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Lispro insulin and electrolyte supplementation for treatment of diabetic ketoacidosis in cats

Abstract Background Intravenous continuous rate infusion (IVCRI) of lispro at a starting dose of 0.09 U/kg/h and the use of 0.9% sodium chloride (NaCl) for fluid resuscitation in cats with diabetic ketoacidosis (DKA) have not been reported. Protocols for correction of electrolyte deficiencies in cats with DKA are lacking. Objectives To characterize the use of IVCRI lispro at an initial dose of 0.09 U/kg/h and the use of NaCl for resuscitation. Explore protocols for electrolyte supplementation in cats with DKA. Animals Twelve cats with DKA enrolled from the cat population of a university hospital. Methods Randomized, controlled, blinded study. Six cats were randomized into each group, the lispro insulin treatment group (LITG) and regular insulin treatment group (RITG). All cats received IVCRI fluid resuscitation with NaCl. Solutions with higher than previously published electrolyte concentrations were used to treat electrolyte deficiencies. Results The median time to blood glucose (BG) concentration <250 mg/dL was significantly shorter in the LITG (median 7 hours, 2‐10 hours) than the RITG (median 12.5 hours, 8‐20 hours; P = .02). Two cats had nonclinical hypoglycemia (BG = 40 mg/dL). The most rapid change in 157 measurements of corrected sodium concentrations was 0.7 mmol/L/h. Low concentrations of serum sodium, potassium, phosphate, and magnesium were over 3 times more common than above normal electrolyte concentrations, despite supplementation with fluids of high electrolyte concentrations. Conclusions and Clinical Importance Lispro at a starting dose of 0.09 U/kg/h and NaCl administered for fluid resuscitation are safe and effective for treatment of DKA in cats.

DKA in cats include the use of IV continuous rate infusion (IVCRI) regular insulin, intermittent IM injection of regular insulin, a combination of IM regular insulin and SC glargine, or a combination of IM and SC glargine. [1][2][3][4] The use of IVCRI lispro insulin for treatment of DKA in cats has also been described in a case series in which cats were treated with an initial insulin dose 0.045 U/kg/h. 5 It is important to validate alternative IVCRI insulin treatment protocols because the production of regular insulin could be discontinued. According to the 2017 annual report of Eli Lilly, the revenue associated with lispro is now more than double the revenue associated with regular insulin (https://investor.lilly.com/financialinformation/annual-reports). Additionally, the patent for lispro has expired in several countries, and a Sanofi-Aventis lispro insulin has been granted FDA approval in the United States and European Medicines Agency approval in the European Union (https://www.fda.gov/newsevents/ newsroom/pressannouncements/ucm588466.htm; http://www.ema. europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/ 004303/human_med_002129.jsp&mid=WC0b01ac058001d124). These factors could contribute to a more competitive pricing of lispro and could influence its use in veterinary medicine.
Lispro is a genetically engineered human analogue insulin in which proline at position B28 and lysine at position B29 are transposed. 6 In humans with critical illness, IVCRI of lispro more rapidly decreases blood glucose (BG) concentration, and with lower risk of hypoglycemia, compared to IVCRI of regular insulin. 7 In dogs, the median time to resolution of hyperglycemia, ketosis, and acidosis with IVCRI of lispro is significantly shorter (26 hours; range 26-50 hours) than in dogs treated with IVCRI of regular insulin (61 hours; range, 38-80 hours; P = .02) when the initial insulin dose of both products is 0.09 U/kg/h. 8 In cats, the median times to resolution of hyperglycemia, ketosis, or acidosis with IVCRI of lispro are not significantly different (8,29, or 8 hours, respectively) than these times when cats are treated with IVCRI of regular insulin (9, 26.5, or 20 hours, respectively) when the initial insulin dose of both products is 0.045 U/kg/h. 5 The median times to resolution of hyperglycemia, ketosis, or acidosis in cats with intermittent IM regular insulin administered in combination with SC glargine insulin are significantly shorter (9, 44, or 23 hours, respectively) than times in cats treated with IVCRI of regular insulin (12,62, or 41 hours, respectively) when the initial insulin dose of the IVCRI is 0.045 U/kg/h. 3 For the purpose of the current study, an initial IVCRI insulin dose of 0.09 U/kg/h (prepared by adding 2.2 U/kg/240 mL bag of 0.9% NaCl) was chosen rather than an initial IVCRI insulin dose of 0.045 U/kg/h because treatment with the higher dose has been associated with a better prognosis in cats with DKA. 1 The type of fluid used for resuscitation has not been standardized in cats with DKA. Although 0.9% NaCl is recommended for the initial phase of fluid resuscitation and as long as hyponatremia is present in humans with DKA, the use of 0.9% NaCl has not been investigated in an original study of cats with DKA. 9 Similarly, protocols for correction of potassium, phosphate, and magnesium deficiencies in cats with DKA have not been established.
The objectives of this study were 3-fold. The first objective was to further characterize the use of IVCRI lispro for the treatment of DKA in cats in a randomized, controlled, blinded study in which cats received an initial IVCRI of lispro or regular insulin at a dose of 0.09 U/kg/h, and to compare the times to resolution of hyperglycemia, ketosis, and acidosis in cats treated with lispro and regular insulin IVCRI at this dose. The second objective was to characterize the use of 0.9% NaCl for fluid resuscitation and determine if this treatment is effective and safe in resolving hyponatremia in cats with DKA. The third objective was to explore new protocols for electrolyte supplementation in cats with DKA while using solutions with higher than previously reported electrolyte concentrations to correct low serum concentrations of potassium, phosphate, and magnesium. This study had 3 hypotheses. The first was that lispro insulin is effective and safe in treating DKA in cats and that resolution of hyperglycemia would be faster in cats treated with lispro insulin compared to those treated with the same dose of regular insulin. The second hypothesis was that 0.9% NaCl is effective and safe for treatment of hyponatremia in cats with DKA. The third hypothesis was that electrolyte supplementation with solutions that contain higher than previously reported electrolyte concentrations are effective and safe in correction of low serum concentrations of potassium, phosphate, and magnesium in cats with DKA.

| Study design
A prospective, randomized, controlled, blinded clinical study was performed. Client-owned cats with naturally occurring DKA were randomly assigned to receive either lispro or regular insulin IVCRI. Twelve sealed opaque envelopes containing either 1 of 6 "Lispro insulin" or 1 of 6 "Regular insulin" inserts were used, and the insulin assignment was known to nurses only, until the cat was discharged from the hospital or euthanized. Cats examined at a veterinary university hospital were enrolled between July 2011 and July 2013. Inclusion criteria were clinical signs suggestive of DM (polyuria, polydipsia, polyphagia, or weight loss), BG >300 mg/dL, serum Bhydroxybutyrate (BOHB) >2 mmol/L, venous pH <7.35, glucosuria on urine dipstick, and a signed owner consent form (which included consent for necropsy should the cat die or be euthanized during hospitalization).
The study protocol and owner consent form were approved by the University's Institutional Animal Care and Use Committee. Cats were excluded if venous pH was <7.0 or if the owner did not consent. The study protocol called for exclusion of cats with a venous pH <7.0 because in dogs and humans with DKA, this pH is associated with death. 9,10 Ultimately, none of the cats were excluded from the study due to pH <7.0.

| Treatment protocol
Upon admission, all cats received IV fluid resuscitation with 0.9% NaCl. The initial fluid rate and bolus rate were determined by the emergency clinician based on the cat's body weight, estimated percentage of dehydration, estimated ongoing fluid losses, and maintenance fluid requirements. A fluid bolus was administered over a 20-minute time period if the cardiovascular system evaluation indicated that it was needed. Fluid boluses were not supplemented with electrolytes. The cardiovascular system evaluation included an assessment of the mucous membrane color, capillary refill time, heart rate, pulse quality, and extremities' temperature. The cardiovascular status of each cat was reevaluated every 20-120 minutes depending on the rate of fluid administration and the initial cardiovascular system evaluation to determine the need for fluid rate adjustments.
The study protocol required that IVCRI of insulin begin after 6 hours of fluid resuscitation. However, the emergency room clinician was given discretion to deviate from the protocol as dictated by the clinical needs of each cat. Identical protocols were used for IVCRI of regular and lispro insulin, as described in Table 1. The initial dose of IVCRI insulin was 0.09 U/kg/h. Serum potassium concentration was corrected as described in Bayer Healthcare, LLC, Shawnee Mission, Kansas). The protocol dictated that the same broad-spectrum antibiotic treatment be administered to all cats after cystocentesis was performed to obtain urine for an aerobic bacterial culture and sensitivity. This inclusion criteria was chosen because urinary tract infections are common in cats with DKA, and it was thought that clinicians would wish to treat cats for suspected infections, at least until results of the urine culture were obtained. 1 Broad antibiotic coverage was chosen to satisfy this clinical need and to maximize treatment uniformity. Additional medications including antiemetics, gastroprotectants, analgesics, and vasopressors were administered as deemed appropriate by the attending clinician.

| Definitions of the time of SC insulin administration and duration of hospitalization
The time to SC insulin administration was defined as the time interval from admission until SC glargine was administered. Glargine was administered once acidosis had resolved and the cat was eating well.
The IVCRI of insulin was discontinued 4-6 hours before the planned administration of SC glargine to ensure that the cat had some degree of hyperglycemia before glargine administration. The duration of hospitalization was defined as the time interval between admission and the time at which the cat was discharged from the hospital or euthanized.

| Evaluation for the presence of concurrent disorders
Data recorded in all cats at the time of admission included clinical signs, physical examination findings, and results of a CBC, serum biochemical profile, urinalysis, and aerobic urine bacterial culture and were not given to any of the cats at the time of admission nor were they reported to have been given in the past.

| Initial fluid treatment and initiation of IVCRI insulin
Initial fluid treatment consisted of a 20-minute fluid bolus in 11 of 12 cats. Six of these cats were in the LITG and 5 were in the RITG. The median fluid bolus rate given to cats in the LITG and RITG was 15 mL/kg/h (10-20 mL/kg/h) and 20 mL/kg/h (20-30 mL/kg/h), respectively. One cat in the RITG did not require a fluid bolus and received an initial fluid rate of 4 mL/kg/h. After the bolus, the median fluid rate given to 6 cats in the LITG and 5 cats in RITG was 5 mL/kg/h (4-7 mL/kg/h) and 4 mL/kg/h (4-6 mL/kg/h), respectively. Two cats (1 from each treatment group) received dopamine at 5-10 μg/kg/min or 12.5-15 μg/kg/min. These 2 cats were among the 4 cats that were euthanized.
The median time interval between admission time (when fluid resuscitation was initiated) until IVCRI of insulin began was 7.5 hours for the LITG (range 4-14 hours) and 7 hours for the RITG (range 6-9 hours). The median BG in all 12 cats at the time that IVCRI of insulin began was 344 mg/dL (175-579 mg/dL) and was significantly lower than the median BG at the time that fluid resuscitation was initiated (491 mg/dL, 300-698 mg/dL; P = .008).

| Resolution of hyperglycemia, ketosis, and acidosis
Median BG concentration, BOHB concentration, and pH at the time of admission to the hospital and during the first 96 hours of hospitalization are reported in Table 3. Some of the reporting related to BG, ketosis, and acidosis is limited to the first 96 hours of hospitalization because most of these variables normalized within this time frame.
The median times to resolution of hyperglycemia, ketosis, and acidosis are also reported in Table 3.

| Electrolyte concentrations
Electrolyte concentrations are reported in

| DISCUSSION
The median time to resolution of initial pronounced hyperglycemia was significantly shorter in the LITG compared with the RITG. However, when focusing on the lowest BG measured in each of the cats throughout the study, it was noted that the median lowest BG in the LITG was significantly higher than the median lowest BG in the RITG.
It was therefore concluded that in cats with DKA, lispro insulin leads to a faster resolution of initial pronounced hyperglycemia, with less overall risk of hypoglycemia compared to regular insulin. However, larger studies including more cats with hypoglycemia are needed to further investigate these findings and potential conclusion.
Faster resolution of initial pronounced hyperglycemia with less overall risk of hypoglycemia has also been documented in humans with critical illness and is attributed to the rapid onset of action and shorter duration of action of lispro when compared to regular insulin. 7 Lispro's short onset of action could have contributed to a faster resolution of initial pronounced hyperglycemia in the LITG compared to the RITG. Lispro's short duration of action means that when lispro insulin is discontinued, or when its dose is reduced, its lingering effect on BG concentration is dampened quickly, and as a result, it is less likely to cause hypoglycemia in comparison to regular insulin. A case series describing the use of lispro and regular insulin in 15 cats with DKA found that lispro was safe and effective at a starting IVCRI dose of 0.045 U/kg/h. 5 However, a different retrospective study of 93 cats with DKA treated with regular insulin found that cats treated with an initial IVCRI dose of 0.09 U/kg/h had a better outcome compared to cats treated with an initial IVCRI dose of 0.045 U/kg/h. 1 Therefore, the protocol of the study reported here was designed to begin the lispro and regular insulin IVCRI at a dose of 0.09 U/kg/h. The T A B L E 3 Median blood glucose (BG) concentration, beta-hydroxybutyrate (BOHB) concentration, and venous pH at the time of admission to the hospital and during the first 96 hours of hospitalization, and median times to resolution of hyperglycemia, ketosis, and acidosis   When analyzing the BG in all 12 cats, a significant decrease in BG concentration was detected between the time that fluid resuscitation was initiated and IVCRI of insulin began. It is therefore concluded that fluid resuscitation alone is effective in significantly decreasing BG during the first 7 hours of treatment. This finding, which has also been reported in dogs, raises a concern that early treatment with IVCRI of insulin, before 7 hours of fluid resuscitation, could cause too rapid a decrease in BG concentration as the effects of fluid resuscitation and insulin are combined to decrease BG. 8 This concern over early IVCRI of insulin administration is different than the conclusion reached in a retrospective study which concluded that early insulin treatment (within the first 6 hours of hospital admission) resulted in faster resolution of ketonuria compared to when insulin was given after 6 hours of admission. 13 However, because of the retrospective nature of the study, it is not known why some patients received insulin later than others. It is possible that patients with severe morbidity received insulin later than others, and due to this severe morbidity had later resolution of ketonuria, which was unrelated to the time at which the insulin treatment began. 13 It is important to note that the more rapid resolution of hyperglycemia observed in the LITG compared to the RITG is probably not associated with the eventual outcome of the patient. The median time to administration of SC insulin and median duration of hospitalization are likely better indicators of overall treatment success. These times were not significantly different between the LITG and the RITG. It was therefore concluded that in cats with DKA, lispro can be used as an efficient and safe alternative to regular insulin. However, the overall outcome of DKA treatment in cats is unlikely to be different with the use of lispro or regular insulin.
The same fluid type, 0.9% NaCl, was administered for fluid resuscitation, maintenance fluid therapy, and as a vehicle for IVCRI insulin administration in all cats. This is the first such use of 0.9% NaCl reported in an original study of cats with DKA. Original studies of DKA treatment in cats have not reported the type of fluid used for resuscitation or reported more than 1 fluid type for this purpose. [3][4][5]13,14 One study did report using 0.9% NaCl only for IVCRI insulin administration, similar to the protocol used in this study. 3 The protocol for IVCRI insulin administration reported in most studies is based on a study of dogs with DKA. 15  This study has several limitations. First, it is a small study, which was undertaken to ascertain the safety and effectiveness of a new lispro insulin IVCRI protocol. Another limitation is that cats with DKA have concurrent illness. 1 Therefore, response to treatment and electrolyte concentrations were likely influenced not only by treatment protocols but also by the presence of concurrent diseases. Additionally, the protocol required that IVCRI of insulin begin after 6 hours of fluid resuscitation. However, the emergency room clinician was given latitude to deviate from the protocol and IVCRI of insulin was begun up to 14 hours after fluid resuscitation was initiated. It is not known why some cats had IVCRI insulin introduced later than others. Possible explanations could include the busy and unpredictable setting of an emergency room, ongoing conversations with the owners about the decision to treat or enroll in the trial, and the cardiovascular status of the cat. The effect of these limitations on the study findings is not known.
In conclusion, IVCRI lispro insulin administered at an initial dose of 0.09 U/kg/h is safe and effective for treatment of DKA in cats. Should regular insulin become unavailable, or if lispro insulin becomes more competitively priced, lispro insulin is a reasonable option for IVCRI treatment of cats with DKA. Additionally, 0.9% NaCl is effective and safe for treatment of hyponatremia in cats with DKA. Finally, electrolyte supplementation with solutions that contain higher than previously reported electrolyte concentrations are effective and safe for correction of potassium, phosphate, and magnesium deficiencies in cats with DKA. Larger future studies can build on these findings to further validate or modify the treatment protocols reported here.

ACKNOWLEDGMENT
Presented as an abstract at the 2018 American College of Veterinary Internal Medicine Forum, Seattle, Washington.