The use of equine surfactant and positive pressure ventilation to treat a premature alpaca cria with severe hypoventilation and hypercapnia

Abstract

A 5-hour-old, premature alpaca cria was presented with failure to nurse, weakness, hypoglycemia, hypercapnia, and respiratory distress. The cria was treated with 3 doses of fresh, crude equine surfactant, positive pressure ventilation, and supplemental intranasal oxygen. Recovery to discharge was uneventful, and the cria regained apparently normal respiratory function. Three years after hospital discharge, the alpaca was a healthy adult.

Surfactant has important functions such as reducing the work of breathing by increasing lung compliance, and supporting alveolar stability during the respiratory cycle (1,2). Alveolar stabilization and decrease of the surface tension of the air-fluid interface help to maintain the gas exchange surface of the lung (3). These effects enhance alveolar fluid clearance and counteract edema formation by balancing hydrostatic forces (3). Surfactant also helps in the formation of a nonspecific barrier against adhesion and invasion of microorganisms into the lung (3).

In the horse, sheep, and cow, surfactant maturation occurs late in gestation, and is not always fully developed at term (1,2,4). During this time there is an increase in fetal adreno-corticosteroids that is associated with final lung maturation and the production of surfactant (2). Whether this also occurs in the newborn cria is uncertain. Foals, calves, and lambs born before lung maturation are at high risk of developing neonatal respiratory distress syndrome (RDS) due to surfactant deficiency (1–4), and a similar risk of developing RDS may be seen in the premature cria. This report describes the use of crude equine surfactant harvested from a freshly euthanized horse along with positive pressure ventilation in a premature neonatal cria with severe hypoventilation and hypercapnia.

Case description

An approximately 5-hour-old, male Suri alpaca cria was presented to the Large Animal Hospital for evaluation after premature birth at 312-days gestation. The patient presented with weakness, hypoglycemia, respiratory distress, and had been unable to stand or nurse since delivery. Initial physical examination revealed that the cria was weak with poor muscle tone and was unable to maintain sternal recumbency. There was no suckle reflex and mucous membranes were hyperemic. Signs of prematurity included unerupted incisors, curled ears, bilateral carpal valgus, flexor tendon laxity, a silky hair coat, and low body weight of 5 kg (5). A 1-cm reducible umbilical hernia was also palpated. Body temperature was at the low end of normal at 37.7°C, reference interval (RI): 37.7°C to 38.9°C (6). The patient was bradycardic with a heart rate fluctuating between 60 to 70 beats/min (RI: 70 to 100 beats/min) (6), and a continuous heart murmur characteristic of a patent ductus arteriosus was ausculted in the left hemithorax. The cria had a respiratory rate between 10 to 20 breaths/min (RI: 20 to 30 breaths/min) (6), but within an hour after admission progressed to 40 to 50 breaths/min with intermittent open-mouth breathing. Auscultation of the thorax revealed crackles in the left lung fields and a lack of breath sounds in the right lung fields suggestive of atelectasis.

Upon admission, an intravenous catheter was placed in the right jugular vein and blood was collected for blood culture, complete blood (cell) count (CBC), packed cell volume and total solids concentration, blood glucose concentration, and serum chemistry profile. An arterial blood gas sample was also collected from the left saphenous artery at admission. The pH was 7.35 (RI: 7.46 to 7.48) (7), partial pressure of arterial carbon dioxide (P_aCO₂) was 48.6 mmHg (RI: 27.2 to 33.8 mmHg) (7), and partial pressure of arterial oxygen (P_aO₂) was 37 mmHg (RI: 87.7 to 96.4 mmHg) (7), SpO₂ was 64%. Calculated alveolar-arterial (A-a) gradient from the initial blood gas while the cria was on room air was 65 mmHg (RI: 23.9 ± 14.4 to 35 ± 11.3 mmHg) (8). Continuous pulse oximetry on the external ear pinna revealed oxygen saturations between 60% to 70%. A nasal cannula was placed immediately after blood collection to administer supplemental oxygen at a rate of 1 to 2 L/min. The CBC and packed cell volume were within normal limits. Total solids concentration was low (43 g/L, RI: 54 to 62 g/L) and stall-side blood glucose concentration was markedly low (0.8 mmol/L, RI: 5.6 to 8.5 mmol/L) consistent with the inadequate consumption of colostrum reported in the patient’s history. Relevant abnormalities on serum chemistry included elevated sodium concentration (157 mmol/L; RI: 143 to 151 mmol/L), osmolality (310 mmol/kg; RI: 290 to 306.5 mmol/kg) and markedly low glucose concentration (0.83 mmol/L; RI: 5.6 to 8.5 mmol/L), low albumin (30 g/L; RI: 35 to 42 g/L), and globulin concentrations (11 g/L; RI: 21 to 31 g/L). These values were also consistent with failure to nurse.

A 50-mL bolus of Lactated Ringer’s Solution (LRS) with 5% dextrose was administered intravenously in order to immediately address the marked hypoglycemia. Two additional 50-mL boluses of LRS-dextrose were administered over 90 min, after which the blood glucose stabilized, the cria became more responsive, and was able to maintain himself in sternal recumbency. Commercially available camelid plasma (Triple J Farms, Llama Plasma, Bellingham, Washington, USA) was administered IV at a rate of 5 to 10 mL/kg body weight (BW) per hour (2 units, approximately 500 mL) to treat failure of transfer of passive immunity (FTPI). The cria was maintained on intravenous partial parenteral nutrition (PPN) at 2 mL/kg BW per hour in the form of 8.5% amino acids (Aminosyn, 8.5% Amino Acids; Hospira, Lake Forest, Illinois, USA) added to the remaining LRS with 5% dextrose for 7 d along with goat’s milk supplemented between 10% to 15% BW and milk from his dam once the cria began attempting to nurse 12 h after admission. Potassium penicillin (Pfizerpen; Pfizer, NewYork, New York, USA), 22 000 U/kg BW, IV, q6h, and amikacin (Amiglyde-V; Fort Dodge Animal Health, Fort Dodge, Iowa, USA), 25 mg/kg BW, IV, q24h, were administered for broad-spectrum antibiotic coverage as the cria was considered to be at high risk for pulmonary infection and sepsis. A second arterial blood gas sample taken approximately 2 h after the cria had been receiving nasal oxygen, revealed values of pH 7.386, P_aCO₂ 54.1 mmHg, P_aO₂ 238 mmHg, and SpO₂ of 100%. The cria’s clinical condition was markedly deteriorating and as he was persistently open-mouth breathing in the face of supplemental oxygen therapy, it was decided to ventilate the cria with concurrent surfactant administration.

An 8-year-old Quarter Horse gelding was euthanized for medical reasons unrelated to the respiratory system, and the lungs and caudal trachea were harvested for surfactant collection. Four liters of sterile saline were administered through a sterile endotracheal tube and diverted into the right and left lung fields to wash the lungs. The lungs were gently massaged and inverted to facilitate fluid retrieval. The surfactant-saline lung wash was collected into a sterile container. The cria was placed in sternal recumbency. Sterile lubricant mixed with 4 mg of lidocaine (Lidocaine HCl Injectable 2%; Vedco, St. Joseph, Missouri, USA) was used to lubricate the distal portion of a 3.5-mm cuffed Murphy endotracheal tube (Endotracheal tube; Sheridan Clear, Jorgenson Laboratories, Loveland, Colorado, USA). The tube was passed into the left nasal passage and into the trachea of the cria without anesthetic. A non-rebreathing system was connected to the end of the nasotracheal tube and the patient was administered 100% oxygen. A 5-mL/kg BW dose (1) (25 mL) of the surfactant-saline lung wash was administered in 5-mL aliquots into the nasotracheal tube. Positive pressure ventilation (PPV) was applied at 35 cm and 40 cm H₂O immediately prior to and after administration of the surfactant-saline lung wash to aid in alveolar recruitment. Between each 5-mL aliquot of lung wash the cria was rotated to sternal, right, and left recumbency to evenly distribute the surfactant-saline to all lung fields. This was repeated until all 25 mL of surfactant-saline lung wash had been given. The PPV was then continued for several breaths at 20 cm H₂O after which the cria was allowed to breathe spontaneously for 10 min; during this time he was tachypneic. Coarse crackles were ausculted bilaterally and tachypnea was observed immediately after surfactant-saline lung wash treatment but the tachypnea resolved within 1 h while the coarse crackles persisted. The nasotracheal tube was removed and the cria was watched closely for respiratory difficulty. The cria had normal respiratory effort during this time. The remaining surfactant-saline lung wash fluid was stored in the sterile container in the refrigerator at 1.6°C to 4.4°C, and a second surfactant-saline treatment was performed approximately 5 h later. A 25-mL volume of the refrigerated surfactant-saline was placed in a sterile syringe and brought to room temperature. The cria was placed in sternal recumbency and was less tolerant of handling while passing the nasotracheal tube. Lidocaine, 4 mg, was administered into the left nasal passage and 5 μg of fentanyl (Fentanyl Citrate Injection; West-Ward Pharmaceuticals, Eatontown, New Jersey, USA) were given intravenously to facilitate passage of the nasotracheal tube. Surfactant-saline lung wash administration and positioning were repeated as described. Five centimeter H₂O positive end expiratory pressure (PEEP) was utilized for additional alveolar recruitment. After each treatment nasal oxygen therapy was reinstituted and maintained continuously. Transient tachypnea and coarse crackles were again observed bilaterally after treatment. A single dose of flunixin meglumine (Prevail; VetOne, Meridian, Idaho, USA), 1.1 mg/kg BW, IV, was administered for its analgesic and anti-inflammatory effects between the first and second surfactant-saline lung wash treatments. Parenteral vitamin E and selenium were administered once subcutaneously (Bo-Se; Schering-Plough Animal Health, Union, New Jersey, USA) for their antioxidant properties.

An arterial blood gas sample was collected the following morning while the cria was receiving nasal oxygen at 1 L/h, prior to the final ventilation and surfactant-saline lung wash treatment, and the values were improved, with pH = 7.43, P_aCO₂ = 47.3 mmHg, P_aO₂ = 114 mmHg, and SpO₂ = 98%, except for a lower P_aO₂. Coarse crackles were ausculted bilaterally but the cria was bright, making attempts to stand, and had started to nurse from a bottle. A third surfactant-saline lung wash treatment was given approximately 15 h after the second, and was administered as described, except the nasotracheal tube was introduced into the right nasal passage.

Nasal oxygen was discontinued at 36 h after admission as the cria had begun moving freely about the stall and was nursing more consistently from his dam; however, he began open-mouth breathing after increased activity and the nasal oxygen cannula was replaced. Repeat CBC revealed a mild regenerative anemia as evidenced by a low hematocrit of 0.25 L/L (RI: 0.27 to 0.4 L/L), low hemoglobin concentration (95 g/L; RI: 105.5 to 173.4 g/L), and high nucleated red blood cells (12/100 WBC; RI: 0 to 2/100 WBC), leukopenia (2.77 × 10⁹ cells/L; RI: 6.39 to 18.91 × 10⁹ cells/L) characterized by neutropenia (1.22 × 10⁹ cells/L; RI: 3.25 to 13 × 10⁹ cells/L), and hyper-fibrinogenemia (0.1 μmol/L; RI: 0.04 to 0.06 μmol/L). Immunoglobulin G (IgG) level measured by radial immunodiffusion (RID) (Camelid IgG radial immunodiffusion assay; Triple J Farms, Bellingham, Washington, USA) was 9.55 g/L. A third unit of plasma was given at this time. An arterial blood gas sample drawn 49 h after admission with the cria on nasal oxygen at 1 L/h had the following values: pH = 7.39, P_aCO₂ = 53.2 mmHg, P_aO₂ = 228 mmHg, and SpO₂ = 100%. Oxygen therapy was again discontinued and the cria showed no further signs of respiratory difficulty. A final arterial blood gas sample drawn on day 4 revealed pH = 7.41, P_aCO₂ = 44.5 mmHg, P_aO₂ = 71.0 mmHg, and SpO₂ = 93% while the cria was breathing room air. Calculated A-a gradient at this time was 35.03 mmHg, which is just outside the high end of the reference range (8). Hematologic abnormalities had resolved completely by day 7, the cria was eupneic for the remainder of hospitalization, and was discharged with normal breath sounds in all lung fields 10 d after admission. Blood culture was negative. A brief ultrasonographic evaluation at the time of discharge showed mild comet-tailing of the ventral aspects of the right lung fields as the only abnormality. Normal, aerated lung was observed beneath the pleural surface in all other lung fields. No complications were observed at a 3-year follow-up and he was a normal sized healthy adult.

Discussion

To the authors’ knowledge, this is the first reported use of a saline lung wash containing surfactant in the treatment of severe hypoventilation and hypercapnia and possible respiratory distress syndrome (RDS) in a premature alpaca cria. Respiratory distress syndrome occurs in neonates when insufficient oxygen uptake and retention of carbon dioxide result in respiratory acidosis (1); it is more common in the premature neonate and a lack of surfactant is a major determinant for the development of RDS (9). Respiratory distress syndrome has been reported in humans, calves, and foals and recently in 1 premature alpaca cria (10).

In 2007, the definition of veterinary acute respiratory distress syndrome (ARDS) included meeting 4 criteria: acute onset tachypnea (< 72 h) or labored breathing at rest, the presence of certain risk factors (sepsis, SIRS, trauma), evidence of abnormal gas exchange, and respiratory capillary leak, with diffuse pulmonary inflammation as a “recommended but optional” fifth criterion (11). This cria met several of the required criteria for ARDS. He had acute onset tachypnea and labored breathing, and abnormal gas exchange on arterial blood gas, with an initial PaO₂/FiO₂ of < 200 mmHg. Equine neonatal acute lung injury (ALI) is defined as a PaO₂/FiO₂ of < 250 mmHg and ARDS is defined as a PaO₂/FiO₂ of < 160 mmHg at 4 days after birth (11). Exact cut-off values for ALI or ARDS have not been determined in neonatal crias, and extrapolating these values from other species may not be appropriate; however, these equine values suggest that initial ratios in this cria met definitions of ALI and possibly ARDS (11). While blood culture results were negative, and although sepsis was not definitively diagnosed, the cria was at high risk due to the FTPI and premature birth.

Advanced imaging of the thorax would have helped to assess the degree of suspected pulmonary atelectasis and to further characterize any abnormal lung patterns, but was not performed upon arrival due to owner financial constraints, and the perceived poor prognosis for the cria after initial response to therapy. It was decided to focus resources on treatment of the cria, limiting diagnostics and thereby preventing a more definitive diagnosis of RDS. Other differential diagnoses for the clinical signs seen in this cria were meconium aspiration, which was considered unlikely given the lack of meconium staining of the cria, or idiopathic persistent pulmonary hypertension (PPH) of the newborn that occurs with retained fetal circulation. The diagnosis is suspected in human infants that show lability in oxygenation state (large swings in PaO₂ and frequent desaturation episodes) or progressive cyanosis (12), and diagnostic tests beyond the history and physical examination include chest radiographs, blood gases, hyperoxia test and echocardiogram (12). No cyanosis was observed in this cria; however, the cyanosis can be intermittent with this condition and could have been missed; therefore, PPH could not be excluded as a primary differential in this case. In addition, echocardiography was not performed to confirm the presence of a cardiac shunt. Humans with PPH report perinatal asphyxia, meconium-stained fluid, or predisposing factors such as prolonged rupture of membranes, oligohydramnios, maternal infection, and antenatal use of NSAIDs (12). The cria’s birth was unobserved and reproductive evaluation of the dam was declined by the owner, despite the dam having birthed 2 premature crias in the past 2 seasons. Information regarding any perinatal risk factors, therefore, was unavailable. Treatments for PPH include oxygen supplementation which may require mechanical ventilation, blood pressure support, surfactant, inhaled nitrous oxide, and the use of other vasodilators such as sildenafil (12,13). It is unclear if the underlying cause for the respiratory distress observed in this cria was due to PPH or primary surfactant deficiency due to prematurity; however, surfactant can be used to treat both conditions (14). The cria in this case was supported by insufflation of oxygen and fluid therapy, but continuous mechanical ventilation was not an option for the client due to financial constraints. The cria showed significant improvement in arterial oxygenation when administered insufflated nasal oxygen thereby making a cardiac circulatory defect less likely. The work of breathing was greater than normal in this cria as evidenced by persistent open-mouth breathing, and it was felt he could not sustain this respiratory effort without additional therapy.

Based on knowledge in other species, the earlier surfactant is administered, the better the chance for a positive clinical outcome (2) through the prevention of lung inflammation and injury (1). Thus, it is possible that the early presentation of this cria to the hospital and the rapid administration of the surfactant-saline lung wash may have contributed to the successful outcome; however, it is also possible that the PPV alone helped this cria as others have reported (15). Although the use of surfactant with mechanical ventilation is the preferred method of administration, there is a recent report on the use of bovine lung surfactant obtained from the lungs of freshly slaughtered young cattle, administered to 20 premature calves without the use of mechanical ventilation (16). Twelve of the 20 calves in the surfactant-treated group survived using this method of surfactant instillation. Three animal-derived surfactants, Infasurf (Calfactant; ONY, Amherst, New York, USA), Survanta (Beractant; Abbvie, North Chicago, Illinois, USA), and Curosurf (Poractant alfa; Chiesi, Cary, North Carolina, USA) have been used in premature surfactant-deficient lambs and are currently the most commonly used in human neonates (17,18). The first 2 agents are extracts of bovine lung, and the third porcine lung; they could all have potential use in the neonatal cria. Surfactant therapy, however, is usually cost-prohibitive and so collection of surfactant from healthy lungs of other species appears to be a safe and economical alternative in crias.

There is no information available as to the surfactant composition of camelids, but composition and function vary according to species, degree of lung development, and physiological need (1). Some limitations to the use of surfactant obtained from freshly slaughtered animals are the lack of sterility associated with the collection method, the possibility of disease transmission from donor to recipient, and lack of an exact dose of active surfactant obtained in harvested samples. Our methods could have been improved through sample centrifugation and organic extraction as described elsewhere, although an attempt was made to collect the foamy portion of the lung wash (1). Complications of surfactant therapy reported in human infants include serious transient hypoxemia and bradycardia because of acute airway obstruction with the instilled fluid and a vagal effect from handling the head and neck of the infant. Cyanosis and bradycardia were noted in calves treated with surfactant (16).

Improved oxygenation of blood was seen after PPV and surfactant-saline lung wash administration in the reported case. Surfactant may have decreased the work of breathing by reducing surface tension, improving lung compliance, and maintaining lung stability. A marked improvement in clinical appearance, along with a decrease in PaCO₂ and decrease in acidemia, was seen after the second lung wash treatment. It is possible that the increased P_aCO₂ observed in the first arterial blood gas taken when the cria was on supplemental oxygen was due to reduced ventilatory drive resulting from the elevation of arterial oxygen with oxygen insufflation. Additionally, available reference ranges for arterial blood gas parameters may not be fully representative of the camelid population; however, in comparison to other species this cria was hypercapneic, and markedly hypoxemic at presentation. The calculated A-a gradient, was high at presentation on room air, consistent with either impaired diffusion or a ventilation-perfusion mismatch. The A-a gradient improved significantly by day 4 and was essentially normal suggesting improved ventilation post-treatment. While it could be argued that a third dose of lung wash was not indicated in this patient due to the improvement observed after 2 treatments, it was administered based on the human literature. Repeat dosing of up to 3 doses of surfactant is recommended for human neonates with persistent oxygen requirements within the first 72 h of life, and those who received 3 doses as opposed to 1 had decreased oxygen and ventilator needs within the first week and lower mortality at 28 d (19). Transient tachypnea and abnormal bilateral breath sounds were the only adverse findings associated with the administration of surfactant-saline but had resolved approximately 24 h after the last treatment. The neutropenia and hyperfibrinogenemia observed in blood taken 12 to 15 h after the last treatment suggested an inflammatory process, which could have been due to pneumonia secondary to FTPI or from pulmonary inflammation secondary to PPV. Mechanical stress associated with the reopening of airways injures pulmonary epithelial cells (20) and pulmonary epithelial injury provokes an influx of neutrophils into the interstitium and bronchoalveolar space (21). This could also potentially explain why the PaO₂ was lower on blood gas between the second and third treatments. A third unit of plasma was given after RID results revealed a value < 10 g/L as crias with IgG concentrations of > 10 g/L have a decreased risk of mortality (22). Nasal oxygen was needed for 49 h in this cria, but once discontinued the cria maintained a normal respiratory rate until discharge with no signs of dyspnea.

This report describes the use of positive pressure ventilation and surfactant-saline lung wash without long-term complications in a premature cria with suspected atelectasis, hypoxemia, and hypercapnia. It is possible that multiple doses may be needed in severe cases to achieve a lasting clinical effect (23). CVJ