6 Manifestations of Septicemia

’03 Hufflepuff, a 48-hour-old Thoroughbred foal, presented to a referral hospital after an uncomplicated, attended birth of 337 days of gestation. Hufflepuff, the six-year-old dam, is a primiparous mare in good general health. There was no colostrum leakage prior to parturition. Her foal stood within 110 minutes after birth and attempted to nurse the mare by 180 minutes. Hufflepuff, however, acted restless and agitated after parturition with minimal interest in the foal. The farm manager bottle fed approximately 80 ml of colostrum to the foal and subsequently assisted the foal to nurse every four hours by restraining the mare.

Eighteen hours after parturition, the foal was evaluated by the farm veterinarian.’03 Hufflepuff was reported to lie down frequently, but was readily aroused to stand for examination and nursed from the mare. Physical examination did not reveal any significant abnormalities at the time. Based on the history of delayed nursing and the possibility of inadequate colostrum intake, the farm veterinarian administered 1 liter of intravenous plasma to the foal. An IgG level >800 mg/dl was confirmed after transfusion. During the following 12 hours, the foal became increasingly lethargic, with a weak suckle reflex. The decision was made to refer the foal to a full-care facility.

On presentation, ’03 Hufflepuff was markedly depressed (Figure 6-1). The foal had a poor suckle reflex and bright pink mucous membranes with a capillary refill time of two seconds. His temperature was 100.3°F, heart rate was 112 beats per minute, and respiratory rate was 48 breaths per minute with an increased respiratory effort (excessive rib excursion). Auscultation revealed harsh broncho-vesicular lung sounds, without other abnormalities. The remainder of the physical examination was considered normal.

Fig. 6-1 ’03 Hufflepuff was maintained in sternal recumbency to limit positional atelectasis.

HISTORY AND PHYSICAL EXAMINATION

The respiratory system of the neonatal foal is particularly vulnerable to injury. In one retrospective study, 50% of all foals presented to a referral hospital had some form of pulmonary involvement.¹ Foals with respiratory dysfunction also showed the highest mortality rate. This was reflected in a recent postmortem study of equine neonates, where the respiratory system was the most common system affected.²

Pneumonia as a clinical manifestation of sepsis shares similar historical findings as a foal with sepsis, as described in Chapter 5. Colostrum leakages prior to parturition or colostrum deprivation (poor colostrum quality or quantity or delayed intake) are risk factors of bacterial pulmonary disease in neonatal foals, as they are in sepsis.³ In the current case, a delayed and inadequate colostrum intake was probably the result of partial rejection of the foal by an inexperienced mare. Infectious neonatal respiratory diseases are usually part of complex multiorgan systemic infections (sepsis), commonly precipitated by failure of passive transfer (FPT).⁴ Administration of 1 liter of intravenous plasma at 18 hours of age resulted in adequate immunoglobulin levels upon admission of the foal, but may have only been partially protective due to the foal’s exposure to facultative pathogens prior to effective immune protection.

Early in life, localizing clinical signs of respiratory disease may be absent even in the presence of extensive disease. Dyspnea may be seen in affected foals and manifest as an increase in respiratory rate and effort. After the first deep breaths taken at birth, foals should breathe with a subtle chest excursion. As respiratory disease progresses, one might notice signs of increased breathing effort by an excessive movement of the intercostal muscles and an increased abdominal component to respiration. Finally, thoraco-abdominal asynchrony (paradoxical breathing) may ensue in foals in respiratory distress, fatigue, or failure. However, the initial signs of respiratory distress and hypoxemia are frequently vague. Even some severely hypoxemic foals may only show restlessness, and considerable resistance and struggling when being handled or restrained. Abnormal respiratory sounds (crackles or wheezes) may be heard on auscultation. However, even normal foals may show crackles on the down lung after having remained in lateral recumbency for a prolonged period of time. Furthermore, foals with no auscultable abnormalities may still have extensive pulmonary disease. Cough and nasal discharge are usually absent in the early stages of neonatal pulmonary disorders.⁵

Cyanosis is a sign of severe hypoxemia (Figure 6-2). The arterial PaO₂ (partial pressure of oxygen), however, must reach very low levels (35 to 45 mm Hg) before clinical cyanosis is observed. Approximately 5 g/dl of unoxygenated hemoglobin in the capillaries generates the dark-blue color that is appreciated as cyanosis in humans.⁶ Therefore, severely anemic foals may never appear cyanotic even in the face of profound hypoxemia. Weakness, depression, anorexia, weak or absent suckle reflex, dehydration, and fever may also be noted in foals with respiratory disease. In this case, evidence of depression, weakness, and injected mucous membranes should alert the clinician of possible underlying sepsis.

Fig. 6-2 Cyanotic mucous membranes occur when PaO₂ is <40 mm Hg.

Courtesy of Dr. Michelle Barton.

Respiratory disease is often related to aspiration, descending or hematogenous spread of infection, birth asphyxia, or prematurity. In this case, underlying sepsis posed a risk factor for septic pneumonia.

PATHOGENESIS

Respiratory disease and dysfunction in neonatal foals may present as a primary condition or may occur secondary to other disease processes.⁷ Equine neonatal pneumonia is generally defined as inflammation of the pulmonary parenchyma in foals less than four weeks of age. The etiologies of pneumonia in the newborn foal include systemic inflammatory response syndrome (SIRS), hematogenous spread of infection, aspiration of foreign material, and inhalation of airborne pathogens.⁵ Hematogenous (ascending) infections occur in association with bacteremia or sepsis, which may be acquired in utero from a placental infection or perinatally through environmental contamination (e.g. omphalitis, omphalophlebitis).

Perinatal pulmonic infections are more common in foals that are immunocompromised due to failure of absorption of maternal antibodies (FPT). An immature ciliary apparatus and the presence of fewer alveolar macrophages in neonates in comparison to adult horses lead to decreased bacterial clearance from the lungs.⁸ Reduced complement values in neonates may further contribute to decreased humoral defense against invading bacterial infections. If colostrum intake is insufficient and immunoglobulin G levels remain low, the foal is not only deprived of specific antibody protection, but neutrophil function is also seriously impaired.⁹

E. coli, Klebsiella spp, Actinobacillus equuli, Salmonella spp, and Streptococcus spp are some of the more common bacteria involved in neonatal foal pneumonia.^5,¹⁰ Equine viral arteritis (EVA) and herpes viral infections (EHV 1 and 4) have been implicated in in utero viral infections.¹¹ Although involvement of adenovirus in the pathogenesis of pneumonia has also been reported in a Thoroughbred foal, fatal adenoviral pneumonia is primarily associated with combined immunodeficiency (CID) in Arabian foals.^12,¹³ Additionally, a recent report documents the isolation of influenza A virus from a seven-day-old foal with bronchointerstitial pneumonia.¹⁴ Rare opportunistic fungal pathogens may include Pneumocystis carinii (renamed Pneumocystis jiroveci in humans), Aspergillus, Candida, and Mucor spp in immune-deficient foals.

Descending respiratory infections may be related to inhalation pneumonia (transmission of viral, bacterial, or fungal airborne pathogens), aspiration of infected amniotic fluid due to placental infection, aspiration of gastric reflux, iatrogenic aspiration (oil, medication, oral supplements), and aspiration of milk and meconium (see Case 8-3). Aspiration of meconium occurs in utero in foals that experience fetal distress. Though the meconium is commonly sterile at this time, it creates mechanical airway obstruction, surfactant inactivation, and pulmonary inflammation (caused by vasoactive mediators, chemotactic and inflammatory cytokines, including tumor necrosis factor α, interleukin 1β, and interleukin 8).¹⁵ The resulting edema and vasoconstriction may lead to hypoperfusion of the pulmonary parenchyma, with damage to type II pneumocytes and decreased production of surfactant.¹⁶ This type of “secondary surfactant deficiency” may also be induced by other forms of generalized pulmonary inflammation, including diffuse bacterial pneumonia.

Neurologic dysfunction, severe inflammation, or structural abnormalities of the upper airways predispose to aspiration pneumonia postpartum (see Case 8-3). Descending infection secondary to bacterial colonization of the mucosal surfaces of the oropharynx and nasopharynx rarely occurs, except when other predisposing factors are present.

Initial laboratory analysis of ’03 Hufflepuff revealed leukopenia (1.5 × 10³/μL) with a marked lymphopenia (0.32 × 10³/μL), neutropenia (0.62 × 10³/μL), and a band neutrophil count of 405/μL. Cytological findings were consistent with a severe degenerative left shift and associated toxic changes. The foal was hypoglycemic with a blood glucose level of 49 mg/dl. A brachial arterial blood gas analysis demonstrated a pH of 7.4, hypoxemia (58 mm Hg), and mild hypercarbia of 49.5 mm Hg. The foal’s alveolar to arterial oxygen gradient (A-a gradient) was calculated to be increased at 36.5. The calculated sepsis score was also increased at 18. Blood cultures were submitted.

Because the foal exhibited signs of increased respiratory effort and evidence of hypoxemia on blood gas analysis, further diagnostic evaluation included right- and left-sided thoracic radiographs in lateral recumbency. A moderate, diffuse alveolar-interstitial lung pattern within the caudo-dorsal lung was observed on both views. Mild to moderate diffuse interstitial infiltrates were also noted within the remaining lung quadrants.

DIAGNOSTIC TESTS

Bloodwork

As seen in the previous chapter, the effect of sepsis on the circulating neutrophil count is variable. Acute neutropenia, with or without a left shift, is commonly related to bacterial sepsis or endotoxemia when there is overzealous production of cytokines. With the appropriate stimulus, neutrophilia with or without a left shift may be present. Profound lymphopenia may be found in acute viral diseases as well as sepsis and endotoxemia.¹⁷ Lymphocyte counts are generally higher than neutrophil counts in the fetus and may reflect the degree of immaturity in premature foals. Physiologically, neutrophil counts in neonatal foals increase to mean values of approximately 8 × 10³ neutrophils/μl during the first 24 hours postparturition, due to endogenous glucocorticoid steroid release. Lymphocyte counts may physiologically decrease to mean values of 1.4 × 10³ lymphocytes/μl a few hours after birth, and then gradually increase to 5 × 10³ lymphocytes/μl at three months of age.¹⁸ Neonatal respiratory disease is not consistently related to specific abnormalities in the serum biochemistry analysis, but may depend upon underlying conditions such as sepsis, SIRS, or perinatal asphyxia.

Blood Gas Analysis

Arterial blood gas analysis is preferentially used to determine oxygenation and ventilation in neonates. Although pulse oximetry provides a continuous measure of arterial oxygen saturation, this technique has not been rigorously tested in the foal, and accurate readings are often difficult to obtain in the awake foal. Technically, an arterial blood sample can be obtained from any artery where a pulse can be felt. The more common sampling sites include the dorsal metatarsal artery located between the third metatarsal (cannon) bone and the cranial ridge of the forth metatarsal (lateral splint) bone of the hind limb; the branchial artery on the medial aspect of the elbow; the femoral artery at the external inguinal ring; the carotid artery, which runs medial and deep to the jugular vein; and the transverse facial artery, which is located caudal to the lateral cantus of the eye (ventral to the zygomatic arch). Successful arterial sampling is somewhat dependent upon the cardiovascular status of the foal. It is difficult to feel a pulse at the more distal sites in foals that are hypotensive or hypothermic. Additionally, peripheral oxygenation may not be equivalent to partial oxygen pressures obtained from central arteries.

Clipping and applying alcohol to the site of arterial puncture may help to visualize the artery. It is best to use a 22- to 25-gauge needle and a special blood gas syringe that contains an anticoagulant (e.g. sodium heparin) to obtain your sample. These syringes are usually self-filling. Once the sample has been drawn, all air bubbles should be evacuated from the syringe and the syringe should be capped to prevent exposure to room air. Room air will falsely increase the true PaO₂ and decrease the PaCO₂. Samples should be analyzed as soon as possible. If there is a delay (>10 minutes), then the sample can be refrigerated for two hours without significant problems. New handheld blood gas analyzers make this a practical test even in farm settings. Table 6-1 and Figure 6-3 are guidelines for the interpretation of arterial blood gas results in equine neonates.

Table 6-1 Arterial Blood Gas Interpretation

Parameter	Rounded Mean Normal Values (mm Hg)	Age of Foal Postpartum^*
PaO₂	55–60	30 minutes (lateral recumbency)
	70–80	6 hours (lateral)
	70–80	12 hours (lateral)
	70 (lateral) to 90 (standing)	24 hours
PaCO₂	50–55	30 minutes (lateral recumbency)
	43–47	6 hours (lateral)
	43–47	12 hours (lateral)
	42 (standing) to 50 (lateral)	24 hours
Caution
• Mild hypoxemia may be observed in foals after prolonged recumbency (especially if peripheral samples are taken). • Changes in body temperature result in large changes in PaO₂, PaCO₂, and pH without affecting HCO₃. A low body temperature decreases PaO₂ and PaCO₂ while raising pH. • Air contamination in the ABG sample will falsely increase measured PaO₂ and decrease PaCO₂ levels. • Metabolism continues within the ABG syringe after the sample is taken (tends to decrease PaO₂ and produce CO₂). Therefore, specimens held at room temperature must be analyzed within 10 minutes of drawing; iced samples should be analyzed within two hours.

* Summarized from Harvey JW: Normal hematologic values, In Koterba AM, Drummond WH, Kosch PG, eds: Equine clinical neonatology, Philadelphia, 1990, Lea & Febiger.

Fig. 6-3 Interpretation of arterial blood gases in neonatal foals.

In the absence of alterations in the inspired oxygen fraction (FiO₂), arterial hypoxemia may result from four basic processes, including hypoventilation, diffusion impairment, ventilation-perfusion inequality (VQ mismatch), and shunt (intrapulmonary and extrapulmonary shunt).¹⁹

Alveolar hypoventilation is defined as a reduced volume of inspired air reaching the alveoli per unit time, and is always related to an increase in PaCO₂ (hypercarbia). Conditions associated with alveolar hypoventilation include drug-induced respiratory depression (morphine, barbiturates), brain stem disease, abnormal respiratory muscle function (botulism, diaphragmatic hernia, dysfunction, or fatigue), thoracic cage abnormalities (rib fractures), increased airway resistance (upper and lower airway obstruction) and pleural space disease.²⁰ Although the mainstay of hypercarbia is hypoventilation, hypercapnic respiratory failure may also be multifactorial and can be exacerbated by severe VQ mismatch, shunt, or diffusion impairments. However, hypercarbia in foals with respiratory failure due to consolidating pneumonia, atelectasis, ARDS, etc., is more likely related to hypoxic diaphragmatic failure (secondary hypoventilation) than VQ mismatch, shunt, or diffusion impairment.

Impaired diffusion results from an increase in the blood-gas barrier. Since carbon dioxide diffuses more readily than oxygen, the PaCO₂ is usually not increased in conditions that only cause impaired diffusion, until the lesion is severe. Diffusion impairments may be seen in conditions such as pulmonary edema, pneumonia, atelectasis, or pulmonary contusion.²⁰

The adequacy of pulmonary gas exchange is also determined by the balance between pulmonary ventilation and capillary blood flow, which is commonly expressed as the ventilation-perfusion (VQ) ratio. A VQ ratio above 1 describes conditions in which ventilation is excessive relative to capillary blood flow (dead space ventilation). In normal human subjects, dead space ventilation accounts for 20% to 30% of the total ventilation. Dead space ventilation increases when the alveolar-capillary interface is destroyed (e.g. emphysema), when blood flow is reduced (e.g. low cardiac output, pulmonary thrombo-embolism, persistent pulmonary hypertension), or when the alveoli are overdistended by positive pressure ventilation. A VQ ratio below 1 describes the condition in which capillary blood flow is excessive relative to ventilation (pulmonary edema, pneumonia, atelectasis, etc.).²¹

Shunting, on the other hand, is defined as any mechanism by which blood that has not passed through ventilated areas of the lung is added to arteries of the systemic circulation.²⁰ In normal human subjects, intrapulmonary shunt flow (venous admixture) represents less than 10% of the total cardiac output.²¹ Rose and colleagues calculated the extent of physiologic shunt in neonatal foals and reported values of 16% to 18% in newborn term foals restrained in temporary lateral recumbency.²² In contrast, a 15% true shunt in adult humans is generally regarded as requiring oxygen therapy and 30% as life-threatening.²³

Increased intrapulmonary anatomical shunting can result from pulmonary artery to venous fistulas or severe lung lobe consolidation. Cardiac shunting (right to left shunt) may be related to congenital heart disease (e.g. tetralogy of Fallot, patent ductus arteriosus) or persistent fetal circulation (PFC). It is important to note that hypoxemia that is unresponsive to oxygen therapy is suggestive of shunt.²⁰

Alveolar to Arterial Oxygen Gradient

The difference in partial pressure of oxygen between alveolar pressure of oxygen (PAO₂) and arterial pressure of oxygen (PaO₂) is termed A-a gradient. The A-a gradient can be used as an indirect measure of VQ abnormalities, severe diffusion impairment and shunt, and is determined by the alveolar gas equation.

Index:

PiO₂ = inspired oxygen pressure (150 mm Hg in animals’ breathing room air)

PAO₂ = alveolar pressure of oxygen

PaO₂ = arterial pressure of oxygen

PaCO₂ = arterial pressure of carbon dioxide

RQ = respiratory quotient (ratio of CO₂ production over O₂ consumption); is equal to 0.8 at resting conditions

A simplified formula of the A-a gradient in animals’ breathing room air is

A-a gradient = 150 − (PaCO₂/0.8) − PaO₂

The normal A-a gradient is less than 15 mm Hg in healthy foals’ breathing room air, and increases with VQ mismatch, shunt, and severe diffusion impairments. The normal A-a gradient increases 5 to 7 mm Hg for every 10% increase in the inspired oxygen fraction in humans (FiO₂ = 21% in room air). This effect is presumably caused by the loss of regional hypoxic vasoconstriction of the lungs after oxygen administration.²¹ Normal A-a gradients in foals receiving supplemental oxygen have not been established.

’03 Hufflepuff’s A-a gradient was more than double that of a normal foal. This was compatible with a diffusion impairment or VQ mismatch from pulmonary atelectasis, edema, consolidating pneumonia, pulmonary hypertension, or pulmonary thrombo-embolism.

Radiographic Examination

Thoracic radiography is often helpful in establishing the presence of respiratory disease and in determining the type and extent of pulmonary involvement.⁷ In contrast to noninvasive and invasive pulmonary function testing (PFT, see below), thoracic radiography is used extensively in the clinical setting. Neonatal radiographic evaluation of the chest is facilitated by classifying the image appearance into radiographic patterns of pulmonary disease. Three major lung patterns (interstitial, alveolar, and bronchial patterns) are commonly used to define evidence of radiographic respiratory disease in neonatal foals. Although the vascular pattern may be helpful in assessing pulmonary perfusion, venous congestion, and cardiac anomalies, it plays a lesser role in the assessment of foal pneumonia.

A recent study has documented that radiographic abnormalities involving the caudodorsal lung region were most common in foals admitted to a referral center.²⁸ Bedenice and colleagues showed that the presence of dyspnea, tachypnea, a fibrinogen concentration >400 mg/dl, SIRS, hypoxemia, or FPT in neonatal foals may be predictors of underlying respiratory disease and should prompt an early radiographic evaluation of the thorax, even in the absence of other localizing clinical signs.^3,²⁸

’03 Hufflepuff was tachypneic upon presentation and showed diffuse radiographic infiltrates with a predominance of caudodorsal distribution. This is consistent with previous findings that tachypnea most reliably related to diffuse (caudodorsal, caudoventral, and cranioventral) pulmonary changes.²⁸ The presence of underlying sepsis or SIRS in this foal may further explain the predominant caudodorsal pulmonary infiltrates. Pulmonary ventilation and perfusion is closely matched in horses, and the percent regional blood flow is increased in the caudal lung lobes.²⁹ Additionally, Amis and coworkers documented that ventilation and perfusion follow a vertical gradient and increase in the dorsal lung regions of horses.³⁰ SIRS may initiate severe vascular leakage and thus contribute directly to the pathogenesis of lung injury in regions of increased relative blood flow.²⁸

Ultrasonography

Thoracic ultrasonography has become a popular diagnostic tool for the assessment of equine lung and pleural disease. Consolidation, pleural effusion, abscesses, penetrating thoracic wounds, rib fractures, and diaphragmatic hernias are some of the diseases that have been detected ultrasonographically in the lung and pleural cavity of adult horses and foals. The side(s) of the thorax affected, as well as the precise location of the lesion, can be determined in most cases.

Computed Tomography

Additionally, computed tomography (CT) may serve as an important and sensitive means of thoracic imaging in anesthetized patients. Computed tomography has played an important role in improving our knowledge of the pathophysiology, morphology, and progression of pulmonary dysfunction in humans.³¹ It is not only a research tool, but an invaluable technique that allows for the quantitative and qualitative characterization of structural lung abnormalities, assessment of lung structure–pulmonary function relationships, the effect of ventilation strategies (e.g., PEEP), and therapeutic maneuvers (e.g., patient position) on lung structure and the progression of pulmonary disease (Figure 6-6). However, the use of CT in equine neonatal pulmonary disease is currently restricted to referral centers.