Diabetes Clinical Guideline INVESTIGATION AND MANAGEMENT OF

SETTING Oxford Children’s Hospital. Oxford University Hospitals Trust

FOR STAFF Clinical staff in the Paediatric Haematology/Oncology departments, and others

______GUIDANCE This guidance is recommended for use by staff looking after children with or at risk of Steroid Induced Diabetes, for example oncology patients.

We recommend that the ward staff monitor and commence treatment according to the following guidelines, but also contact the diabetes team via the registrar (bleep 1775) to inform them of the patient details at an early stage. The diabetes specialist nurses should also be contacted to arrange teaching for the patient and family regarding injections and blood glucose (BG) monitoring (telephone 28737 or 28736). Out of hours and at weekends (but not in the middle of the night) please telephone the out of hours mobile 07823 533466.

DIAGNOSING STEROID DIABETES (SDM): There are no clear guidelines in the literature about the timing or diagnosis of SDM. It is known that S DM can start at any point after commencing steroid treatment, and is more likely in the first week of treatment with highdose steroid protocols. Studies have also shown that affect postprandial BG levels more than fasting levels. It is therefore important to measure BG levels throughout the day in addition to fasting levels.

RECOMMENDATIONS for DIAGNOSIS: All children on highdose steroid treatment should have BG levels monitored. Fasting BG and preevening meal BG levels should be measured twice a day. If not feasible in an individual patient, glucose in the urine will indicate whether the threshold of around 10 mmol/l has been reached and after that BG levels should be monitored.

The diagnosis of Diabetes is made when the following occur

• a random venous plasma glucose concentration > 11.1 mmol/l, or

• a fasting plasma glucose concentration > 7.0 mmol/l (whole blood > 6.1mmol/l).

However in asymptomatic patients the diagnosis should not be based on a single capillary glucose test but requires a confirmatory plasma venous BG. At least one additional capillary BG test result on another day with a value in the diabetic range is essential, either fasting, or from a random sample.

NB: It is not necessary to use the Oral Glucose Tolerance Test for diagnosis of SDM.

Monitoring of Blood Ketone levels • If BG levels at any time are above 16 mmol/l capillary ketone levels should be measured. • If they are above 1.0 mmol/l then should be started at the time of that BG test according to section 2 below.

Version 6 Review 20 16 Author : Dr Taffy Makaya Page 1 of 4

MANAGEMENT OF STEROID DIABETES:

• Patients tend to be insulin resistant and so are likely to need high and escalating amounts of insulin. • Response may be very individual, so keep thinking! Subcutaneous insulin doses need daily review in the first few days of treatment.

1. BG above 11 but below 16mmol/L: a. Start Lantus (insulin Glargine) at 0.7 Units per kg for first day, given as a once daily subcutaneous injection, increasing to 1 unit per kg for subsequent days if still hyperglycaemic. In overweight patients the same dose applies at the start, but they may require escalating doses. The Lantus should be given in the morning for children under the age of 5 years and in the evening for those over 5 years b. Check BG reading AIM FOR BLOOD GLUCOSE LEVELS: regularly: at least 4 times • Preprandial (before a meal): 5 7 mmols/l a day: premeal • Postprandial (2 hours after a meal) : 7 9 mmols/l (including fasting) and • Before bed: 5 9 mmols/l prebed. c. If BG targets are not achieved: • If fasting BG not controlled, or if BG levels consistently high throughout the day, increase the Lantus dose. • This can go up by 15 units each day.

• If postprandial BG levels high, or if fasting BG fine but rest of day high, add in NovoRapid ( Insulin Aspart shortacting insulin): • Start with fixed doses premeal, usually at a dose of 0.5 units per kg per day in three divided doses. • NovoRapid can be increased if postprandial BG levels are high. • Carbohydrate counting can be introduced at a later stage. • Please note that due to insulin resistance a largerthannormal insulin to carbohydrate ratio may be required.

• Oral hypoglycaemic agents, in particular metformin, can be considered in patients with severe insulin resistance, especially in patients with high BMIs and at risk of . Metformin can be started at a dose of 250mg a day, provided liver function tests are within normal range, and there are no risk factors for metabolic acidosis. Doses can be increased gradually by 250mg a week, to minimise gastric side effects, to a maximum of 2000mg a day in divided doses.

2. BG above 16mmol/L for more than 2 values, with glycosuria (or ketones above 1.0mmol/L):

Start IV soluble insulin at 0.1Units per kg per hour together with maintenance iv fluids: 0.9% sodium chloride with 20mmol KCl in 500ml as a sliding scale (this is available on the Intranet). • This has the advantage of early stabilization of high BG levels, minimizing glucotoxicity, and allows an estimation of daily insulin requirements if continued for at least 24 hours. • A disadvantage of this option is the need for frequent, hourly BG monitoring. • Aim to change patients to basal bolus (Lantus + NovoRapid once the dose is calculated after 24 hours).

3. Diabetes Education: It is important to have regular diabetes education and support including input from the entire paediatric diabetes multidisciplinary team. a. Particular guidance on diet is required as steroids tend to cause a massive increase in appetite. b. Management of hypoglycaemia and sick day rules should be according to standard diabetes protocols.

Version 6 Review 20 16 Author : Dr Taffy Makaya Page 2 of 4

FOLLOWUP:

It is important to note that once the initial insulin resistance is under control, and the steroid doses begin to reduce, the insulin requirement can fall rapidly. Therefore appropriate adjustment is imperative. The patient and family should have easy access to the diabetes team to facilitate this.

• It is difficult to predict how quickly or by how much the insulin requirements will drop. This will depend largely on the weaning regimen for the steroids, intercurrent illnesses and calorie intake.

• To minimise the number of injections given daily we recommend weaning the NovoRapid doses first, and maintaining the long acting Lantus. NovoRapid doses for the previous meal should be weaned if preprandial BG is low, and Lantus should be lowered (usually by 2units a day) if fasting BG is low. The insulin:carbohydrate ratio may also need to be decreased.

• We recommend close follow up by the diabetes team. Hypoglycaemic episodes should be treated as per standard diabetes management.

• Patients and parents should be provided with contact details for the diabetes team (below).

Day: Diabetes Specialist Nurses (Leave a message please) 28737 or 34584 or 28736

Diabetes Registrar: Bleep 1775

Out of hours: Mobile phone: 07823 533466

FURTHER INFORMATION:

Steroidinduced diabetes mellitus (SDM) is also referred to as ‘steroid diabetes’. The term refers to a prolonged state of hyperglycaemia due to therapy for another medical condition. Steroids are frequently used in the management protocols of a variety of subspecialties including rheumatology, respiratory, gastroenterology, nephrology and haemoncology. The mechanism for SDM is multifactorial. (e.g , ) cause hyperglycaemia via: • increased insulin resistance, • augmented hepatic , and • decreased glucose uptake by peripheral tissues such as muscle cells and adipocytes.

Other possible culprits in protocols are: • LAsparaginase reduces insulin secretion and causes hyperglycaemia. • Thiazide Diuretics causes possible reduction in insulin production, and reduced insulin sensitivity. • Tacrolimus and Cyclosporin likely cause reversible betacell damage.

Proposed risk factors for SDM in children include high steroid doses, high BMI, impaired glucose tolerance before therapy, cumulative dose, and long duration of steroid therapy.

SDM is associated with all the usual problems of diabetes including: • Hyperglycaemia: This results in renal overflow if the BG level is above 10mmol/L, and patients feel lethargic and unwell once BG levels are in the teens. • Osmotic diuresis results in polyuria with dehydration and weight loss. • Acidosis: occurs once ketones begin to rise, and also related to lactic acid excess. • Increased susceptibility to infections such as thrush, skin and urinary tract infections.

Version 6 Review 20 16 Author : Dr Taffy Makaya Page 3 of 4

SUMMARY FLOWCHART: ↑ Blood Glucose (BG) in a patient on steroids.

BG: 11 16mmol/L on more BG: >16mmol/L or than 2 occasions ketones≥1.0mmol/L

Start Lantus at 0.7units/kg s/c Start i.v.soluble insulin at OD. 0.1units/kg/hr with <5 years : morning dose maintenance fluids as sliding >5 years: evening dose. scale.

Inform Diabetes Team: Diabetic Specilaist Nurse ext 28737 / 28736, Registrar bleep 1775, Out of Hours mobile: 07823 533466

Calculate insulin requirement Monitor BG regularly: over 24 hours. Then change At least 4 times a day: pre to s/c Lantus (50% of total) meal and prebed. and NovoRapid (50% of total as 3 divided doses premeal.

Increase Lantus dose if fasting Increase Lantus dose if BG still high. fasting BG still high.

If fasting BG fine but BG high If fasting BG fine but BG high throughout the day then add in throughout the day then fixed premeal NovoRapid increase NovoRapid doses. doses.

Continue to monitor progress carefully and adjust insulin doses as needed. Liaise closely with the Diabetes Team. Consider metformin in patients with severe insulin resistance.

Once the initial insulin resistance is under control, and the steroid doses begin to reduce, the insulin requirement can fall rapidly. Appropriate adjustment is imperative. The patient and family should have easy access to the Diabetes Team to facilitate this.

Version 6 Review 20 16 Author : Dr Taffy Makaya Page 4 of 4