Adverse effects associated with inadvertent intravenous penicillin G procaine-penicillin G benzathine administration in two dogs and a cat

Megan I. Kaplan Section of Emergency and Critical Care, Department of Clinical Studies, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108.

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Justine A. Lee Section of Emergency and Critical Care, Department of Clinical Studies, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108.

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Lynn R. Hovda Pet Poison Helpline, 8009 34th Ave S, Ste 875, Bloomington, MN 55425.

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Ahna Brutlag Pet Poison Helpline, 8009 34th Ave S, Ste 875, Bloomington, MN 55425.

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Abstract

Case Description—2 dogs and a cat were inadvertently given penicillin G procaine–penicillin G benzathine IV instead of propofol during induction of anesthesia for routine dental prophylaxis. One dog and the cat required hospitalization because of severe neurologic impairment and cardiopulmonary arrest (cat); the remaining dog did not develop any clinical signs.

Clinical Findings—In the 2 animals that developed signs consistent with an immediate adverse reaction, clinical signs included muscle tremors, seizures, blindness, vocalization, agitation, and transient loss of vision. Hypothermia, pruritus, hypotension, and cardiac arrest were also documented.

Treatment and Outcome—The 2 affected patients responded to treatment with anticonvulsant medications, centrally acting muscle relaxants, sedation, and intensive supportive care including IV fluid administration and oxygen supplementation as needed. Cardiopulmonary cerebral resuscitation was performed successfully in the cat. The dog that did not develop any clinical signs was not treated. The 2 affected patients recovered fully and were discharged from the hospital after 3 to 4 days with no apparent sequelae.

Clinical Relevance—Penicillin G procaine–penicillin G benzathine and propofol are common drugs in veterinary practice and may both be administered to patients undergoing elective procedures. Because of their similar milky white appearance, veterinarians should label syringes and take care to avoid this medication error. There is no specific antidote for penicillin orprocaine toxicosis. Aggressive and immediate treatment is required in patients that develop an adverse reaction to ensure a successful outcome.

Abstract

Case Description—2 dogs and a cat were inadvertently given penicillin G procaine–penicillin G benzathine IV instead of propofol during induction of anesthesia for routine dental prophylaxis. One dog and the cat required hospitalization because of severe neurologic impairment and cardiopulmonary arrest (cat); the remaining dog did not develop any clinical signs.

Clinical Findings—In the 2 animals that developed signs consistent with an immediate adverse reaction, clinical signs included muscle tremors, seizures, blindness, vocalization, agitation, and transient loss of vision. Hypothermia, pruritus, hypotension, and cardiac arrest were also documented.

Treatment and Outcome—The 2 affected patients responded to treatment with anticonvulsant medications, centrally acting muscle relaxants, sedation, and intensive supportive care including IV fluid administration and oxygen supplementation as needed. Cardiopulmonary cerebral resuscitation was performed successfully in the cat. The dog that did not develop any clinical signs was not treated. The 2 affected patients recovered fully and were discharged from the hospital after 3 to 4 days with no apparent sequelae.

Clinical Relevance—Penicillin G procaine–penicillin G benzathine and propofol are common drugs in veterinary practice and may both be administered to patients undergoing elective procedures. Because of their similar milky white appearance, veterinarians should label syringes and take care to avoid this medication error. There is no specific antidote for penicillin orprocaine toxicosis. Aggressive and immediate treatment is required in patients that develop an adverse reaction to ensure a successful outcome.

A 15-year-old 3.7-kg (8.1-lb) spayed female domestic shorthair cat was inadvertently administered 0.8 mL (64,864 U/kg [29,484 U/lb]) IV of a common penicillin formulation not intended for IV administration (penicillin G benzathine [150,000 U/mL] and penicillin G procaine [150,000 U/mL] injectable suspensiona) because it was mistakenly identified as propofolb during induction of anesthesia for a routine dental prophylaxis procedure. Prior to this incident, the cat was reportedly well, with stable chronic kidney disease. Immediately following injection, the cat underwent cardiac arrest. An endotracheal tube was placed, and 0.2 mg of epinephrine (1:10,000 solution) was given intratracheally via the endotracheal tube. The cat responded to cardiopulmonary cerebral resuscitation, and spontaneous circulation returned within 1 minute, followed by spontaneous ventilation several minutes later. At the time of cardiopulmonary arrest, dexamethasone sodium phosphate (0.5 mg/kg [0.23 mg/lb], IV), methylprednisolone (27 mg/kg [12.3 mg/lb], IV), and furosemide (4.3 mg/kg [2.0 mg/lb], IV) were also administered. Thoracic radiography was performed by the referring veterinarian at this time, and results were unremarkable.

After the cat's condition was stabilized, the cat was referred to the University of Minnesota Veterinary Medical Center for further supportive care and treatment. On initial examination, the cat had poor pulse quality, bradycardia (140 beats/min), and hypothermia (36.3°C [97.3°F]) as well as intermittent episodes of open-mouth breathing. Profound neurologic abnormalities, including altered mentation, bilateral mydriasis, and bilateral loss of the pupillary light reflex, were noted. Menace and dazzle reflexes were within normal limits bilaterally. Initial diagnostic tests included a CBC, serum biochemical analysis, and venous blood gas analyses. Hematologic abnormalities included neutrophilia (neutrophils, 15.6 × 103/μL; reference range, 1.2 × 103/μL to 13.2 × 103/μL) with band neutrophilia (1.14 × 103/μL; reference range, 0 to 0.16 × 103/μL) and monocytosis (1.14 × 103/μL; reference range, 0 to 0.8 × 103/μL). Serum biochemical analysis revealed mild azotemia, with BUN concentration of 43 mg/dL (reference range, 12 to 39 mg/dL) and creatinine concentration of 2.55 mg/dL (reference range, 0.5 to 2.1 mg/dL). Other abnormalities included hyperglycemia (330 mg/dL; reference range, 74 to 143 mg/dL), hypercholesterolemia (308 mg/dL; reference range, 56 to 226 mg/dL), and hypokalemia (2.5 mmol/L; reference range, 3.9 to 5.3 mmol/L).

Blood pressure measured by use of an indirect Doppler technique at the time of initial examination was 78 mm Hg (reference range, 100 to 120 mm Hg). A bolus of a balanced crystalloid solutionc (14 mL/kg [6.4 mL/lb]), IV) was administered over 30 minutes, followed by a CRI (5.5 mL/kg/h [2.5 mL/lb/h]) of the same solution with additional potassium chloride (0.3 mEq/kg/h [0.14 mEq/lb/h], IV). Despite fluid administration, the cat again developed severe hypotension, and a blood pressure measurement could not be obtained. External heat support was provided,d and an additional IV bolus of the crystalloid solution was administered (14 mL/kg, IV) over 30 minutes. Systolic blood pressure increased to 125 mm Hg and remained stable. After 5 hours of supportive care and treatment, the cat was sternal and more responsive but remained hypothermic (36.3°C [97.3°F]). Follow-up serum electrolyte analysis indicated that potassium concentration had increased to 3.2 mmol/L.

Additional treatment included ampicillin (22 mg/kg [10 mg/lb], IV, q 8 h), famotidine (0.5 mg/kg, SC, q 24 h), and application of a topical lubricating ophthalmic ointment to both eyes (q 8 h). Mannitol (1 g/kg [0.45 g/lb], IV) was given over 30 minutes to help decrease intracranial pressure secondary to presumptive cerebral ischemia and edema; this was initiated when the cat was no longer hypotensive.

The cat remained in the intensive care unit over the course of the next 60 hours and continued to show signs of neurologic improvement. Within 48 hours, the cat was responsive, ambulatory, interactive with the environment, eating on its own, and had appeared to have recovered visual function. Values for blood pressure, temperature, and heart rate were all within reference limits. A follow-up CBC revealed mild anemia (PCV, 21%; reference range, 26.1% to 46.7%) and a normal leukogram. In addition, serum glucose (101 mg/dL) and potassium (3.7 mmol/L) concentrations had returned to reference limits.

The patient continued to improve and was discharged from the hospital to the owners 3 days after the cardiopulmonary arrest. A recheck examination was performed 8 days after the cardiopulmonary arrest, at which time the patient was noted to be almost fully recovered. Whereas the menace response was still noted to be absent bilaterally and pupils were slightly mydriatic bilaterally, the patient still had a positive dazzle response and was able to maneuver easily around the examination room.

A 5-year-old 20.4-kg (44.8-lb) sexually intact male English Springer Spaniel accidentally received 4.5 mL (66,176 U/kg [30,080 U/lb]) of a penicillin G formulationa IV instead of propofolb during a routine dental prophylaxis procedure. Five minutes after penicillin G administration, the dog began to tremble, and 1 hour later, the dog had a grand mal seizure. Shortly thereafter, it began to vocalize extensively and became pruritic. Treatment prior to referral included diazepam (0.5 mg/kg, IV) for seizures, acepromazine maleate (0.05 mg/kg [0.023 mg/lb], IV) for vocalization and agitation, methocarbamol for muscle twitching and trembling (44 mg/kg [20 mg/lb], IV), and cyproheptadine hydrochloride (1.1 mg/kg [0.5 mg/lb], per rectum) for pruritus.

On initial examination at the Veterinary Medical Center, the dog was noted to have profound neurologic abnormalities. The dog was laterally recumbent, dysphoric, vocalizing, and appeared to be blind. No menace reflex was present, although pupillary light reflexes and palpebral reflexes were within normal limits. Physical examinations findings were otherwise unremarkable, except for mild increases in bronchovesicular sounds evident bilaterally during auscultation of the thorax. Initial laboratory testing included a CBC, which revealed leukocytosis (27.2 × 103/μL; reference range, 4.1 × 103/μL to 13.3 × 103/μL) with neutrophilia (25.3 × 103/μL; reference range, 2.1 × 103/μL to 11.2 × 103/μL). Results of a serum biochemical analysis were within reference limits.

The dog was admitted to the intensive care unit, where treatment included administration of 0.9% sodium chloride (4 mL/kg/h [1.8 mL/lb/h], IV CRI), potassium chloride (0.08 mEq/kg/h [0.04 mEq/lb/h], IV), diazepam (0.5 mg/kg/h, IV CRI) for seizure control, supplemental oxygen via an oxygen cage (inspired oxygen fraction, 40%) and continuous ECG monitoring. Three hours after admission, the dog had a grand mal seizure that responded to treatment with diazepam (0.5 mg/kg, IV) followed by a single bolus injection of phenobarbital (5 mg/kg [2.3 mg/lb], IV). The next morning, mannitol (0.5 g/kg, IV) was given slowly over 30 minutes because of persistent delayed pupillary light reflexes bilaterally and deteriorating mental status. Because of the presence of agitation and profound vocalization, the CRI of diazepam was discontinued and replaced with a CRI of butorphanol tartrate (0.1 mg/kg/h [0.045 mg/lb/h], IV). After 48 hours of intensive care, neurologic improvements were noted. The dog had an improved gait and was able to walk unassisted. The dog also had increased responses to external stimuli and apparent improvement of visual function. However, signs of agitation and vocalization persisted, requiring mild sedation with butorphanol (0.2 mg/kg [0.09 mg/lb], IV) intermittently for the duration of hospitalization. Blood pressure was monitored by use of an oscillometric technique throughout hospitalization and remained within reference limits. The dog was discharged 4 days after admission; the owners were instructed to administer tramadol hydrochloride (2.4 mg/kg [1.1 mg/lb], PO, q 12 h) as needed for signs of agitation. During a follow-up examination 6 days after initial examination, the dog appeared to be doing well and its vision had apparently returned to normal. No other adverse effects were identified at this time.

An 11-year-old 8.1-kg (18-lb) spayed female Dachshund undergoing induction of general anesthesia for routine dental prophylaxis was inadvertently administered 0.6 mL (22,222 U/kg [10,101 U/lb]) of a penicillin G formulationa IV instead of propofol.b The dog had no clinical signs at the time the veterinarian contacted the Pet Poison Helplinee for assistance. The veterinarian was instructed to insert an IV catheter, obtain an ECG, and monitor the dog closely for signs of adverse neurologic and cardiovascular effects. No signs of toxicosis were noted, and the dog recovered without complications.

Discussion

Penicillin is widely used in veterinary medicine in a variety of salts and dosage forms. It is an inexpensive bactericidal agent with a wide margin of safety when given appropriately. However, a suspension of penicillin G procaine or a combination of penicillin G procaine and penicillin G benzathine, when drawn into a syringe, bears a very strong resemblance to propofol, an injectable hypnotic agent that provides rapid, shortterm anesthesia. In veterinary medicine, both these formulations of penicillin as well as propofol are widely used and may be used during the same procedure. Therefore, the potential for error is great.

All 3 animals described in the present report received an IV dose of an aqueous suspension containing a combination of penicillin G procaine (150,000 U/mL) and penicillin G benzathine (150,000 U/mL), and 2 of the 3 developed severe adverse reactions. The most important clinical signs in the 2 patients that developed adverse effects involved the CNS. These included seizures, muscle tremors, vocalization, agitation, and partial or complete loss of vision or oculomotor dysfunction. Various other clinical signs, including hypothermia and pruritus, also occurred, and immediate cardiac arrest that responded to cardiopulmonary cerebral resuscitation developed in the cat.

Penicillin G procaine, also known as benzylpenicillin procaine, is the procaine monohydrate salt of penicillin G. Procaine is added to prolong the pharmacological effects of benzylpenicillin,1 and most benzylpenicillin procaine suspensions contain 37.5% to 40.5% (wt/wt) procaine, although the exact amount of procaine in the formulation administered to the patients in the present report is not known. Penicillin G benzathine is the benzathine tetrahydrate salt of penicillin G and contains no procaine.1,2 Additionally, various amounts of preservatives and buffers, including carboxymethylcellulose and povidone, are found in products packaged in multiple-use vials.

We speculate that the clinical signs associated with drug toxicosis in the patients described in the present report were associated with the procaine moiety, although multiple mechanisms may have been responsible. Hypersensitivity reactions to penicillin, embolism, and reactions to other inactive ingredients in the product may also have played a role.

Rapid IV administration of procaine has been associated with toxic effects in a number of species.3–5 In cats, the LD50 of procaine is 45 mg/kg (20.5 mg/lb),3 and cats given IV doses in excess of 2 mg/kg/min (0.9 mg/lb/min) develop respiratory failure.4 The LD50 of procaine in dogs is not known, but IV administration of procaine at 20 mg/kg (9.1 mg/lb) results in neck and muscle tremors, muscle weakness, and incoordination, and IV administration at doses of 36 to 80 mg/kg (16.4 to 36.4 mg/lb) causes excitation, increased extensor muscle tone, running movements, seizures, and respiratory failure.3 In the present report, only 2 of the 3 patients developed evidence of toxicosis. Of these, the second dog reported had no appreciable clinical signs. This may have been because of the lower dose of procaine penicillin administered.

Importantly, when the concentration of soluble procaine in several commercially available veterinary preparations was studied,6 the mean procaine concentration varied considerably between preparations. Heating the product markedly increased the procaine concentration, whereas cooling it to room temperature returned the procaine concentration to baseline values. This variability in soluble procaine concentrations may have played a role in the development of clinical signs in the animals described in the present report.

Systemic adverse reactions to procaine may manifest as an allergic anaphylactic response,7 and immediate systemic hypersensitivity to procaine likely played some role in the development of clinical signs in the dog, whereas acute anaphylactic shock may have played a role in the signs seen in the cat. However, immediate systemic hypersensitivity reactions likely did not account for all of the signs seen in our patients, particularly those involving the CNS.

Hypersensitivity to penicillin may also account for some of the signs seen in the animals described in the present report, in that neurotoxicosis has been reported8 following direct administration of penicillin into the CNS in monkeys and humans. In other studies,9,10 dogs with CSF penicillin concentrations > 300 U/mL after injection into the cisterna magna consistently developed seizures. In a study11 involving healthy cats with no evidence of renal dysfunction, clinical signs were evident when penicillin G was administered IV at doses up to 1.3 million U/kg. These cats consistently developed nonspecific encephalopathy with myoclonus, with higher IV doses resulting in status epilepticus and death.11

The possibility that the cardiac arrest that occurred in the cat in the present report may have developed, in part, as a result of pulmonary embolization following rapid IV administration of the aqueous penicillin suspension is worthy of mention. Acute, massive showering of emboli to the lungs is associated with rapid and severe respiratory distress and may result in cardiopulmonary arrest.12–14 Generally, however, residual respiratory signs are still apparent, despite aggressive supportive care and provision of supplemental oxygen, after successful resuscitation. The cat in the present report had only mild to moderate tachypnea when first examined at the Veterinary Medical Center, and this resolved within 24 hours. However, advanced diagnostic imaging modalities, such as ventilation-perfusion scanning or contrast computed tomography, were not used to further evaluate respiratory function in this cat.

The inactive ingredients in the penicillin formulation that was administered to the patients in the present report may also have played a role in the development of clinical signs. Carboxymethylcellulose, a stabilizer present in low concentrations, has been associated with anaphylaxis in cattle15 and humans,16 and povidone has been reported to cause hypersensitivity reactions in human beings and small animals.17

On the basis of the outcome for the patients in the present report, recovery from an adverse reaction to inappropriate IV administration of penicillin G procaine–penicillin G benzathine appears possible in affected dogs and cats, despite temporary neurologic deficits, seizures, and blindness. Treatment should include aggressive, immediate cardiopulmonary cerebral resuscitation with intubation (if indicated), followed by intensive, supportive 24-hour care. Placement of an IV catheter is advisable immediately upon recognition of this medication error. Administration of IV fluids is indicated to increase tissue perfusion, stabilize blood pressure, and maintain hydration in the presence of severe neurologic deficits. Neurologic complications should be treated as needed with anticonvulsant medications such as diazepam or phenobarbital and muscle relaxants such as methocarbamol. Antihistamines such as cyproheptadine or diphenhydramine hydrochloride may be used for pruritus and urticaria. Additional sedation may be needed if vocalization and agitation are persistent. Basic nursing care for treatment of cerebral ischemia should be initiated. This includes minimizing intracranial pressure (eg, head elevation at a 15° to 30° angle, mannitol administration, and minimal jugular restraint) and correction of hypotension (eg, IV fluid administration, vasopressor administration, or both). Additional supportive care, including supplemental oxygen, eye lubrication, physical therapy to prevent lung atelectasis and peripheral limb edema (eg, turning every 6 hours and passive range of motion exercise), thermal support, and manual bladder expression or placement of a urinary catheter to allow for urinary collection, may be necessary.

Veterinarians should use caution when choosing anesthetic and antimicrobial protocols. Appropriate labeling of syringes should be implemented to distinguish propofol from penicillin G procaine–penicillin G benzathine formulations because both have a similar milky white appearance. There is no specific antidote for procaine or penicillin toxicosis, and adverse reactions can be severe or fatal.

ABBREVIATION

CRI

Constant rate infusion

a.

Durapen, Vedco, St Joseph, Mo.

b.

Rapinovet, Mallinckrodt Veterinary, Mundelein, Ill.

c.

Plasmalyte-148, Baxter Healthcare Corp, Deerfield, Ill.

d.

Bair Hugger Temperature Management Unit, Model 505, Arizant Healthcare Inc, Eden Prairie, Minn.

e.

Pet Poison Hotline, Bloomington, Minn.

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