Using glargine intravenously for diabetic ketoacidosis

Diabetic ketoacidosis results from prolonged inadequate insulin activity. The main aims of therapy are to supply exogenous insulin, restore hydration status and manage electrolyte disturbances. Ketoacidotic cats usually present severely dehydrated and as such, have reduced absorption from subcutaneous tissue (from reduced blood flow). Until hydration is restored, insulin must be administered either intravenously or intramuscularly.

For many years, the insulin of choice for treating ketoacidosis has been regular insulin due to its rapid onset, potent glucose lowering effect and predictably short duration of action. Glargine has almost identical properties to that of regular insulin when used intravenously (Scholtz et al, 2003). Its actions are so similar that glargine can simply be substituted for regular insulin (for all your current protocols just draw glargine up instead of regular insulin). There are no reported clinical trials in the human literature assessing glargine administered intravenously as it was accepted to have no benefit over regular insulin. Regular insulin is used solely to treat diabetic ketoacidosis and many veterinary clinics chose not to stock it (or use it well after the expiry date) as the disease is seen so infrequently and most of the vials are wasted. Glargine on the other hand, can be used in DKA as well as maintenance therapy and most clinics have it on hand for diabetic cats. We mix glargine with normal saline, hartmann’s or 2.5% glucose solution. It is uncertain how long it will stay active in these solutions so suggest a new solution is made every 24hrs.

Glargine can be administered to ketoacidotic cats by:

• infusing intravenously at a rate of 0.05-0.1 U/kg/hr and rate adjusted to maintain blood glucose between 10-14mmol/L or
• injected s/c at the normal dose rate (0.25-0.5U/kg) as well as 0.5-1U of glargine injected IM or IV

As soon as I have a diagnosis of DKA, I immediately administer 0.5U/kg subcutaneously as well as 1U into the quadriceps muscles. I often administer glargine before I have discussed the diagnosis and treatment plan with owners. If they decide not to treat the cat,  little has been lost as the syringes and insulin probably cost the clinic less than $1. I have found most cats require 1U of glargine given IM every 2-4hrs based on glucose concentration. The dosing of glargine IM or IV is continued until hydration is restored and appetite returns, which usually occurs in 1-3 days. Glargine is then injected s/c and dosed as for an uncomplicated cat (see Table 1).

Please note When injected s/c, glargine reacts with the tissue and forms micro-precipitates which are slowly absorbed and is responsible for its long duration of action. Mixing or diluting glargine with any solution inhibits micro-precipitates forming and significantly reduces the duration of action. It is only when using intravenously for treating DKA that it can be mixed with other solutions as a long duration of action is not required.

Rhett Marshall BVSc MACVSc
The Cat Clinic
189 Creek Road,
Mt Gravatt, 4122

Basic information

• Glargine must not be diluted or mixed with anything because the prolonged action is dependent on its pH
• Glargine has a shelf-life of 4 weeks after opening and kept at room temperature. Refrigeration prolongs its shelf-life and allows opened vials to be used for up to 6 months. The manufacturer however recommends discarding opened vials after 4 weeks
• When performing a blood glucose curve, samples probably only need to be taken every 4hrs over 12 hr in many cats (ie. 0h [before morning insulin], 4h, 8h and 12h after morning insulin)
• Dose changes should be made based on pre-insulin glucose concentration, nadir (lowest) glucose concentration, daily water drunk, and urine glucose concentration.
• Better glycaemic control is achieved with twice daily dosing rather than once daily
• More accurate dosing may be achieved using 0.3ml U-100 insulin syringes

Indications for starting glargine

• All newly diagnosed diabetic cats (to increase chance of remission)
• Poorly controlled or unstable diabetic cats (glargine’s long duration of action is likely to benefit these cats)
• When SID dosing is desired or demanded (glycaemic control and remission rates are higher if glargine is dosed BID)
• Ketoacidosis – replaces regular insulin and can be used IM or IV
• When corticosteroid administration is required in cats at high risk of developing clinical signs of diabetes or cats in remission.

For initial insulin dose,

• BG > 20mmol/L à start with 0.5U/kg ideal body weight twice daily (BID)
• BG < 20mmol/L à start with 0.25U/kg ideal body weight BID

Blood glucose should be sampled every 3-4hrs for several days, either at home or in hospital. Dose reductions can be made (based on the blood glucose parameters in Table 1) but it is suggested that you do not increase the dose until about 7 days of therapy as many cats have negligible glucose lowering effect in the first few days despite being on an adequate dose of insulin.

After this, cats should have their blood glucose sampled weekly (or more frequently) as outpatients and insulin dose adjusted according to Table 1. If biochemical hypoglycaemia develops and is not severe, it can usually be managed by feeding the cat a higher carbohydrate containing meal. Renal diets and many supermarket lines of dry food are high in carbohydrates. Clinical hypoglycaemia requires immediate IV glucose therapy.

Table 1. Blood glucose parameters used for adjusting insulin dose

Urine glucose measurements
With the long duration of action of glargine, there should be minimal periods when blood glucose is >14mmol/L (240mg/dL) for cats treated for more than 2 to 3 weeks, and hence well controlled cats should almost always be 0 or 1+ for urine glucose. A value 2+ or greater likely indicates that an increase in dose is required.

Serial blood glucose curves or single blood glucose sampling?
The aim of dosing, when using shorter-acting insulins, is to select the maximum dose that can be safely given without causing hypoglycaemia. To determine this, we use nadir glucose (lowest) and aim for 7-10mmol/L. A serial blood glucose curve is required to determine the nadir hence single outpatient blood glucose samples have traditionally been considered meaningless.

After several days of glargine therapy, the long duration of action and carry-over effects (Marshall et al, 2008) usually results in a flatter blood glucose curve and a much smaller difference between pre-insulin levels and the nadir. For this reason, most cats can be monitored as outpatients with single blood glucose sampling. In most cats, glargine exerts its peak effect approximately 14hrs after injection (Marshall et al, 2008), so sampling blood glucose just prior to injection is recommended. This also allows insulin dose to be changed immediately (if required) rather than waiting until the next injection. Single glucose sampling provides less information than a serial curve but has the added benefit of reduced stress for the cat and costs for the owner as no hospitalisation is required. Confusing or unexpected single glucose samples should be investigated with a serial blood glucose curve.

How to recognise and approach remission
Good glycemic control soon after diagnosis reverses glucose toxicity and many newly-diagnosed diabetic cats can have their insulin dose gradually reduced and many can have their insulin completely withdrawn. It is suggested that insulin not be withdrawn completely for at least two weeks after starting insulin therapy to ensure adequate time for beta cells to recover from glucose toxicity.

Insulin dose can be reduced when indicated by low blood glucose parameters listed above. If pre-insulin glucose is below 10mmol/L and insulin dose has been reduced to 1U, insulin should be withheld and blood glucose measured for 12hrs (if the pre-insulin glucose is below 10mmol/L and insulin dose greater than 1U, insulin dose should be reduced to 1U rather than withheld and pre-insulin glucose measured again in 3-7 days). In most cases, if when insulin is withheld the blood glucose concentration

• rises rapidly or significantly over 10mmol/L cats should be discharged on 1U twice daily
• rises slowly towards or just above 10mmol/L, then cats should be discharged on 1U once daily
• remains below 10mmol/L for 12hrs with no insulin, they can be assumed to be non-insulin dependant and cats should be discharged without insulin with their blood glucose monitored every 2-3 days for several weeks. Confirmed non-insulin dependant diabetic cats should have their blood glucose checked weekly for 3 months and then monthly forever.

Some cats may have a pre-insulin glucose concentration below 10mmol/L within 2 weeks, but insulin therapy should be maintained for at least 2 weeks to give beta cells adequate time to recover from glucose toxicity. Use 1U BID or SID until insulin is withdrawn.

What to do with the diabetic cat in remission
Once remission has occurred, it is vital that blood glucose concentration be measured regularly (initially weekly then monthly) to quickly diagnose a relapse. To facilitate the cat remaining in diabetic remission, it is recommended that a low carbohydrate diet is fed, physical activity is increased, calories are restricted to avoid obesity, and that diabetogenic drugs are contraindicated unless a life threatening situation arises.

How to increase the chance of remission
Our study in diabetic cats (Marshall et al, awaiting publication) found better glycaemic control and higher remission rates when newly diagnosed diabetic cats were treated with glargine compared to lente or PZI insulins. This study also showed that, regardless of insulin type, good glycaemic control soon after diagnosis (within 3 weeks) increases the chance of achieving remission.

For reasons that are presently unknown, glargine treated cats appear to tolerate slight overdosing with insulin very well. For this reason, it is suggested that for the first 4-6 weeks of therapy, insulin be slightly overdosed and cats monitored carefully. Slightly overdosing with glargine increases the risk of hypoglycemia but usually results in achieving early good glycemic control which reverses glucose toxicity and results in a non-insulin dependant state. The benefits of remission far outweighs the risks of hypoglycaemia.

To maximise glycaemic control and hence the chance of remission

• select glargine as initial insulin
• administer glargine TWICE daily rather than once daily
• slightly overdose with insulin for the first 4-6 weeks
• use a low carbohydrate diet
• restrict calories if overweight and encourage physical activity

Concurrent corticosteroid administration
Corticosteroid administration causes insulin resistance and should be avoided in diabetic cats. When required, local or topically acting preparations should be used to reduce systemic levels. Budesonide (1mg/cat sid or bid) is useful for treating inflammatory bowel disease. Asthmatic cats should be treated with inhaled steroids such as Flixotide (Fluticasone proprionate) which maximises the concentration of steroid delivered to the respiratory mucosa without significant systemic release.

Glargine is very useful to use in cats requiring intermittent or chronic corticosteroid administration that are either in remission or at risk of developing diabetes. Most cats can be safely be placed on 1U SID or BID with very little monitoring.

The best method of monitoring response to insulin therapy is measurement of blood glucose concentrations. The vast majority of cats will allow blood collection if they are handled in the right way. Things that help with collecting blood from fractious cats are

• don’t make them wait
• do the collection in a quiet place such as a consulting room
• don’t let them see other cats or dogs
• consider the medial saphenous vein
• use the smallest amount of restraint possible
• use staff that like cats and involve the owner if possible
• if admitted for a blood glucose curve, try housing in a quiet separate location like a spare consult room or the office
• home glucose sampling by staff or owner

Most fractious cats are much better behaved with just their owners present, in a consulting room. I like to sample blood from the jugular vein with the help of the owner. I get owners to stand behind the cat and speak gently to them while petting their head. I slowly but firmly grab hold their heads by placing my thumb under their chin and fingers on top of their head and rotate upwards until vertical. Most cats have a 10 second window of opportunity so without releasing this grip, I use the other hand to shave the skin, swab with alcohol and then direct the owners index finger over the top of the vein and then collect blood using an insulin syringe. Having owners involved like this can be extremely daunting for many veterinarians but with confidence and competence, most fractious cats can have their blood sampled.

Stress induced hyperglycaemia occurs commonly in fractious cats making blood glucose taken under duress or from a stressed cat meaningless so don’t even bother if you have to pin a cat down with force.

Unfortunately, there are times when blood glucose sampling is simply not possible due to the temperament of the cat. What are we to do in such circumstances? Daily water drunk is often overlooked, but is an important tool for monitoring diabetic cats. Blood glucose concentrations above the renal threshold (14 – 16mmol/L in cats) result in glycosuria, osmotic diuresis, and compensatory polydipsia. Measurement of water consumption at home is simpler, cheaper, and less stressful to measure for the owner, cat and practitioner, and correlates better with mean daily glucose concentration than does fructosamine concentration.

Get the owner to start therapy at a dose of 0.25 units/kg of glargine s/c twice daily. Owners then measure the 24hr water intake and record it. Despite seeming obvious, owners must be instructed on how to accurately measure water intake. A measuring cup should be used to pour a known amount of water into the drinking bowl at the start of the period and then to measure it again at the end of the period. Access to alternate drinking sites must be removed and it may be necessary to confine the cat in part of the house if it drinks significantly from a source that can’t be measured, like a pond or swimming pool. Confinement will also be required in multi-pet households so as to be sure of the patients water intake.

Insulin dosage changes are then based on the water intake of the cat with the aim of keeping water intake to around 40mls/kg/day or 200mls per day for an average diabetic cat (normal daily water intake is 20mls/kg if fed wet food only and 70mls/kg if fed dry food only). Insulin dose can be increased weekly by 0.5-1U until water intake is at the desired level.

It is desirable, but not essential, to get pre-insulin blood glucoses in as many of these patients as possible. For some cats that cannot be handled in the clinic a housecall may be worth a try. A pre-insulin glucose of less than 10 mmol/L (on insulin glargine) should trigger a dose reduction.

Another useful tool to help is to get the owners to measure urinary glucose with a dipstick a couple of times a week. Diabetic cats should have some degree of glycosuria. A persistent negative urinary glucose should trigger a dose reduction whereas persistent 4+ urine glucose requires a dose increase. Owners can place paper based litters in a syringe and squeeze urine onto the dipstick with little impact on accuracy.

Management by measuring water intake will not work if there are concurrent factors causing polyuria, eg renal disease, drug therapy with frusemide. Diabetic cats can live many years and many eventually develop renal disease which then makes using water intake invalid for monitoring insulin therapy.

It is imperative to educate owners that this is not the best way of managing the disease and that the risks are increased and the quality of control is likely not as good. However, it provides a method of managing the fractious feline diabetic patient that is stress free to all involved. It can also be useful for those clients that lack the financial resources to manage their diabetic cat more intensively.

How to recognise and approach diabetic remission

Good glycemic control soon after diagnosis reverses glucose toxicity and many newly-diagnosed diabetic cats can have their insulin dose gradually reduced and many can have their insulin completely withdrawn. It is suggested that insulin not be withdrawn completely for at least two weeks after starting insulin therapy to ensure adequate time for beta cells to recover from glucose toxicity.

Insulin dose can be reduced when indicated by low blood glucose parameters listed above. If pre-insulin glucose is below 10mmol/L and insulin dose has been reduced to 1U, insulin should be withheld and blood glucose measured for 12hrs (if the pre-insulin glucose is below 10mmol/L and insulin dose greater than 1U, insulin dose should be reduced to 1U rather than withheld and pre-insulin glucose measured again in 3-7 days). In most cases, if when insulin is withheld the blood glucose concentration

• rises rapidly or significantly over 10mmol/L cats should be discharged on 1U twice daily
• rises slowly towards or just above 10mmol/L, then cats should be discharged on 1U once daily
• remains below 10mmol/L for 12hrs with no insulin, they can be assumed to be non-insulin dependant and cats should be discharged without insulin with their blood glucose monitored every 2-3 days for several weeks. Confirmed non-insulin dependant diabetic cats should have their blood glucose checked weekly for 3 months and then monthly forever.

Some cats may have a pre-insulin glucose concentration below 10mmol/L within 2 weeks, but insulin therapy should be maintained for at least 2 weeks to give beta cells adequate time to recover from glucose toxicity. Use 1U BID or SID until insulin is withdrawn.

What to do with a diabetic cat in remission
Once remission has occurred, it is vital that blood glucose concentration be measured regularly (initially weekly then monthly) to quickly diagnose a relapse. To facilitate the cat remaining in diabetic remission, it is recommended that a low carbohydrate diet is fed, physical activity is increased, calories are restricted to avoid obesity, and that diabetogenic drugs are contraindicated unless a life threatening situation arises.

How to increase the chance of remission occurring
Our study in diabetic cats (Marshall et al, awaiting publication) found better glycaemic control and higher remission rates when newly diagnosed diabetic cats were treated with glargine compared to lente or PZI insulins. This study also showed that, regardless of insulin type, good glycaemic control soon after diagnosis (within 3 weeks) increases the chance of achieving remission.

For reasons that are presently unknown, glargine treated cats appear to tolerate slight overdosing with insulin very well. For this reason, it is suggested that for the first 4-6 weeks of therapy, insulin be slightly overdosed and cats monitored carefully. Slightly overdosing with glargine increases the risk of hypoglycemia but usually results in achieving early good glycemic control which reverses glucose toxicity and results in a non-insulin dependant state. The benefits of remission far outweighs the risks of hypoglycaemia.

To maximise glycaemic control and hence the chance of remission

• select glargine as initial insulin
• administer glargine TWICE daily rather than once daily
• slightly overdose with insulin for the first 4-6 weeks
• use a low carbohydrate diet
• restrict calories if overweight and encourage physical activity

Measurement of blood glucose concentration (BG) is usually the best method of determining the correct insulin dose for diabetic cats. Stress hyperglycaemia occurs commonly when cats visit a veterinary surgery and can result in the wrong dose of insulin being selected. Thus, the stress-free environment at home is the best place to measure a cats BG.

Most human glucometers are very accurate at measuring cat blood. We prefer the Accu-Chek brand which can be purchased from any chemist for approximately $60.

The easiest and safest place for owners to sample blood from is the ear veins. Cats have small veins that run around the outside of their ears and these veins can be easily accessed from the dorsal surface. Blood can be sampled on both the cranial and caudal border of each ear giving a total of 4 sites to sample. Shaving the hair directly over the vein with a scalpel blade allows much better visualisation and with very slow hair regrow, will last for many weeks.

Procedure
1. Turn the glucometer on or insert test strip so the digital display is requesting blood.
2. Hold the edge of the ear between index-middle finger and thumb-fourth finger and firmly pull taut.
3. Quickly prick the vein with an insulin needle so a small drop of blood is produced on the skin surface. Pre-used insulin syringes are fine to use for this.
4. Bring glucometer down to the skin and place the end of the test strip into the blood until it beeps.
5. Read the number on the display and record it.
6. Wipe any excess blood away with a moist tissue.

Cats rarely react to their ears being pricked but topical anaesthetic creams such as EMLA can be applied prior to sampling if required. The most common complaint from owners is spraying of blood around the house if they shake their heads while blood is pooled on the skin. This can be minimised by not releasing the initial grip on the ear until blood has been transferred (with one hand) to the glucometer and a tissue applied to the ear.  Blood glucose samples are best collected just before an insulin dose is due so dose adjustments can be made immediately if required rather than waiting until the next injection.

Selecting insulin dose
à For newly diagnosed diabetic cats (less than 2 months):
If BG is above 12mmol/L then increase insulin dose 0.5 units (half a unit)
If BG is between 6 and 11mmol/L then keep insulin dose the same
If BG is between 3 and 6mmol/L then reduce dose by 0.5 units
If BG is less than 3mmol/L then don’t give insulin and call the clinic to discuss

à For longer-term diabetic cats (more than 2 months of insulin therapy):
If BG is above 25mmol/L then increase insulin dose 1 units
If BG is between 14 and 25mmol/L then increase insulin dose 0.5 units
If BG is between 6 and 13mmol/L then keep insulin dose the same
If BG is between 4 and 6mmol/L then reduce dose by 0.5 units
If BG is less than 4mmol/L then don’t give insulin and either check for remission or call the clinic to discuss.

How often to sample
Ideally, diabetic cats should have BG sampled several times daily (just like humans do) but for many reasons this is not practical. We recommend that newly diagnosed cats should have their BG checked every 2-3 days for the first few weeks and longer-term diabetic cats be sampled every 1-2 weeks. If insulin dose is changed, then a repeat BG should be done 2-3 days afterwards to check the right decision was made, whereas if the insulin dose is kept the same then a repeat BG is probably not required for 1-2 weeks.

Record keeping
A table should be kept which contains the date, current insulin dose, the BG reading and the new insulin dose selected. Initially, this table should be reviewed by a veterinarian in consultation every few weeks. Your veterinarian will assess the BG readings and the decisions you have made and comment as necessary. Most owners rapidly become competent at sampling blood and selecting the correct insulin dose making it unnecessary to consult us for long periods.

Diabetes mellitus is a hormonal disease that occurs in about 1 out of every 400 cats. It is characterised by elevated blood glucose (blood sugar) levels.  If untreated, it can lead to life-threatening metabolic disturbances.  Diabetes in cats is most similar to type II or adult onset diabetes in humans.

The hormone insulin is produced in the pancreas and is responsible for allowing glucose to be taken into cells to provide energy.  If there is resistance to this action or there is a reduction in the total amount of insulin produced, then the cat becomes diabetic.

The cats who are most at risk for developing diabetes are cats over eight years old, male cats, Burmese cats and cats who are overweight.

Signs and Symptoms

Clinical signs of diabetes include:

• excessive drinking
• excessive urinating
• increased appetite
• problems walking or jumping.  (This is caused by neuropathy which causes poor nervous control to the cat’s hind legs)

Diagnosis

Diagnosis involves blood and urine tests to demonstrate high blood glucose and the presence of glucose in the urine. Sometimes a test for fructosamine is required to distinguish between cats which are stressed and those that are truly diabetic.

Treatment

Diabetes is a very treatable disease, but requires long term commitment. Treatment options include:

• treating underlying disease (if there is one)
• insulin therapy (the preferred method, and the one that provides the best control of blood sugar)
• dietary management  (there have been significant advances in dietary treatment of feline diabetes recently)

After your cat has been diagnosed with diabetes, the next step is to determine the correct type and dose of insulin for her.  This varies from cat to cat, and your cat will probably have to spend several days in the hospital.  She will have her blood glucose measured every few hours as the vet determines the correct treatment for her.

Your cat will need to return to the vet:

• Every week for 3 weeks and then
• Every month until a stable dose is determined.
• From then on cats usually return to the clinic every 3 months for a check up.

Insulin Instructions

• Insulin must be stored in the refrigerator.
• If your cat is on a crystalline insulin it must be gently mixed by rolling for 30 seconds prior to each use.
• Glargine (Lantus) insulin does not need to be mixed.
• A new syringe should ideally be used for each injection.
• Injections can be given under the skin anywhere on the body but the “scruff” is often easiest and less painful.

Your cat must be monitored closely while he is on insulin therapy.

DO NOT change the dose without consulting your veterinarian. If your cat gets too much insulin it can cause blood glucose levels to become dangerously low.  Your cat could become weak, lethargic or unsteady on her feet.  She could go blind, go into a coma or die.

If your cat accidentally gets too much insulin or if it shows any of these signs, take her to the vet immediately. You might try rubbing honey or glucose syrup on her gums as an emergency treatment.

Remission

Approximately 50% of cats diagnosed with diabetes and treated appropriately will go into remission and no longer require insulin injections.  Early diagnosis and aggressive treatment with long-acting insulin and a low carbohydrate diet will increase the chance of your cat going into remission.