Severe (grade IV) hypersensitivity to iodinated contrast agent in an anesthetized dog

Abstract

An 8-year-old female Labrador dog was anesthetized for contrast-enhanced computed tomography. The dog was sedated with dexmedetomidine and butorphanol and anesthetized with propofol and isoflurane. Upon IV injection of iohexol 350 mg/mL (72 mL), tachycardia, hypotension, and lower airway obstruction developed. Severe hypersensitivity to the contrast agent was suspected. Bronchospasm was treated successfully with epinephrine. Phenylephrine was used for pressure support. While rare, severe hypersensitivity to iodinated contrast agents can occur without evidence of prior exposure.

Case description

An 8-year-old, spayed female black Labrador dog was admitted to the Emergency Service with signs of stranguria. Physical examination revealed painful abdomen and thickened urethra on rectal palpation with no discrete mass. Complete blood (cell) count (CBC) and chemistry panel were consistent with moderate azotemia, metabolic acidosis, and dehydration. A urinalysis revealed an abnormal population of epithelial cells, and neoplasia was suspected. Subsequently, endoscopy of the urinary tract under general anesthesia revealed a grossly abnormal urethral wall. Biopsies were obtained and cytology of those samples was compatible with transitional cell carcinoma. Abdominal ultrasound and thoracic radiographs did not reveal any evidence of metastasis. The following day, a urethral stent was placed under general anesthesia, and treatment with piroxicam (10 mg daily) was initiated. On each occasion, preanesthetic sedation was provided with dexmedetomidine and fentanyl (first procedure) or hydromorphone (second procedure), and maropitant. Anesthesia was induced and maintained with propofol and isoflurane in oxygen, respectively. No complications arose during either procedure. Further consultation with the oncology service was pursued and ultimately, treatment with radiation therapy was recommended. The dog was then scheduled for computed tomography (CT) and radiation therapy planning under general anesthesia.

Prior to general anesthesia, the dog was quiet, alert, and responsive. Physical examination revealed a rectal temperature of 38.8°C, respiratory rate of 20 breaths/min, and pulse rate of 84 beats/min. Mucous membranes were pink and moist with a capillary refill time < 2 s. Thoracic auscultation was normal, and no arrhythmias or murmurs were detected. The patient’s weight was 35.7 kg with a body condition score of 6/9. The dog was receiving piroxicam, and the following blood analysis was obtained: hematocrit 47%, total plasma proteins 67 g/L, blood urea 5.4 to 9.3 mmol/L, and blood glucose 6.6 mmol/L. She was classified as an ASA physical status II and was sedated with dexmedetomidine (Dexdomitor; Zoetis, Kalamazoo, Michigan, USA), 3 μg/kg body weight (BW), and butorphanol (Torbugesic SA; Zoetis), 0.4 mg/kg BW, both IM. General anesthesia was induced with propofol (Rapanofol; iVaoes Animal Health, Miami, Florida, USA), 100 mg after oxygen was supplemented, via face mask for ~2 min. The trachea was intubated with a cuffed tube and anesthesia was maintained with isoflurane in oxygen and positive pressure ventilation [tidal volume 430 mL, peak inspiratory pressure (PIP) 12 cmH₂O, rate 10 breaths/min]. Lactated Ringer’s solution (Lactated Ringer’s Injection; Baxter Healthcare Corporation, Deerfield, Illinois, USA) was infused at 5 mL/kg BW per hour. Monitoring consisted of electrocardiogram, pulse oximetry, capnography, oscillometric arterial pressure (every 2 min), and intermittent rectal temperature. The patient was moved into the CT (Toshiba Aquilion LB 16 slice scanner; Toshiba America Medical Systems, Tustin, California, USA) suite and positioned in right lateral recumbency; the same monitoring and parameters for positive pressure ventilation were continued. During positioning and initial imaging acquisition (pre-contrast CT of the caudal thorax through pelvis, 320 mm FOV, 120 KV, automatic mA using Toshiba SureExpose, 2.0 mm slice thickness, and 512 × 512 matrix), anesthesia was uneventful, with an average heart rate (HR) of 80 beats/min, and blood pressures [SAP/DAP (MAP)] of 110/60 (80) mmHg; hemoglobin saturation remained > 97% and the end-tidal CO₂ averaged 35 mmHg. A 72-mL volume of nonionic iodinated contrast medium [Omnipaque (Iohexol 350 mg Iodine/mL); GE Healthcare, Marlborough, Massachusetts, USA] was then injected IV to obtain enhanced images. Almost immediately, the HR increased to 140 beats/min. Insufficient depth of anesthesia was ruled out upon assessment of palpebral reflex and muscular (jaw) tone; palpebral reflexes could not be elicited, eyes were rotated ventromedially, and there was no noticeable muscular tone. Next, an abnormal capnographic waveform, compatible with partial airway obstruction, was observed (Figure 1). Soon after, all capnographic waveforms were lost despite continual positive pressure ventilation. Manual positive pressure ventilation was attempted but thoracic excursions were only possible if PIP exceeding 40 cmH₂O was delivered. Capnographic waveforms remained absent despite noticeable spontaneous inspiratory efforts by the patient and positive pressure manual breaths by the anesthetist. The tracheal tube was quickly examined for kinks, obstructions, or distal migration and accidental endobronchial intubation; all were quickly ruled out. The SpO₂ reached a nadir value of 83% during these maneuvers. Coupled with tachycardia, the temporal relation to the injection of contrast medium, and the exclusion of any equipment malfunction, it was suspected that the patient was experiencing a severe hypersensitivity reaction to the contrast agent and that bronchospasm was the cause of the ventilatory failure. Closer inspection revealed injected mucous membranes and weak femoral pulses; the oscillometric monitor failed to measure arterial blood pressure. Epinephrine (Adrenalin; Par Pharmaceutical, Chestnut Ridge, New York, USA), 5 μg/kg BW, was administered IV along with a bolus of Lactated Ringer’s solution (350 mL). Within the next minute, thoracic excursions became possible during positive manual ventilation with a PIP of 20 cmH₂O, and a normal capnographic wave was restored. Blood pressure following these resuscitation maneuvers was 65/42 (52) mmHg. An infusion of phenylephrine (Vazculep; Avadel Legacy Pharmaceuticals, Chesterfield, Missouri, USA), 0.2 μg/kg BW per minute, was started for pressure support, and diphenhydramine (DiphenhydrAMINE; West-Ward, Eastontown, New Jersey, USA), 2 mg/kg BW, IM, and famotidine (Famotidine; Mylan, Rockford, Illinois, USA), 0.5 mg/kg BW, IV, were administered. Computed tomography of the thorax was conducted (using the same parameters) to rule out pneumothorax or pulmonary edema. The results of the scan showed severe diffuse bronchoconstriction and moderate (dependent) atelectasis of the right lung. Repeat imaging of the abdomen and pelvis for radiation therapy planning was not pursued. Arterial blood gas revealed a pH of 7.15, PaO₂ of 83 mmHg, PCO₂ of 40 mmHg, and a base deficit of (−14). Isoflurane administration was discontinued and 60 mEq of bicarbonate were infused IV over the next 20 min.

Figure 1.

A — A normal capnographic waveform in a spontaneously breathing dog. The upstroke represents the mixing of dead and alveolar gas during early expiration. The alpha angle shows the change from airway gas to alveolar gas (plateau) during expiration. B — A capnograph from a different dog with partial lower airway obstruction (tracheal collapse) during spontaneous breathing. Note the gradual slope at the beginning of expiration and loss of alpha angle.

Extubation occurred 30 min after isoflurane was discontinued; at this time the swallowing reflex was present and the dog appeared sedated. Two doses of atipamezole (Antisedan; Zoetis, Kalamazoo, Michigan, USA), 15 μg/kg BW, IM, were administered to accelerate recovery. Shortly after the second dose the dog was transferred to the intensive care unit. The patient experienced diarrhea and hematochezia over the next day. The dog was treated with pantoprazole (Pantoprazole; AuroMedics Pharma, E. Windsor, New Jersey, USA), ondansetron (Ondansetron; Accord Healthcare, Durham, North Carolina, USA), and ampicillin/sulbactam (Ampicillin and Sulbactam; Mitim SRL, Brescia, Italy), and crystalloid fluids. Arterial blood was monitored for the following 24 h. The dog was discharged 2 d later.

Discussion

Hypersensitivity reactions can differ in their etiology and mechanism and can be divided into immunologic and nonimmunologic. Immunologic (anaphylactic) reactions are mediated by immunoglobulins (IgE); prior exposure, although not necessary, is often required. In contrast, nonimmunologic or anaphylactoid reactions occur by release of mediators from mast cells and/or basophils, or from direct complement and/or bradykinin cascade activation (1,2). The clinical presentation, however, is practically indistinguishable between both forms and in severe cases, immediate treatment is necessary regardless of the classification.

Several studies have reported complications in dogs receiving contrast media (3–5); to our knowledge, however, severe cases of complete or near complete bronchospasm requiring aggressive ventilatory support and administration of epinephrine, as the one described here, have not been reported. Different grading scales exist to describe the severity of the anaphylactic/anaphylactoid reaction (1,6). One scale grades them from 1–5 (1), each category corresponding, respectively, to minor, low severity, life-threatening, cardiac or respiratory arrest, and death. A retrospective study in 49 dogs receiving sodium iothalamate reported that important changes in blood pressure or heart rate were documented in 37% of the cases, however, no cases required treatment with epinephrine (3). A larger retrospective study evaluated 356 dogs receiving nonionic iodinated contrast media, and reported that mild and moderate reactions occurred in 18% of the cases each, and that severe reactions occurred in 0.8% of dogs (5). In those animals with severe reactions, signs were confined to body twitching, sinus tachycardia and other dysrhythmias, and hyperventilation; no dog required treatment with epinephrine. A report of a severe case of hypersensitivity secondary to contrast medium documented that bronchoconstriction could be detected during CT examination; however, treatment with positive pressure ventilation or epinephrine was apparently not necessary (4). In the postcontrast CT scan images (Figure 2B) showing severe diffuse bronchoconstriction, the acquisition was made after treatment with epinephrine and positive pressure ventilation, and restoration of a normal capnographic waveform. Bronchospasm was likely more severe prior to treatment. The severity of the bronchoconstriction at the time of the second scan is demonstrated when compared with the pre-contrast images (Figure 2A). In addition, when comparing the pre-contrast and post-contrast images, there is moderate thickening (congestion) of the esophageal wall (Figures 3A, B). Reports in dogs, cats, and humans show that most hypersensitivity events are mild to moderate, many not requiring treatment. In humans, the overall incidence of hypersensitivity reactions during surgery is approximately 15/10 000 (1). Severe cases (grades 3–5) are rarer, occurring in approximately 2/10 000 cases (1). In our case, bronchospasm resulted in ventilatory failure, qualifying this case as grade 4.

Figure 2.

Pre-contrast (A) and post-contrast (B) CT images of the thorax, acquired at the level of the 9th intercostal space (the patient’s right is to the left of the images). Severe narrowing of the bronchi is demonstrated by comparison of the pre-contrast and post-contrast images. There is moderate thickening (i.e., congestion) of the esophageal wall and dependent atelectasis of the right lung in the post-contrast image.

Figure 3.

Pre-contrast (A) and post-contrast (B) 3D surface rendered CT reconstructions of the caudal aspect of the thorax demonstrating severe narrowing of the bronchi and moderate thickening (i.e., congestion) of the esophageal wall in the post-contrast image (the patient’s right is to the left of the images).

Treatment of severe hypersensitivity involves, if possible, interruption of the triggering agent, and administration of epinephrine, which contributes to normalizing blood pressure and reversing bronchospasm. In humans, initial IV doses of 100 to 300 μg (~1.5 to 4 μg/kg BW for a 70-kg person) are recommended (7), as higher doses may result in fatal dysrhythmias (8). Given the short duration of action of epinephrine, repeated doses might be required. In our case, hypotension was not documented during the crisis; however, weak femoral pulses, tachycardia, and the inability of the oscillometric blood pressure to register values, could be the result of arterial hypotension. Oscillometric arterial pressure was registered soon after treatment, and phenylephrine was required to overcome hypotension, supporting the hypothesis that the patient had experienced low blood pressures. Aggressive fluid therapy is also recommended in humans to palliate the vasodilatory component of the reaction (2). Airway instrumentation is also recommended in severe cases, as edema of the pharynx and larynx can ensue rapidly (9).

In our case, hemoglobin desaturation was observed. The use of oxygen as carrier gas during anesthesia, and the rapid recognition and treatment of airway obstruction, likely prevented a more severe decrease in hemoglobin saturation. Partial airway obstructions can be readily identified by capnographic waves that are characterized by an increase in the amplitude, or loss of a distinct alpha angle. The authors believe that the use of capnography was essential for a prompt recognition of bronchospasm.

Further treatment with antihistamine drugs is also suggested. Corticosteroids may also be considered in severe cases. Our patient received H1 and H2 blockers, but steroids were withheld, as resolution was fast and appeared to be complete. In humans experiencing intraoperative hypersensitivity, it is also recommended that the patient be closely monitored in an ICU for at least the next 24 h (7). The dog herein was transferred to the ICU for the next 2 d, and required supportive treatment.

Recovery from anesthesia was perceived as slow in this dog, but was successfully accelerated by the administration of atipamezole. It is unclear whether the delayed recovery was a consequence of dexmedetomidine, of reduced perfusion/oxygenation to the brain that may have produced a degree of depression, or both. Follow-up communications with the owner revealed that the dog’s behavior at home normalized only after 5 d had elapsed. No subsequent long-term sequelae were identified by the owners or veterinarians caring for this dog.

There are several agents in addition to contrast media that have been implicated in triggering intraoperative hypersensitivity reactions in humans. Triggers frequently involved include neuromuscular blocking agents, antibiotics, and latex. With lower frequency, hypnotic agents, local anesthetics, opioids, antiseptics, and contrast agents have been identified (2). Fortunately, the incidence of severe hypersensitivity reactions in anesthetized animals is apparently low; however, severe cases, even when infrequent, can have devastating consequences. Peri-anesthetic monitoring can allow early recognition of hypersensitivity cases, and help assess the success of treatment. CVJ