Manifestation of sepsis in neonatal crias (Proceedings)

The accepted working definition of sepsis in humans is based on a 2010 Consensus Conference statement on sepsis and organ failure, which identified sepsis as a systemic inflammatory response (SIRS) associated with suspected or proven infection (fungal, bacterial, viral or rickettsial). A subsequent international pediatric sepsis consensus conference adapted the current criteria to define sepsis and SIRS in neonatal patients In this context, the definition of SIRS revolves around the clinical signs of fever or hypothermia, leukocytosis or leukopenia, tachycardia, and tachypnea, while infection is not a requirement.

These clinical variables, used to define SIRS and organ dysfunction, are greatly affected by the normal physiologic changes that occur as neonates mature. There is a significant overlap between species in regards to the constellation of clinical signs that are associated with sepsis and SIRS. However, no large scale studies have been conducted to date to define these syndromes in neonatal camelids. With this in mind, it has been proposed to utilize the following adapted criteria, as a basis for defining sepsis, SIRS, severe sepsis, and septic shock in neonatal camelids:

SIRS (Systemic inflammatory response syndrome): The presence of at least two of the following five 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 SD above normal for age in the absence of external stimulus, chronic drugs, or painful stimuli

3.        Bradycardia, defined as a mean heart rate below normal range for 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 mechanical ventilation for an acute process not related to underlying neuromuscular disease or the receipt of general anesthesia

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

Infection = A suspected or proven infection (by positive culture, tissue stain, or polymerase chain reaction test) caused by any pathogen OR a clinical syndrome associated with a high probability of infection. Evidence of infection includes positive findings on clinical exam, imaging, or laboratory tests (e.g. white blood cells in a normally sterile body fluid, perforated viscus, chest radiograph consistent with pneumonia, or petechia)

Sepsis = SIRS in the presence of or as a result of suspected or proven infection.

Severe sepsis = Sepsis plus one of the following: cardiovascular organ dysfunction OR acute respiratory distress syndrome OR two or more other organ dysfunctions.

Septic shock = Sepsis and cardiovascular organ dysfunction.

Although the overall presentation of neonatal sepsis is similar between species, the prevalence of selected disease manifestations (e.g. septic arthritis, umbilical infection) may significantly vary. A recent, retrospective cohort analysis evaluated the clinical and laboratory variables of 201 critically ill neonatal alpaca and llama crias that presented to a referral center. In this study, the most common diagnoses included FPT (61.2%), SIRS (40.3%), lower airway disease (33.8%), diarrhea (23.9%), congenital defects (22.4%), neonatal encephalopathy (20.4%), clinical signs of prematurity (16.9%) and confirmed sepsis (13.4%). Overall survival was 71.1% (143/201), whereas 26 crias died and 30 were euthanized due to terminal illness (death unspecified in 2/58).These data thus identified the overall disease distribution in crias at risk for systemic inflammation or sepsis. Similar to data in horses, lower respiratory disease and diarrhea were one of the most common manifestations of potential infection in critically illness.

A study of 21 crias with culture positive sepsis reported that affected crias may not necessarily have localizing clinical signs in the early stages of disease. However, hypothermia, tachypnea, tachycardia and failure of passive transfer, as a risk factor of infection, were commonly reported. Tachypnea can be present as a response to central, respiratory, thermoregulatory, or acid-base abnormalities and may also be a component of SIRS. Tachycardia can be present as a response to fever, excitement, poor oxygen delivery to tissues, poor cardiac output, hypovolemia, hypotension, or other factors, including SIRS. Although the number of patients was small in the latter study, gram-negative and gram-positive organisms were isolated in approximately the same frequency and had identical survival percentages. However, crias without gastrointestinal or central nervous system involvement survived in greater numbers.The most common isolates in this study included Escherichia coli, Enterococcus spp., Listeria monocytogenes, and Citrobacter spp, while Escherichia coli, Actinobacillus sp, and Klebsiella pneumoniae were isolated from 6 crias with gram negative sepsis of a different report.

The cardio-vascular in sepsilar systems

Sepsis or SIRS may induce significant systemic vasodilatation due to local metabolites like lactic acid, H-ions, K-ions, induced nitric oxide release and cytokine response with ensuing loss of smooth muscle reactivity and failure of vascular tone. The subsequently impaired microcirculation potentiates arterio-venous shunting, capillary leak and interstitial edema, with secondary hemoconcentration, sludging and intravascular coagulation. Sepsis initially triggers a pro-coagulant state, which may lead to disseminated intravascular coagulation and secondary consumptive coagulopathy.

Depression of myocardial function is common in advanced stages of sepsis and may worsen hypotension due to absolute and relative hypovolemia. Tachycardia (heart rate > 90 beats per minute [bpm] in adult camelids, > 120 bpm in crias) is a physiological defense against hypovolemia and aims to maintain cardiac output. Bradycardia in the face of significant volume depletion, however, may suggest advanced tissue damage and ensuing organ failure.

On physical examination, poor peripheral perfusion in camelids may be indicated by cold extremities, a dull mentation and poor peripheral pulses or jugular fill. The color and capillary refill of the patient's mucous membranes may vary according to the underlying disease. In the face of early, compensated septic or endotoxic shock, camelids may show hyperemic mucous membranes with a fast capillary refill time (CRT < 1 second) due to peripheral vasodilation and relative hypovolemia. Peripheral vasoconstriction on the other hand can manifest as tacky mucous membranes and prolonged CRT, and usually indicates more advanced or severe disease.

The gastro-intestinal (GI) system in sepsis

Diarrhea in neonatal crias may be a sign of gastro-intestinal inflammation due to various viral (coronavirus, rotavirus, BVDV), bacterial (E. coli, clostridium, salmonella), nutritional and protozoal causes (giardia, coccidia, cryptosporidium). The GI tract may thus serve as both a source and manifestation of sepsis in crias. Hypoperfusion, enteric bacterial overgrowth, endotoxemia and bacterial translocation all potentiate intestinal injury in sepsis.

The onset of GI injury due to ischemia is rapid and will likely induce denudation to intestinal villi (by 30-60 min), transmucosal necrosis (by 4 hrs) and transmural necrosis (by 6 hr). In a study by Dolente et al 2/21 septic crias presented with a complaint of diarrhea.3 In contrast, 11/21 [52.3%] septic crias were diagnosed with GI dysfunction during hospitalization (intolerance to feeding [signs of gastrointestinal pain, reflux], diarrhea, colic, or ileus). Similarly, 9/27 [33%] critically ill crias with confirmed sepsis at TCSVM had diarrhea. The latter institution further reported diarrhea in 16/61 [26.2%] culture positive septic foals, thus identifying a similar prevalence of diarrhea in neonatal septic crias and foals.

The central nervous system (CNS) in sepsis

Meningitis is a potential complication of sepsis, although the incidence in camelids is rare. Nonetheless, meningitis or meningoencephalitis due to Listeria monocytogenes, Salmonella Newport Streptococcus bovis and E.coli have been reported in crias. Failure of autoregulation, hypoperfusion, impaired oxygenation, metabolic encephalopathy and endotoxemia also affect CNS function in sepsis, even in the absence of direct infection of the brain. Manifesting clinical signs may include depression, altered behaviour (e.g. abnormal suckle) and potentially stupor, coma, convulsions and death. At TCSVM, 16/27 (59.3%) critically ill crias with confirmed sepsis showed  significant mental depression. Similarly, 32/61 (52.5%) neonatal, culture positive septic foals showed mental depression upon admission to the same institution.

Vertebral and brain abscessation may rarely be observed as a sequel to sepsis in crias. Infection with E. coli and Fusiformes spp was reported as a cause of brain abscessation in a 2 week old and a one month old cria respectively. Discospondylitis has also been reported as a cause of neurological signs in a 2 months old llama, with an onset of ataxia at 1 week of age.

The skeletal system in sepsis

Fortunately, the incidence of septic arthritis and physitis is low in neonatal crias. The clinical manifestation is similar to foals and may include significant to non weight bearing lameness, joint distension and pain to palpation. A study of 201 critically ill crias identified septic arthritis in 2/201 animals (1%).

The renal system in sepsis

Nephrotoxins, stress hormones, hypovolemia, hypotension and hypoperfusion may lead to oliguria and subsequent anuria.Hypovolemia is expected to result in an elevated packed cell volume, hemoglobin concentration, plasma protein, blood urea nitrogen (BUN) and creatinine concentration over time. However, significant variations may occur based on the age of the patient and the type, duration and severity of underlying disease.

In the author's opinion, azotemia alone is not a reliable indicator of hypovolemia in the immediate post partum period, as neonatal crias may show transiently elevated creatinine levels within the first 48 hrs after birth. Aside from volume depletion, perinatal azotemia may be attributed to maternal placental dysfunction (decreased creatinine clearance), perinatal asphyxia leading to fetal distress and ingestion of creatinine-rich fetal fluids, reduced renal clearance in premature neonates and less commonly congenital or acquired renal disease.

However, nursing neonatal crias often reduce serum creatinine levels below 1.5 mg/dL within 2-3 days post partum. The neonate's physiologically low creatinine may be associated with the low muscle mass and high fluid ingestion of nursing animals. The assessment of trend changes in creatinine concentration is considered a superior diagnostic tool, compared to the evaluation of absolute values in individual patients. In general, normal urine production can be used to estimate that cardiac output and vasomotor tone are normal.

The umbilicus in sepsis

Umbilical infections are rare in camelids, when compared to their incidence in neonatal foals. Clinical signs may include discharge, pain, heat and swelling of the umbilicus, although some infections of deeper structures may only be confirmed via ultrasound. In a recent study of 201 critically ill neonatal crias, umbilical infection was only diagnosed in 2/201 (1%) animals.

Metabolism and adrenal function in sepsis

Glucose metabolism may be significantly altered in septic patients, most commonly leading to hypoglycemia and weakness. Severely hypoglycemic crias may be unable to rise, show depression, convulsions and eventually death. Clinical signs suggestive of relative adrenal insufficiency (RAI) have been identified in patients with prolonged sepsis. Primary RAI can occur after a direct insult to the adrenal glands (hemorrhage or adrenal ischemia). Additionally, it has been speculated that chronic illness-induced stress may exhaust the adrenal reserve and deplete the production of cortisol. Cortisol regulates blood glucose during times of fasting and stress, by increasing the catabolism of proteins for gluconeogenesis. In most cases of RAI, production of both cortisol and aldosterone is affected.

Lack of cortisol results in gastrointestinal signs (diarrhea, anorexia), as well as systemic symptoms due to hypoglycemia and hypotension. Decreased aldosterone levels result in further hypotension due to hypovolemia, with potentially severe electrolyte abnormalities.Hypotension that is refractory to fluid therapy and requires vasopressors is the most common presentation of RAI in humans (Martin 2004). Although used empirically in crias, the low-dose adrenocorticotropin hormone stimulation tests to diagnose RAI have not been rigorously tested in camelids to date.

The respiratory system in sepsis

Hematogenous infection of the lung occurs in association with sepsis, which may be acquired in utero from placental infection or perinatally through environmental contamination (e.g. omphalitis, omphalophlebitis). Aside from direct lung infection, pulmonary abnormalities may also be triggered by cardiovascular dysfunction and systemic inflammation. The accumulation of protein rich fluid in the interstitium and alveoli due to increased vascular permeability may thus impair pulmonary function. Serious complications may include acute lung injury (ALI) and acute respiratory response syndrome (ARDS).

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