a 14-year - old , domestic shorthair cat was treated for transient diabetes mellitus for 3 months with glargine insulin , which was discontinued when the diabetes mellitus resolved .
approximately 36 months later the diabetes mellitus recurred and glargine insulin was restarted . within 23 mins of the first injection the cat collapsed , developed profuse vomiting and diarrhea , as well as facial swelling and diffuse erythema .
a hypersensitivity reaction was suspected and the cat was treated with antihistamines , aggressive fluid therapy and gastrointestinal support .
six months later the cat re - presented for relapse of its diabetes mellitus and an intradermal skin challenge with 1:20 diluted insulin was performed confirming a hypersensitivity to glargine .
the cat continues to be well regulated on porcine zinc insulin without any hypersensitivity reactions noted .
this is the first reported case of a hypersensitivity reaction secondary to glargine insulin in a cat .
clinicians should be aware of this potential complication , particularly in animals with a previous history of insulin administration and the potential to utilize intradermal testing with insulin .
hypersensitivity reactions ( hrs ) most commonly occur after an allergen binds to ige on the surface of mast cells and basophils precipitating release of vasoactive substances such as histamine , chymase , tryptase and other chemokines .
it is usually associated with prior exposure to the antigen causing sensitization of the immune system .
clinical manifestations can range from facial pruritis and urticaria , to cardiovascular collapse and death .
previous reports of suspected hrs to pharmaceuticals in veterinary medicine include dexamethasone , ophthalmic medication and human albumin among others .
the purpose of this case report is to describe the clinical manifestation and management of a cat with an hr to subcutaneous glargine insulin ( gi ) administration .
a 14-year - old , female , spayed , domestic shorthair cat weighing 5.68 kg presented on referral to our hospital for evaluation of acute collapse .
the cat had a history of diabetes mellitus ( dm ) , which was first treated with gi in 2013 .
the cat was treated for diabetes , which became transient after 3 months of treatment .
one week prior to presentation at our institution , the dm had recurred and re - initiation of gi was recommended .
the bottle had not been opened prior to use and it was stored in a refrigerator .
the evening of presentation the cat had ingested all of its meal ( which had not been changed in over a year ) , according to the owner , and received 1 unit of gi subcutaneously for the first time since 2013 . approximately 23 mins after administration , the cat collapsed and started panting .
the cat also demonstrated projectile vomiting and diarrhea . on presentation to the primary veterinarian , the cat was noted to be laterally recumbent and was exhibiting horizontal nystagmus . a blood glucose ( bg )
was not obtained , but the cat was given dextrose submucosally as there were concerns about a hypoglycemic crisis .
the cat was then referred to our facility . on presentation to our institution , the cat was noted to be obtunded , was tachycardic ( heart rate of 220 beats per minute ) and tachypneic ( respiration of 50 breaths per minute ) .
the respiratory effort was increased and infrequent stridor noted . the face and muzzle were swollen and edematous .
the cat again produced a large amount of vomiting and diarrhea ; at this time hematochezia was also noted . though mentation was dull , the nystagmus had resolved and no cranial nerve deficits were noted .
bg was measured on presentation with a handheld glucometer ( alphatrak ; abbott animal health ) and was noted to be 517 mg / dl ( reference interval [ ri ] 75116 mg / dl ) ; this was approximately 2 h after the gi had been administered .
the cat had no measurable systolic blood pressure on doppler measurement ( parks doppler machine ) and a 10 ml / kg bolus of crystalloids was administered .
owing to the concerns about an hr to the insulin , diphenhydramine ( 2 mg / kg ) was administered intramuscularly . within an hour , the muzzle swelling and erythema had improved after antihistamine administration .
the cat continued to experience recurrent systemic hypotension in the subsequent hours and after receiving a 3 ml / kg synthetic colloid bolus , was started on a continuous crystalloid ( 75 ml / kg / day ) and colloid infusion ( 8 ml / kg / day ) and the systemic hypotension resolved . blood work performed on admission revealed hyperglycemia ( 666 mg / dl ; ri 75116 mg / dl ) , hypokalemia ( 3.36 meq / l ; ri 3.624.60
treatment for her gastrointestinal signs consisted of maropitant ( 1 mg / kg sc q24h ) , dolestron ( 0.6 mg / kg iv q24h ) and ampicillin ( 20 mg / kg iv q8h).the cat continued to experience a large volume of diarrhea and hematochezia over the first 24 h after admission , but the vomiting resolved .
an abdominal ultrasound was performed 1 day after presentation and revealed an enlarged and hyperechoic liver with few small hypoechoic nodules throughout the parenchyma , assessed as consistent with a diabetic hepatopathy .
both kidneys had a mild decrease in corticomedullary definition , and the left and right adrenal glands were noted to have normal shape and size .
blood work was also repeated at this time and showed normalization of the lactate and potassium levels . during hospitalization ,
the bg continued to be monitored and ranged from 107355 mg / dl ; the cat s appetite remained poor .
no insulin was administered while hospitalized , owing to the poor appetite , persistent diarrhea and the concerns about an hr to gi .
the cat was discharged 3 days after presentation on metronidazole ( 10 mg / kg po q12h ) and famotidine ( 1 mg / kg po q24h ) .
the owners continued to monitor the cat s bg at home with a handheld glucometer and it ranged between 88 and 380 mg / dl .
the owners tended to measure the bg if they felt the cat appeared lethargic ; they did not have a set protocol of when and how frequently to measure its bg . at this time
the cat was still not consuming its full caloric needs and we recommended that the owners continue to monitor the cat s bg at home to determine when it would require insulin again .
the owners infrequently measured the cat s bg 12 times weekly and it was never greater than 200 mg / dl .
six months later , the cat re - presented for recurrence of polyuria / polydipsia and being lethargic at home .
the owners were continuing to measure the cat s bg at this time and were intermittently obtaining values greater than 250 mg / dl .
the cat was sedated with ketamine ( 0.5 mg / kg iv ) and valium ( 0.3 mg / kg iv ) , and the fur over the lateral left thorax was clipped .
one unit of gi and porcine zinc insulin ( pzi ) were each diluted into 20 units/0.2 ml of 0.9% nacl and from each of these mixtures , 0.05 ml/5 units was injected intradermally . as a negative control ,
within 30 mins of the procedure , a palpable swelling was noted over the gi site .
the cat also developed erythema and swelling of its muzzle ( figure 1 ) and vomited ; diphenhydramine ( 2 mg / kg i m ) was administered and the clinical signs resolved .
two hours after the procedure , the cat s bg was 410 mg / dl ( ri 90180 mg / dl ) and it was elected to administer 0.5 units pzi subcutaneously , owing to the hyperglycemia .
the cat was kept overnight for monitoring and was noted to be painful and intermittently pruritic over the injection site .
the cat was discharged the following day and continues to be on subcutaneous pzi every 12 h and has not exhibited any recurrent signs of systemic or cutaneous hr .
evidence of cutaneous anaphylaxis after the administration of glargine insulin ; note the generalized erythema and swelling over the muzzle and periocular regions
type i hrs , as previously noted , can vary in severity from urticaria to anaphylaxis .
this can occur as a biphasic reaction , with immediate itching and burning at the injection site , followed by a more sustained generalized reaction 48 h later with a combination of cutaneous , gastrointestinal and/or respiratory symptoms reported .
this presents as small , localized tenderness and painful non - erythematous nodules and central hematomas at injection sites , occurring around 68 h after insulin injection and lasting for 48 h. clinical examples of type iii hrs include serum sickness , adenopathy and insulin resistance .
the cutaneous nodules associated with a type iv hr can be distinguished from a type iii hr as the former usually occurs 24 h or more after the insulin injection and last for 47 days . in humans , type iv hrs
it appears , given the acute presentation and history of prior exposure to insulin , the cat in this case demonstrated a type i hr , but this was not conclusively proven .
severe anaphylactic reactions in cats can cause a multitude of signs , but dyspnea is most common as the lungs are believed to be the shock organ of cats . in the case
previous case reports of anaphylactic reactions in cats have also shown that some will also exhibit simultaneous gastrointestinal and respiratory signs .
while a gastrointestinal infection or toxin can not be fully ruled out , the cat s diet was strictly controlled by its owners , owing to its dm , and an infection also seemed less likely as it was kept indoors only and there were no other pets in the house . also , the association of the signs with the administration of the gi is also indicative of an hr .
confirmation of a cutaneous hr to insulin administration is performed by intradermal testing using a 1:20 dilution of insulin preparation .
appearance of a cutaneous lesion within 60 mins of injection indicates a type i hr , as exhibited by the cat in this case , whereas a type iii or iv hr would be suggested by a response seen between 2 and 24 h. human protocols were used as intradermal testing with insulin had never been performed in a cat prior to this .
there was subjectively more swelling and discomfort noted at the gi injection site ; the gi site also appeared more erythematous .
the increased swelling and erythema over the gi site also provides more evidence that the cat was more sensitive to the gi than the pzi .
the cat in this case exhibited more severe cutaneous and gastrointestinal signs than the typical human patients who undergo intradermal testing .
should this protocol be utilized in the future in small animal patients , the insulin may need to be further diluted to reduce the severity of adverse effects .
other diagnostic modalities for hrs reported in dogs include identification of an elevated alanine transaminase and increased gallbladder wall thickness and a striated wall pattern on abdominal ultrasound .
it is unknown if such abnormalities are identified in cases of feline insulin hr ; the abdominal ultrasound performed in the cat reported here failed to identify any gall bladder abnormalities .
management of insulin hr involves exclusion of poor injection technique , use of alternative forms of insulin , splitting the dose and injection into separate sites , and addition of antihistamines .
if these methods fail , a local injection of dexamethasone in combination with insulin is sometimes used .
steroid therapy was not pursued in this cat as we were concerned it would further complicate the management of the dm . similarly , we also did not attempt to divide the dose or inject it in separate sites as the cat had exhibited such severe clincial signs of hypersensitivity initially .
poor injection technique or improper storage of insulin was not considered likely as the owners had successfully managed the cat s dm for 3 years .
desensitization , using gradually increasing dilutions of insulin intradermally in a controlled setting , can be successful in type i hr , but can require long periods of time to be beneficial .
desensitization in people appears to be less successful in patients with the biphasic type i hr .
use of newer insulins such as aspart or gi has also been recommended , but hrs to these insulins have also been recently recognized in human medicine . in the cat
corticosteroids and epinephrine have been recommended for hrs in veterinary patients but were considered potentially contraindicated given the pre - existing dm , severe hyperglycemia and potential to cause ketosis .
the cat appears to be well managed on pzi without any reported signs of an hr .
insulin hrs were much more common in human patients prior to the use of human insulin analogues when bovine and porcine insulin were more commonly administered .
it is believed that humans that have an hr to insulin are reacting to the type of protein in the insulin given that there are molecular differences between insulin from different species .
we elected to use pzi , a protamine - containing recombinant human insulin , in this cat rather than gi , a recombinant human insulin analogue , as this contains a different form of protein .
both gi and pzi also contain different adjuvants , with pzi mostly containing zinc and gi mainly containing metacresol .
as such , it is unclear if the hr developed secondary to the adjuvants rather than the different insulin protein molecules . in human medicine
it is much more common to react to the insulin molecule rather than the adjuvants .
furthermore , while we can not completely rule out improper storage or poor administration , the bottle of gi was newly purchased , stored in a refrigerator and had never been used prior to the suspect hr event .
the owners had also successfully managed the cat s dm for 3 years and were well versed in subcutaneous administration of insulin , so poor technique does not seem likely .
we can not rule out that cats do not naturally develop pruritis and erythema from intradermal gi injections and further studies should evaluate intradermal gi injections in healthy cats .
clinicians should be aware of the possibility of hrs to insulin administration in cats , particularly in cats with a previous history of insulin administration .
the incidence of hrs to insulin and use of intradermal insulin testing for confirmation in veterinary medicine requires further evaluation .
 case summarya 14-year - old , domestic shorthair cat was treated for transient diabetes mellitus for 3 months with glargine insulin , which was discontinued when the diabetes mellitus resolved . 
 approximately 36 months later the diabetes mellitus recurred and glargine insulin was restarted . within 23 mins of the first injection the cat collapsed , developed profuse vomiting and diarrhea , as well as facial swelling and diffuse erythema . 
 a hypersensitivity reaction was suspected and the cat was treated with antihistamines , aggressive fluid therapy and gastrointestinal support . 
 the cat made a full recovery and was discharged 3 days later . 
 six months later the cat re - presented for relapse of its diabetes mellitus and an intradermal skin challenge with 1:20 diluted insulin was performed confirming a hypersensitivity to glargine . 
 the cat continues to be well regulated on porcine zinc insulin without any hypersensitivity reactions noted.relevance and novel informationhypersensitivity reactions to insulin administration are rarely described in human medicine . 
 this is the first reported case of a hypersensitivity reaction secondary to glargine insulin in a cat . 
 clinicians should be aware of this potential complication , particularly in animals with a previous history of insulin administration and the potential to utilize intradermal testing with insulin . 
Case summary
Relevance and novel information
Introduction
Case description
Discussion
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