SEARCH

SEARCH BY CITATION

Keywords:

  • cats;
  • diabetes;
  • insulin;
  • treatment

Abstract

  1. Top of page
  2. Abstract
  3. Background
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Objective

To describe treatment response and outcome in 15 cats with diabetic ketoacidosis (DKA) initially stabilized with glargine administered intramuscularly (IM) with or without subcutaneous (SC) glargine.

Materials and Methods

Fifteen cats diagnosed with DKA were initially administered IM glargine (1–2 U) and in most cats (12/15 cats) this was combined with SC glargine (1–3 U). This was followed by intermittent IM glargine as required at intervals of 2 or more hours (range 2–22 h) and SC glargine (1–2 U) every 12 hours.

Key Findings

All 15 cats survived and were discharged from hospital (median 4 d; range 2–5 d) and one-third (5/15) of cats subsequently achieved remission (median time 20 d; range 15–29 d). Complications included hypokalemia and hypophosphatemia, which were likely the result of DKA therapy rather than glargine treatment specifically.

Significance

This study demonstrates that glargine administered IM is an effective treatment for DKA in cats, and may provide an alternative to regular insulin. The same vial used for initial treatment of DKA can then be used for subsequent management with SC glargine injections. Future prospective randomized controlled trials evaluating clinical outcomes in cats with DKA using different types and routes of administration of insulin are warranted. A prospective randomized controlled trial is required to compare outcomes for IM and IV administration of glargine and regular insulin in DKA cats with or without SC glargine.


Abbreviations
BG

blood glucose

CRI

continuous rate infusion

DKA

diabetic ketoacidosis

IM

intramuscularly/intramuscular

SC

subcutaneous

Background

  1. Top of page
  2. Abstract
  3. Background
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Therapies recommended for treatment of diabetic ketoacidosis (DKA) in cats and the reported survival rates have not changed substantially in 20 years.[1-4] There are no prospective pharmacological studies investigating the effects of regular insulin in healthy or DKA cats and the accepted methods of administering regular insulin to DKA cats by either IV constant rate infusion (CRI) or intermittent intramuscular (IM) injections have been extrapolated from studies in dogs.[4-6] One recent retrospective study of 29 cats compared clinical improvement and biochemical parameters in 3 groups of cats with DKA prescribed varied dosing regimes of regular insulin as a CRI.[4] A key finding from this study was that the actual administered doses of insulin were much lower than the prescribed doses, prompting a reassessment of the published recommended doses of insulin for treatment of DKA in cats.

It is currently accepted that IM administration or CRI of a short-acting insulin such as regular insulin is best suited for the initial treatment of feline DKA.[1] When administered IV in human patients, glargine, and regular insulin are almost identical in their effect on blood glucose (BG) concentration, and duration of action for both insulins is approximately 2 hours.[7] If glargine and regular insulin administered IV or IM have similar glycemic effect in cats as they do in human patients, glargine could provide an alternative to regular insulin in the treatment of DKA in cats. While glargine is not licensed for use in cats with DKA, it is important to note that there is no veterinary insulin licensed for DKA therapy and currently there is no short-acting insulin licensed for use in cats.

The aim of this preliminary study is to describe the treatment and outcome of administering glargine IM with or without subcutaneous (SC) glargine during initial stabilization of DKA in cats. The study involved a retrospective case series of primary accession and referred cases presented to an exclusively feline veterinary clinic.1 Included cases had a diagnosis of DKA and were initially stabilized with IM glargine.2 Cases diagnosed with DKA and treated with IM glargine, with or without concurrent SC glargine between November 2005 and November 2008, were eligible for the study. Informed consent was obtained prior to enrollment into the study.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Background
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Cats were diagnosed with DKA when the BG concentration was >16 mmol/L (288 mg/dL), and signs of systemic illness (eg, depression, anorexia, dehydration), significant glycosuria (urine glucose concentration 3+ or 4+), ketosis (ketonuria or ketonemia; betahydroxybutyrate > 0.6 mmol/L [>10.8 mg/dL]), and acidosis were evident (serum bicarbonate < 12 mmol/L (<216 mg/dL)) (Table 1). Urine glucose and ketone concentrations were assessed using urine dipsticks3 and graded on a scale of 0–4+.

Table 1. Signalment and baseline data of 15 cats diagnosed with diabetic ketoacidosis and treated with intramuscular glargine with or without subcutaneous glargine
 Median and range
  1. ref, reference interval for healthy cats.

  2. *Long-acting depot methylprednisone[5] administered in the 3 months preceding diagnosis (n = 2) and topical ear preparation containing betamethasone[6] (n = 1) for 10 days prior to diagnosis.

Age (years)10.6
 (6.9–14.3)
Body weight (kg)4.9
 (2.8–7.2)
Male:female8:7
Body condition score (on scale of 1–9)4
[n = 12](3–7)
Blood glucose concentration (mmol/L)26
[ref = 3.2–7.5 mmol/L](16–34)
Serum bicarbonate (mmol/L)8.8
[ref = 12–24 mmol/L](2.1–11.8)
Beta-hydroxybutyrate (mmol/L)4.4
[ref ≤0.6 mmol/L](0.6–7.9)
Previous glucocorticoid administration*3
Breed5 Burmese, 1 Oriental, 1 Russian Shorthair, 1 Mainecoon, 7 Domestic Shorthair

The primary focus of treatment in the study was to resolve DKA. Treatment followed accepted recommended guidelines for restoring intravascular volume, correcting intracellular and extracellular fluid losses, correcting electrolyte and acid-base disturbances, and the administration of insulin therapy to decrease BG concentration.[1]

The protocol for insulin therapy using glargine was adapted from published protocols using regular insulin IM for managing DKA in cats[8, 9] and DKA in dogs [5, 6, 10] but substituting glargine for regular insulin.

Initial IM doses of glargine were, to a large extent, calculated on a per cat basis rather than per kilogram, with 14 of 15 cats receiving 1 U IM and the remaining cat received 2 U IM (Table 2). The degree of hyperglycemia did not influence the initial IM dose. The initial SC doses, when used, also tended to be calculated on a per cat basis rather than per kilogram and ranged from 1 to 3 U (Table 2). The effect of glargine on BG concentration was assessed every 2–4 hours and subsequent glargine dose adjusted, aiming to lower BG concentration by 2–3 mmol/L/h (36–54 mg/dL/h) until reaching a concentration of 10–14 mmol/L (180–252 mg/dL). A prescribed protocol was not strictly adhered to with repeated 0.5–1 U IM injections given as required (between 2 and 22 h) and SC injections administered every 12 hours or longer to maintain BG concentration between 10 and 14 mmol/L (180–252 mg/dL) (Table 2). The timing of insulin dosing and the dose administered varied considerably as it was also influenced by the time of day (eg, evening dose might be conservative, particularly if limited or no overnight monitoring) and the frequency of monitoring (eg, injection only given after BG sampled, and as such may have been delayed if BG sampling was delayed). Intravenous glucose was administered if BG concentration fell below 10 mmol/L (180 mg/dL) (standard protocol 1 g/kg of 50% glucose IV over 5 min followed by continuous infusion of 2.5% glucose solution). Where owner finances restricted overnight patient monitoring, the evening insulin dose was conservative or withheld and IV fluids were changed to a 2.5% glucose containing solution4 overnight to reduce the chance of life-threatening hypoglycemia occurring while there was limited or no monitoring.

Table 2. Blood glucose concentration, bodyweight, insulin dose, administration method, and timing of the first three insulin doses in 15 ketoacidotic diabetic cats treated with intramuscular glargine with or without subcutaneous glargine
  Initial blood glucoseBlood glucose concentrationBlood glucose concentration
  concentration (mmol/L)(mmol/L) and second(mmol/L) and third insulin
CatWeight (kg)and first insulin doseinsulin dosedose
  1. *Time interval from initial insulin administration to first subsequent insulin administration.

  2. †Time interval from first subsequent insulin dose to the second subsequent insulin dose.

  3. ‡Cats were receiving concurrent intravenous glucose administration at time of blood glucose sampling necessitated by a low or falling blood glucose concentration from the previous insulin dose or overnight when owner finances restricted patient monitoring.

  4. §Blood glucose not sampled.

14.2BG = 34, 1 U IM + 2 U SCBG = 22, 2 U SC at 18 hours*BG = 16, 2 U SC at 12 hours
25.3BG = 34, 1 U IM + 3 U SCBG = 19, 3 U SC at 20 hoursBG = 12, 1.5 U SC at 12 hours
32.8BG = 20, 1 U IMBG = 22, 1 U IM at 2 hoursBG = 16, 1 U IM + 1 U SC at 12 hours
44.1BG = 23, 1 U IM + 2 U SCBG = 16, 1.5 U SC at 14 hoursBG§, 2 U at 12 hours
53.7BG = 34, 2 U IM + 1 U SCBG = 23, 1 U SC at 10 hoursBG = 18, 1 U IM + 3 U SC at 12 hours
67.1BG = 26, 1 U IM + 2 U SCBG = 20, 2 U SC at 16 hoursBG = 19, 2 U SC at 12 hours
75.1BG = 21, 1 U IM + 2 U SCBG = 13, 0.5 U IM + 1 U SC at 18 hoursBG = 12, 2 U SC at 12 hours
83.3BG = 34, 1 U IM + 2 U SCBG = 17, 2 U SC at 14 hoursBG = 14, 2 U SC at 12 hours
95.6BG = 24, 1 U IM + 3 U SCBG = 14, 1 U IM + 2 U SC at 8 hoursBG = 16, 1 U IM + 2 U SC at 12 hours
105.9BG = 22, 1 U IM + 2 U SCBG = 22, 1 U IM + 2 U SC at 22 hoursBG = 6, 1 U SC at 12 hours
116.4BG = 25, 1 U IM + 1 U SCBG = 21, 1 U IM at 2 hoursBG = 18, 1 U IM at 4 hours
124.5BG = 16, 1 U IM + 1 U SCBG = 13, 2 U SC at 14 hoursBG = 15, 2 U SC at 12 hours
135.1BG = 28, 1 U IMBG = 16, 1 U IM at 4 hoursBG = 14, 1 U IM at 6 hours
145.2BG = 34, 1 U IMBG = 25, 1 U IM + 2 U SC at 6 hoursBG = 21, 1 U IM + 2 U SC at 12 hours
154.9BG = 28, 1 U IM AND 2 U SCBG = 16, 1 U IM at 8 hoursBG = 11, 2 U SC at 12 hours

Cats were managed with SC glargine alone once appetite returned and dehydration had resolved. Cats were discharged from hospital after determining an appropriate SC dose of glargine using serial BG measurements every 3–4 hours. After discharge from hospital, cats were managed and monitored as described by Marshall et al[11] with SC glargine and a low-carbohydrate diet. Remission date was defined as the first date at which normoglycemia (BG 4–7 mmol/L (72–126 mg/dL) was observed and no exogenous insulin had been administered for more than 24 hours.

The outcome of using glargine IM in the initial stabilization of DKA cats was considered successful if ketosis resolved, appetite returned, and the cat was discharged from hospital on SC glargine and survived >2 weeks without requiring re-admission to hospital for management of DKA or related complications.

Results

  1. Top of page
  2. Abstract
  3. Background
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

At time of diagnosis, all 15 cats (Table 1) were depressed and dehydrated based on physical examination findings, 33% (5/15) were moribund or recumbent and 73% (11/15) of cat's owners reported anorexia.

Diabetes mellitus was first diagnosed at the time of presentation with DKA in 73% (11/15) of cats. A history of recent glucocorticoid administration in the previous 3 months was present in 20% (3/15) of cats consisting of long-acting depot injection5 (n = 2) or application of a topical ear preparation6 (n = 1) for 10 days duration. Of the 4 cats previously diagnosed with diabetes, one cat was receiving 2 U lente insulin7 once daily, one cat was receiving 1.5 U glargine twice daily, one cat was suspected of not receiving insulin for 11 days while the owner was away and one cat had had no insulin therapy for 12 days following diagnosis (owner initially declined treatment).

All 15 cats were initially treated with intermittent IM glargine and most of the cats (12/15) also administered SC glargine (Table 2). Median combined (IM and SC) insulin dose administered to all 15 cats during the first 12 hours of therapy (0–12 h) was 3 U/cat (range 2–7 U/cat) or 1.4 U/kg/d. The median combined insulin dose for the following 12-hour period (12–24 h) was 2 U/cat (range 0–4 U/cat) or 0.96 U/kg/d and for the following 12 hours (24–36 h) was 2 U/cat (range 1.5–4 U/cat) or 1.4 U/kg/d. The median time until second insulin was 4 hours (range 2–6 h) in cats (3/12) treated with IM glargine alone and 14 hours (range 2–22 h) in cats (12/15) treated with IM and SC glargine. The median time for all 15 cats to be managed with SC glargine as their sole insulin therapy was 24 hours (range 18–72 h) and of the 12 cats treated with intermittent IM and SC glargine from the outset, half (6/12) were managed with SC glargine alone within 18 hours of initiating treatment. No cat developed clinical hypoglycemia from insulin therapy during the stabilization period, and a minority of cats (2/15; 13%) had biochemical hypoglycemia (BG concentration <3 mmol/L [<54 mg/dL] measured using a portable glucometer.8 Hypoglycemia was managed with IV glucose supplementation, or reducing insulin dose or increasing the time interval between injections. All cats (15/15) were hypokalemic at some point during stabilization and 93% (14/15) of cats were supplemented with IV potassium. Most cats (80%; 12/15) also developed hypophosphatemia and 42% (5/12) of these cats received IV phosphorous supplementation. Two of the hypophosphatemic cats had hemolysis detected in blood sampled at approximately 24 and 36 hours after initiating therapy and both received typed blood transfusions.

All 15 cats survived and were discharged from hospital after a median 4 days (range 2–5 d) of therapy. Thirteen of the 15 (87%) cats surviving to discharge were still alive at the end of the data collection period; median follow-up time was 1.9 years (range 0.6–3 y). The other 2 cats were euthanized after 2 months and 8 months due to financial constraints and feline immunodeficiency virus related immunosuppression, respectively.

One-third (5/15) of cats surviving to discharge subsequently achieved remission; median time to remission was 20 days (range 15–29 d). None of the 5 cats achieving remission had relapse of their diabetes during the study period, with a median duration of remission of 16 months (range 6–29 mo). Four of the 5 cats achieving remission were Burmese and 2 of these were receiving glucocorticoids at the time of diagnosis. Glucocorticoid administration was discontinued in all 3 cats receiving glucocorticoids at time of diagnosis and 2 of the 3 cats (67%) achieved remission.

Discussion

  1. Top of page
  2. Abstract
  3. Background
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

The important finding from this study was that treatment with IM glargine combined with or without SC glargine was effective in the management of feline DKA. Studies in human patients with DKA have similarly demonstrated the efficacy of using subcutaneously administered glargine in a protocol for treatment of DKA.[12, 13] In children with DKA treated with a CRI of regular insulin, the addition of SC insulin glargine led to faster resolution of acidosis and reduced length of hospitalization.[12] In cats with DKA, a similar protocol to ours using SC glargine combined with regular insulin IM also resulted in faster resolution of metabolic acidosis compared with a CRI of regular insulin.9

The severe dehydration that most DKA cats have at presentation is believed to impair insulin absorption from SC tissue sites, hence the recommendation for insulin to be administered IM or IV.[1, 14] However, there are no pharmacodynamic or pharmacokinetic studies documenting this hypothesis in cats. Potentially, SC glargine may be effective as the sole insulin for initial treating DKA in some cats, but further studies are required to evaluate this possibility.

The survival rate of 100% (15/15) is similar to that recently reported by Claus et al,[4] where 93% (27/29) of cats treated with regular insulin survived to discharge. These rates are higher than that previously reported for feline DKA (69% or 11/16 cats9 74% or 31/42 cats;[8] 82% or 18/22 cats;[15] 83% or 31/37 cats).[16] The survival rate in our study when compared to the reported rates may have been positively influenced by a number of other factors as well as the effect of glargine administration IM and SC. Other factors might have included lack of severe concurrent illness such as necrotizing pancreatitis observed in cats in our study, advancements in medical management over the years,[1, 8, 9] expertise of the chief primary care clinician in managing feline diabetes,[18] case management by feline-only staff in a feline-only practice, and differences in pet and client populations influencing survival rates, for example, impact of euthanasia because of financial reasons.

Complications of DKA therapy in this study included common electrolyte imbalances and were similar to those previously reported to occur with DKA therapy in cats. These were likely associated with therapy per se rather than the use of glargine specifically.[1, 8, 9]

Of note was that one-third (33%; 5/15) of cats that survived to discharge achieved remission. Remission in these cats occurred within 30 days (median time 20 d), and all 5 cats remained in remission during the study period (median 16 mo). In this study, achieving remission may have been affected by breed, as 4 of 5 cats achieving remission were Burmese; however, in a previous study, diabetic Burmese cats without DKA were no more likely to achieve remission than non-Burmese diabetic cats.[11] Historically, achieving remission has not been a commonly recognized treatment outcome for DKA cats, but a recent study has reported a remission rate of 58% (7/12) of cats with DKA.[17]

While the aim of monitoring and subsequent insulin doses was to lower BG concentration by 2–3 mmol/L/h (36–54 mg/dL/h) until reaching a concentration of 10–14 mmol/L (180–252 mg/dL), the timing of and the dose administered varied considerably as it was also influenced by the time of day (eg, evening dose was conservative, particularly if limited or no overnight monitoring) and the frequency of monitoring. These factors probably affected insulin dosing more in this primary care facility than might have occurred in a facility with dedicated overnight care. Our current recommendation for the majority of DKA cats is that glargine be administered SC (1–2 U/cat/q 12 h) starting immediately and concurrent IM glargine (0.5–1 U/cat) several hours after fluid resuscitation. Repeated doses of IM glargine (0.5–1 U/cat) can be given as often as every 4 hours to achieve the above glycemic effect, with most cats receiving a total of 1–3 doses of IM glargine before being managed with SC glargine alone.

Cats presenting with DKA to primary care veterinarians may be euthanized without treatment because of the influence of a poor prognosis given to their owners. Cats presenting with DKA in our study all survived the initial therapy and were more likely to resolve their DKA and achieve remission than they were to die from DKA. This positive outcome, despite financial constraints, should encourage clinicians to remain optimistic when discussing prognosis of DKA cats with owners and may encourage treatment with this less-intensive and potentially less-expensive IM insulin protocol.

The protocol used in our study was simpler and less costly to implement than a CRI of regular insulin. It is also more cost effective for owners because the same insulin vial used for initial treatment of DKA, can then be used for later management with SC glargine injections.

In conclusion, this preliminary study demonstrates that glargine administered IM combined with or without SC glargine is an effective treatment for feline DKA, and may provide an alternative to regular insulin. Many clinics already use glargine SC to manage uncomplicated diabetic cats, and are therefore likely to have glargine readily available allowing prompt initiation of treatment. Controlled prospective studies are required to compare outcomes of IV and IM administration of glargine and regular insulin in cats with DKA.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Background
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

The authors wish to thank Caitlin McGuckin for assistance with writing and editing this manuscript.

Footnotes
  1. 1

    The Cat Clinic, Brisbane, Australia.

  2. 2

    Lantus, 100 U/mL glargine, Aventis Pharmaceuticals, Germany.

  3. 3

    Bayer Multistix 10 SG reagent urinalysis strips.

  4. 4

    A total of 0.45% NaCl and 2.5% glucose solution, Baxter Healthcare Pty Ltd, NSW, Australia.

  5. 5

    Ilium Depredil, 40 mg/mL methylprednisolone acetate, Troy Laboratories Pty Ltd, NSW, Australia.

  6. 6

    Otomax Schering Plough Animal Health Corporation, Summit, NJ.

  7. 7

    Caninsulin, 40 U/mL purified pork insulin, Intervet, the Netherlands.

  8. 8

    Accu-Chek Integra, Roche Diagnostics Australia Pty Ltd, NSW, Australia.

  9. 9

    Buob S, Mahony O, Rozanski E, et al. eds. An intermittent insulin protocol improves metabolic acidosis faster than a continuous rate infusion of regular insulin in feline diabetic ketoacidosis. Anaheim: American College of Veterinary Internal Medicine; 2010.

References

  1. Top of page
  2. Abstract
  3. Background
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References
  • 1
    Feldman EC, Nelson RW. Diabetic ketoacidosis. In: Feldman EC, Nelson RW. eds. Canine and Feline Endocrinology and Reproduction, 3rd ed. Philadelphia, PA: Elsevier Science; 2004, pp. 580615.
  • 2
    Feldman EC, Nelson RW. Diabetic ketoacidosis. In: Feldman EC, Nelson RW. eds. Canine and Feline Endocrinology and Reproduction, 1st ed. Philadelphia, PA: WB Saunders; 1987, pp. 274303.
  • 3
    Macintire D. Emergency therapy of diabetic crises: insulin overdose, diabetic ketoacidosis, and hyperosmolar coma. Vet Clin No Am Small Anim Pract 1995; 25(3):639650.
  • 4
    Claus MA, Silverstein DC, Shofer FS, et al. Comparison of regular insulin infusion doses in critically ill diabetic cats: 29 cases (1999–2007). J Vet Emerg Crit Care 2010; 20(5):509517.
  • 5
    Chastain C, Nichols C. Low-dose intramuscular insulin therapy for diabetic ketoacidosis in dogs. J Am Vet Med Assoc 1981; 178(6):561564.
  • 6
    Macintire D. Treatment of diabetic ketoacidosis in dogs by continuous low-dose intravenous infusion of insulin. J Am Vet Med Assoc 1993; 202(8):12661272.
  • 7
    Scholtz H, Pretorius S, Wessels D, et al. Equipotency of insulin glargine and regular human insulin on glucose disposal in healthy subjects following intravenous infusion. Acta Diabetologica 2003; 40(4):156162.
  • 8
    Bruskiewicz KA, Nelson RW, Feldman EC, et al. Diabetic ketosis and ketoacidosis in cats: 42 cases (1980–1995). J Am Vet Med Assoc 1997; 211(2):188192.
  • 9
    Nichols R, Crenshaw K. Complications and concurrent disease associated with diabetic ketoacidosis and other severe forms of diabetes mellitus. Vet Clin No Am Small Anim Pract 1995; 25(3):617624.
  • 10
    Broussard JD, Wallace MS, eds. Insulin Treatment of Diabetes Mellitus in the Dog and Cat. Philadelphia, PA: WB Saunders & Co; 1993.
  • 11
    Marshall RD, Rand JS, Morton JM. Treatment of newly-diagnosed diabetic cats with glargine insulin improves glycemic control and results in higher probability of remission than protamine zinc and lente insulins. J Fel Med Surg 2009; 11(8):683691.
  • 12
    Shankar V, Haque A, Churchwell K, et al. Insulin glargine supplementation during early management phase of diabetic ketoacidosis in children. Intensive Care Med 2007; 33(7):11731178.
  • 13
    Umpierrez GE, Jones S, Smiley D, et al. Insulin analogs versus human insulin in the treatment of patients with diabetic ketoacidosis. Diabetes Care 2009; 32(7):11641169.
  • 14
    Kreisberg R. Diabetic ketoacidosis: new concepts and trends in pathogenesis and treatment. Ann Intern Med 1978; 8:681695.
  • 15
    Kley S, Casella M, Reusch C. Diabetic Ketoacidosis in 22 Cats (1997–2002). In: Proceedings (abstract) of the 12th ECVIM-CA/ESVIM Congress; 2002: Munich, Germany.
  • 16
    Koenig A, Drobatz KJ, Beale AB, et al. Hyperglycemic, hyperosmolar syndrome in feline diabetics: 17 cases (1995–2001). J Vet Emerg Crit Care 2004; 14(1):3040.
  • 17
    Sieber-Ruckstuhl NS, Kley S, Tschuor F, et al. Remission of diabetes mellitus in cats with diabetic ketoacidosis. J Vet Inter Med 2008; 22(6):13261332.
  • 18
    Marshall RD. Clinical management of diabetes mellitus in cats. Thesis. The University of Queensland, Brisbane, Australia; 2011.