History

A 5-year-old 21.0-kg spayed female American Pit Bull Terrier was presented to the University of Wisconsin’s Oncology Service because of a 7-day history of increased respiratory effort. The dog had been evaluated recently by its primary veterinarian for dyspnea, and thoracic radiographic examination at that time revealed an intrathoracic mass effect.

On initial physical examination, the dog was panting and had slightly muffled heart sounds on auscultation of the right hemithorax. No other physical abnormalities were found. Hematologic and serum biochemical analyses were performed 4 days prior to presentation and revealed mild leukocytosis (17.8 × 10³ WBCs/μL; reference range, 5.5 × 10³ to 16.9 × 10³ WBCs/μL), characterized by a neutrophilia (14.9 × 10³ cells/μL; reference range, 2.0 × 10³ to 12.0 × 10³ cells/μL), and mild reticulocytosis (131.7 × 10³ cells/μL; reference range, 10.0 × 10³ to 110.0 × 10³ cells/μL). Results for biochemical analyses (Idexx Laboratories Inc) were all within reference limits.

To further diagnose the mass and rule out metastatic disease, CT of the thorax and aspiration of the mass were planned. Food but not water was withheld overnight. The dog was premedicated with butorphanol (0.38 mg/kg, IM) and dexmedetomidine (2.8 μg/kg, IM), and a 20-gauge 1.5-inch catheter was aseptically placed in the right cephalic vein. Following preoxygenation with 100% oxygen via a tight-fitting face mask, general anesthesia was induced with propofol (1 mg/kg, IV) and the dog was intubated with an 11-mm-internal-diameter cuffed silicone endotracheal tube, the free end of which was then connected to a standard anesthetic machine via a rebreathing circuit. The minimal occlusion volume method was used to inflate the endotracheal tube cuff to prevent an air leak at 20 cm H₂O peak airway pressure. General anesthesia was maintained with 1.0% to 2.5% (vaporizer setting) sevoflurane delivered in oxygen (1 L/min). Immediately after intubation, intermittent positive-pressure ventilation was initiated by use of a volume-controlled, time cycled ventilator (Surgivet paraPAC; Smiths Medical); respiratory rate was set at 14 breaths/min, and tidal volume was approximately 200 mL, with a resultant peak inspiratory pressure of 10 cm H₂O. Throughout anesthesia, an isotonic crystalloid solution (Plasma-Lyte A; 5 mL/kg/h, IV) was administered. Pulse rate and oxygen saturation of hemoglobin (Spo₂) were measured by pulse oximetry, and respiratory rate and end-tidal CO₂ concentration (ETco₂) were monitored with side-stream capnography using a multiparameter monitor (LifeSense; Nonin Medical Inc). Indirect blood pressure was measured with an oscillometric blood pressure monitor (Cardell 9401; Midmark Corp) and a size 3 cuff above the left tarsus. Electrocardiography was not performed throughout the anesthetic procedure due to interference on CT. Initial measurements included a pulse rate of 130 beats/min, Spo₂ of 100%, ETco₂ of 40 mm Hg, and systolic, diastolic, and mean arterial pressures of 120, 80, and 95 mm Hg, respectively. Parameters throughout the procedure were recorded every 5 minutes; ETco₂ remained between 38 and 40 mm Hg, pulse rate ranged between 93 and 103 beats/min, and systolic, diastolic, and mean arterial pressures ranged from 109 to 111 mm Hg, 65 to 71 mm Hg, and 86 to 90 mm Hg, respectively.

Thoracic CT was performed (LightSpeed Ultra 8 slice; GE Healthcare) with a kVp of 120, mAs of 200, matric of 512 × 512, slice thickness of 1.25 mm, and pitch of 1, revealing a large mediastinal mass effect. Following initial scans, an iohexol-based iodinated nonionic contrast solution (Omnipaque 240; 2 mL/kg, IV) was administered at a rate of 5 mL/s. Approximately 2 minutes after contrast administration, ETco₂ decreased rapidly from 40 to 25 mm Hg and the patient began to spontaneously ventilate despite no change in mechanical ventilation. Adequate anesthetic depth was confirmed by absent palpebral reflexes. The preset tidal volume (200 mL; 10 mL/kg) delivered from the mechanical ventilator had not changed; however, the peak inspiratory pressure acutely rose from 10 to 20 cm H₂O, suggesting an increase in airway resistance, decrease in pulmonary compliance, or both. Systolic, diastolic, and mean arterial pressures markedly decreased (greater than approx 60% from baseline) to 54 mm Hg, 30 mm Hg, and 35 mm Hg, respectively; pulse rate was 105 beats/min. Postcontrast CT was quickly completed, and the dog was removed from the CT unit. For the following 5 minutes, the pulse oximeter failed to detect the pulse rate or measure Spo₂ and the indirect blood pressure monitor failed to yield measurements. Femoral pulses were weak during this time. The skin and mucous membranes of the dog were easily visualized and appeared moderately erythematous, hyperemic, and edematous (Figure 1), a substantial change from the light-pink color previously noted. Urticaria became prevalent along the dog’s neck, trunk, and thoracic limbs.

View Full Size

Clinical images of a 5-year-old 21.0-kg spayed female American Pit Bull Terrier during anesthesia immediately after IV administration of contrast medium for thoracic CT, showing that the dog’s skin and mucous membranes are easily visualized and appear moderately erythematous, hyperemic, and edematous (A), compared with the more clinically normal appearance during recovery (B).

Citation: Journal of the American Veterinary Medical Association 260, 12; 10.2460/javma.21.07.0327

• Download Figure
• Download figure as PowerPoint slide

Question

What was the most likely explanation for the physiologic changes following administration of the iohexol-based contrast medium? What would have been the next therapeutic steps?

Answer

The most likely cause of the acute increase in peak airway pressures, hypotension, hypocapnia, urticaria, and erythema was an anaphylactic or anaphylactoid reaction to the contrast medium. The sevoflurane vaporizer was immediately turned off and the anesthetic circuit cleared of inhalant. A lead II ECG was then placed and assessed as sinus rhythm with a rate of 110 beats/min; oscillometric blood pressure measurement did not produce numeric values but reported a weak signal. Epinephrine (2 μg/kg, IV) was immediately administered, then the dog’s pulse rate increased to approximately 200 beats/min with a sinus rhythm within 2 minutes. Pulse oximetry and oscillometric blood pressure measurements began to read 5 minutes following epinephrine administration. Systolic, diastolic, and mean blood pressures reached a maximum of 135 mm Hg, 89 mm Hg, and 100 mm Hg, respectively, with ETco₂ returning to 40 mm Hg. Pulse rate returned to pre-epinephrine levels (100 to 120 beats/min) within 10 minutes. Diphenhydramine (1 mg/kg, IV) and famotidine (1 mg/kg, IV) were administered slowly. An isotonic crystalloid bolus (10 mL/kg, IV) was administered IV over 10 minutes, and dexamethasone sodium phosphate (0.1 mg/kg, IV) was given. The facial swelling and hyperemia began to resolve, and the dog was maintained on 100% inspired oxygen until extubation. The dog quickly regained consciousness and recovered uneventfully. The dog remained hospitalized the remainder of the day for monitoring; all physiologic values remained within normal limits until discharge that evening.

Findings on CT confirmed a large multifocal mediastinal neoplasia, with pulmonary, epaxial, and osseous metastases; intrathoracic lymphadenopathy; vascular compression and invasion; and scant pleural effusion. In addition, bronchoconstriction and pulmonary vasoconstriction were noted in the second set of postcontrast scans (8 minutes after administration of contrast medium; Figure 2), consistent with an anaphylactic or anaphylactoid reaction to contrast medium. A fine-needle aspirate of an epaxial mass was consistent with sarcoma.

View Full Size

Representative transverse caudal thoracic CT images of the dog in Figure 1 before (A) and after (B) administration of contrast medium and acquired in a lung algorithm (window width, 1,400 HU; window level, –500 HU). After administration of contrast medium, the left caudal lung lobe has mild narrowing of the bronchial lumen (white arrows; precontrast, 6.4 mm diameter; postcontrast, 4.2 mm diameter; approx 34% change) and pulmonary vasculature (black arrows; precontrast, 4.3 mm diameter; postcontrast, 3.1 mm diameter; approx 28% change), consistent with bronchoconstriction and vasoconstriction secondary to the anaphylactic or anaphylactoid contrast reaction. The caudal vena cava (CVC) is also mildly narrowed after contrast administration. The multifocal mediastinal masses (M) and pulmonary nodules (asterisks) are also evident.

Citation: Journal of the American Veterinary Medical Association 260, 12; 10.2460/javma.21.07.0327

• Download Figure
• Download figure as PowerPoint slide

Discussion

Advanced imaging techniques using various ionic and nonionic contrast media are becoming increasingly popular in veterinary medicine. They are used in conjunction with routine imaging procedures to confirm and characterize organ size, shape, location, and function. These agents are generally considered safe. However, severe, life-threatening anaphylactic or anaphylactoid reactions have been reported in rare instances with ionic iodinated contrast agents (IICAs) and nonionic iodinated contrast agents (NIICAs; used in this case) in humans, dogs, and cats.^1–4

Anaphylaxis is classified as a type I IgE-mediated hypersensitivity reaction involving mast cells, basophils, and histamine release.⁵ Anaphylaxis usually occurs on second exposure to a specific antigen and subsequent release of proinflammatory mediators. However, it can also occur on first exposure to a specific drug due to cross-reactivity among antigens with similar epitopes such as those associated with commercial products and medications.⁵ Anaphylactoid reactions occur through a direct non–immune-mediated release of mediators from mast cells or basophils, or result from direct complement activation, but they also present with clinical symptoms similar to those of anaphylaxis.⁵ Although we do not have verification that the present case was an anaphylactic or anaphylactoid reaction (such as analyses of histamine breakdown products, β-tryptase activity, or mast cell counts), clinical signs are highly suggestive.

Manifestations of anaphylactic or anaphylactoid reactions can occur within minutes of agent exposure⁵ and include vomiting, diarrhea, cutaneous hyperemia (flushing), urticaria, angioedema, bronchoconstriction, cyanosis, tachycardia, hypotension, and shock, leading to cardiovascular collapse and death.⁵ Decreases in pulmonary compliance and in ETco₂ could result from bronchoconstriction and profound systemic vasodilation and hypotension, respectively. In contrast to systemic vasodilation, histamine and other cyclooxygenase products may also result in pulmonary vasoconstriction.⁶ We speculated that cellular mediator release, systemic hypotension, bronchoconstriction, and pulmonary vasoconstriction contributed to substantial ventilation-perfusion ratio alterations and subsequent arterial hypoxemia, potentially causing the tachypnea seen in the dog of the present report.

In humans, the incidence of anaphylactic or anaphylactoid reactions decreases significantly with the use of NIICAs compared to IICAs.^2,5 Studies concerning the cardiovascular changes caused by NIICAs are limited in veterinary medicine. Changes in heart rate and blood pressure greater than 20% of baseline values after administration of IICAs in veterinary species range from 7%⁷ to 37%⁸ and from 6%⁷ to 18%⁹ for NIICAs. In a large retrospective study of 356 dogs receiving NIICAs, only approximately 1% experienced decreases in mean arterial blood pressure greater than 20% of baseline that required immediate treatment, and no anaphylactic or anaphylactoid reactions were reported.^7,9 In comparison, the dog of the present report had an approximately 60% decrease in mean arterial pressure and heart rate decreased approximately 15% to 19%.

Although contrast medium reactions in humans are generally unpredictable, factors that may predispose a patient to contrast medium–associated reactions include asthma, atopic dermatitis, food allergies, cardiac disease, dehydration, renal disease, previous contrast administration, or age (neonates or aged patients), alone or in combination.² Atopic dermatitis has also been suggested as a risk factor in dogs.¹ In humans, many medications have also been associated with anaphylactic reactions, including artificial colloids, neuromuscular blocking agents, antimicrobials (penicillin and other β-lactams), propofol, and opioids such as morphine and meperidine (butorphanol has not been reported).⁵

In dogs with potential risk factors (eg, atopy, previous contrast reactions, cardiac disease, or renal disease) that are potentially associated with anaphylactic or anaphylactoid reactions, prophylactic antihistamine and corticosteroid administration can be considered. However, the rare incidence and the questionable efficacy in preventing severe life-threatening effects make their routine use in clinically normal patients receiving contrast agents impractical. In addition, evidence for their prophylactic use in humans is lacking, and premedication does not eliminate the risk for reaction.⁵

Although mild reactions are generally self-limiting, treatment for anaphylactic or anaphylactoid reactions usually includes blood pressure support with IV fluid therapy and vasopressors, 100% oxygen administration with assisted ventilation, and epinephrine (mixed α- and β-adrenergic receptor agonist) with or without inhaled β₂-adrenergic receptor agonists to combat refractory bronchoconstriction and hypoxemia. Although tachycardia can be associated with anaphylactic or anaphylactoid reactions, our reported dog had minimal heart rate changes prior to epinephrine administration. During vasodilation and hypotension, baroreceptor stimulation may subsequently increase heart rate. However, injectable and inhalant anesthetics can depress this response in humans and animals.¹⁰ Dexmedetomidine may also have attenuated a heart rate increase.¹¹ Antihistamines and corticosteroids are often administered to reduce delayed clinical signs, and corticosteroids may also decrease the severity of airway or laryngeal edema. If severe and untreated, patients may undergo cardiopulmonary arrest and CPR should be initiated as appropriate.⁴

In summary, imaging procedures using contrast agents are common in veterinary medicine. Although patients undergoing CT contrast studies using NIICAs may have a lower incidence of adverse reactions compared to the use of IICAs, anesthetists should be prepared to deal with mild-to-severe anaphylactic or anaphylactoid reactions that may accompany the use of these agents as well as many other potential perianesthetic medications.