period in foals including aborted fetus, stillborns and < 1 day of age, was due to feto-placental infection.  In large scale Texas study 30% of all deaths of foals < 7 days of age was due to infection.  28 – 50% of foals presented to a neonatal intensive care unit have positive blood cultures or elevated sepsis scores.

Foals can be infected in utero or soon after birth. The mare has an epitheliolchorial placenta that essentially places 6 layers of tissue between the maternal and fetal blood supplies.  This blocks the in utero transfer of immunoglobulins from the mare to the foal.  Thus the foal is vulnerable to infection while in the uterus and after birth and before there has been a chance for absorption of colostral antibodies by the foal.  This vulnerable foal is born into an environment that is populated with numerous bacteria that would not ordinarily infect an animal with a fully functioning immune system. The routes of entry for the bacteria include the umbilicus, breaks in the skin barrier, inhalation and ingestion.

Colostrum is the primary source of antibodies in the foal. Colostrum begins to be made by the mare during the last 3-4 weeks of gestation and is only made once.  Leakage of colostrum from the mare's udder before the foal has a chance to suckle is one reason a foal may not receive adequate colostrum.  The quality of colostrum can also be affected by the mare's age (lower antibodies in older mares) and length of day (decreased sunlight hours decrease antibody levels). 

Inherent problems in the foal may also cause a delay in the foal receiving colostrum thus increasing the chances of infection.  These problems could be secondary to musculoskeletal deformities such as contracture or angular limb deformities.  Perinatal asphyxia may cause a foal to have neurologic problems and a decrease or absence of a suckle response.

The clinical signs of sepsis in a foal can vary in degree of the foal's systemic inflammatory response (SIR) to the infection.  The first clinical signs that an owner may notice is that the foal is a little quieter than usual.  This could easily be overlooked by a person who is unfamiliar with the normal behavior of the newborn foal. As the duration and intensity of the bacterial attack progresses the foal may exhibit increased recumbency, decreased nursing behavior and fever.  Lack of fever does not rule out sepsis.  In fact a third of septic foals may be hypothermic and a third may have normal temperatures.  This may be due to the cyclic nature of fever or to the development hypotension. 

The later stages of sepsis are directly related to the SIR or the release of proinflammatory cytokines.  Tachycardia, tachypnea, scleral injection, reddening of the coronary bands and hyperemia of the mucous membranes denote the beginning of septic shock.  Petechia may develop on the nasal mucosa, on the mucous membranes and in the inside of the ear pinna.  Hyperdynamic shock (good peripheral pulses and warm extremities) if untreated, will progress to hypodynamic shock (weak peripheral pulses and cold extremities).

Diagnosis and treatment of sepsis are aided by certain blood work. Affected foals often present with a neutropenia with the presence of band neutrophils.  Toxic changes in the neutrophils may be noted by the pathologist. Hypoglycemia is often seen in sick foals when presented at <24 hours of age.  IgG levels are typically less than 800 mg/dl indicating either complete or partial failure of passive transfer of maternal antibodies. Fibrinogen levels > 600mg/dl in the less than 24 hour foal indicates that the infection began while the foal was still in the uterus.

A sepsis scoring system was developed in the 80's by Brewer and Koterba combined blood work data, clinical signs and historical information to determine if a foal was septic.  This scoring system is especially helpful in foals that may only be showing signs of depression and not full blown septic shock.  This scoring system can be referenced elsewhere.

Manifestations of Sepsis

Because sepsis involves a bacteremia, secondary sites of infection can develop.  Some of the manifestations of sepsis include pneumonia, septic arthritis/osteomyelitis, omphalitis, enteritis/colitis, uveitis and meningitis/encephalitis. Damage to the adrenal glands has also been noted as a possible consequence of sepsis.  Each of these body systems present with unique challenges to the veterinarian, both in the diagnosis and treatment of the ill foal.  Septic arthritis/osteomyelitis, diarrhea and encephalitis will be covered specifically in later talks. The other involved systems will be discussed here.

Pneumonia

The respiratory tract is the most common secondary site of infection in the septic foal.   Besides the decreased humeral protection from decrease in maternal antibodies, an immature innate immune system related to the respiratory tract probably contributes to the susceptibility of this organ system to infection.  The equine neonate has fewer alveolar macrophages and an immature ciliary apparatus when compared to the adult.  Reduced complement levels in the neonates also contribute to a decreased humeral response in an already compromised defense system from failure of passive transfer of maternal antibodies.  Fifty percent of foals in one post mortem study had respiratory.

Diagnosis of pneumonic conditions in the neonatal foal can be difficult on auscultation alone. One may hear increased bronchovesicular sounds in a normal foal because of the foal's thin chest wall.  Likewise if a foal has been recumbent on one side for a period of time, squeaks and wheezes may be heard due to atelectasis of the down lung in a normal foal for a short period of time. Alternatively a foal with severe consolidation of its lungs may actually auscult normally due to the absence of air moving through the consolidated regions.

Arterial blood gas analysis and thoracic radiographs are the most useful tools in evaluating the lower respiratory system of the foal.  Arterial blood gas analysis reflects the function of the lung in how it exchanges oxygen and carbon dioxide. With the new hand held analyzers, the practitioner can obtain this information stall side. The most common sampling sites for arterial blood are the lateral metatarsal artery located between the third metatarsal and the cranial ridge of the fourth metatarsal bone (lateral splint) and the branchial artery located on the medial side of the elbow. 

Obviously lung disease can affect blood gases by lowering oxygen levels and increasing carbon dioxide levels depending on the severity of the pathology.  Age (< 1day of age) and recumbency can also lower oxygen in the foal and must be taken into account when assess your analysis.

Thoracic radiographs and ultrasound to a lesser extent allows the clinician to evaluate the lung for areas of consolidation.  An increased interstitial or alveolar lung pattern in the dorsal caudal lung field is commonly seen in foals that have a hematogenous route of infection.  A similar lung pattern in the caudal ventral region of the lung denotes possible aspiration pneumonia. Follow up radiographs help one assess response to therapy.

Omphalitis

The umbilicus of the foal can be a port of entry for bacteria in the newborn foal.  The umbilical structures include the stalk, 2 arteries, 1 vein and the urachus.  At the time of birth, the umbilical cord naturally stretched as the mare stands and snaps apart allowing for the retraction and constriction of the blood vessels.  If this process does not happen then the umbilical cord may need to be manually separated or cut.  This often causes problems with infection. Umbilical infections may be localized or can be a source for hematogenous spread through the body.  In one study, 50% of foals that presented for septic arthritis had evidence of umbilical infection. 

Umbilical infections can be overt, visualized as an external swelling on the ventral abdomen or it can be internal with enlargement of the stalk, umbilical arteries or vein.  Ultrasound evaluation of the umbilical structures is important in the determination of the internal infection. For the average size foal, the umbilical stalk should not measure more than 2.5 cm in diameter and the arteries and vein should be less than 1 cm.

Uveitis

Systemic illness in the foal can result in either invasion of the eye by infectious organisms or immune-mediated uveitis.  The clinical signs include blepharospasm, lacrimation, miosis, aqueous flare and fibrin accumulation in the anterior chamber.

Relative Adrenal Insufficiency

Recently several investigators have been looking at the role of adrenal insufficiency in severely septic foals. Though not present in all foals there may be a subset of affected foals that have low cortisol levels and a blunted response to ACTH stimulation. In a post mortem study – hemorrhage and necrosis of the adrenal glands were seen in a certain number of septic foals that died.

Treatment

The goals of treatment in sepsis center on support immunologic, antimicrobial, cardiovascular and nutritional support while treating the specific manifestations of the disease process. If a foal has complete or partial failure of transfer of maternal antibodies then the approach to treatment depends somewhat on the age of the foal.  If the foal is less than 12 hours of age and colostrum is available then it should be given to the foal via a nasogastric tube.  Intravenous plasma should also be administered if the foal has complete failure of passive transfer or the foal is >12 hours of age.

The amount of plasma needed to raise the IgG >than 800 depends on what level of FTP is present in the foal, whether the foal is currently septic and the level of IgG in the transfused plasma.  In general 1-2 liters of plasma should be given to foals with IgG between 400 and 800 mg/ml and more if the level is < 400 mg/dl. IgG levels in the foals should be rechecked 12-24 hours after the transfusion to insure adequate levels.  Inadequate level may be from insufficient levels of IgG in the transfusion or due to consumption from the disease process.

The majority of bacteria that are involved in neonatal sepsis are gram negative bacteria including E. coli, Salmonella, Klebsiella, Pseudomonas, Actinobacillus and Enterobacter.  These can be single organism infections or involve multiple organisms include some gram positive bacteria such as Streptococcus, Enterococcus and Staphylococcus. 

Blood cultures can be helpful in identifying the bacteria involved but should be performed before antibiotics are administered.  Antibiotics should not be withheld once suspicion of sepsis is made apparent. Studies in human medicine show that early treatment of sepsis with antibiotics, is an important indicator of survival.  They speak about the “Golden Hour” of administration where antibiotics are started at the first sign of sepsis.

The choice of antibiotics should center on the broadest coverage for both gram positive and gram negative organisms. Intravenously administered antibiotics give the highest blood levels. The combination that I like to start with includes amikacin and K penicillin. According to sensitivity patterns from different studies, this combination should be affective against 90% of the common isolates. For resistant organisms, imipenem, enrofloxacin (may cause cartilage damage in the growing foal), ceftriaxone, cepftazidime, ceftiofur, chloramphenicol and tetracycline can be considered with decreasing efficacy.

Cardiovascular support for the foal in septic shock consists of intravenous fluids.  In the recumbent foal with poor peripheral pulses, rapid administration of 1 liter of a crystalloid fluid such as LRS or plasmalyte followed by re-evaluation and another liter or 2 of fluids helps to increase the blood pressure of the foal.  Foals are rarely dehydrated unless they are experiencing severe diarrhea.  But they are hypovolemic due to the SIRS. If colloid support is needed, plasma is a good choice. After the third liter of fluids you should check for urine production. If no urine is produced, then use of pressor drugs such as dopamine and dobutamine.

Because many foals are hypoglycemic on presentation, the first fluids should have added dextrose. You can make 5% dextrose in LRS by adding 100 mls of 50% dextrose to a liter of LRS.  Many septic foals are depressed and fail to nurse.  Supplemental nutrition should be considered.  Either mare's milk or a milk supplement can be administered via indwelling nasogastric tube.  Initially, the amount of milk should be calculated at 10% of the foal's body weight divided into 12 feedings. 

Treatment for the specific manifestations of the sepsis may need to be considered.  Intranasal oxygen may be needed for the foal with pneumonia.  If the respiratory component is severe enough to result in an elevated CO2, then mechanical ventilation may be need to support the foal.  Periodic coupage of the chest helps to loosen thick respiratory secretions.

Umbilical infection will often respond to your antibiotic treatment but surgical removal of the umbilical remnants will be important if a substantial abscess is present or the umbilical vein is enlarged all the way to the liver with a resultant liver abscess.

Topical corticosteroids and atropine are the treatments of choice for uveitis but one must insure that there is not corneal ulceration before application of the steroid. If hypopyon is present then injection of TPA into the anterior chamber will help to dissolve the clot.  This should only be done under heavy sedation or anesthesia due the dangers of damaging the eye.

Prognosis

The survival rate for foals with septicemia has increased over the past 30 years from approximately 25% to 70%.  Early recognition and increased levels of care and prevention all contribute to success in the affected foals.