Nicola Trevelyan Consultant Paediatrician Nov 2007 Paediatric Diabetes Nicola Trevelyan Consultant Paediatrician Nov 2007

Aims Case history Diagnosis Diabetic ketoacidosis Treatment regimens Insulin analogues

Case history 9 year old Hannah is brought to A&E by her mum with a 2 week history of increased thirst, increased weeing & being very tired. Over the last 2 days she has been very thirsty, breathing fast & vomiting. O/E – Weight 26kg Alert co-operative afebrile 5% dehydrated Blood gas – pH 7.16, pCO2 2.4, Bicarb 5, BE –24 Glucose 28mmol/L Urine 4+ ketones, 4+ glucose

What is the diagnosis? Newly diagnosed type 1 diabetes mellitus with diabetic ketoacidosis

Types of diabetes sugar lack of useful insulin insulin produced tissues resistant to insulin by pancreas & pancreas unable to produce enough insulin type 1 type 2

What are the abnormal results & what do they signify? High glucose = diabetes Ketones in urine = ketosis (in absence of glycosuria may be starvation ketones) Low pH = acidosis Low Bicarbonate & negative base excess = metabolic acidosis Low pCO2 = compensatory respiratory alkalosis

The role of insulin Uptake of glucose from blood into muscle & fat cells Stops hepatic gluconeogenesis Increases glycogen production in liver & muscle Stimulates fat & protein synthesis

What are the 2 problems which need treating? Insulin What are the 2 problems which need treating? Decrease in glucose uptake from blood MUSCLE LIVER Gluconeogenesis Decrease intracell glucose Rise in blood for metabolism glucose Counter regulatory hormones Osmotic diuresis Lipolysis Ketones Vomiting Dehydration

Treatment of DKA Aims To slowly restore metabolic homeostasis To correct lack of insulin Correct dehydration over 48 hours Switch off lipolysis and hence acidosis Reduce hyperglycaemia

Treatment of DKA – IV fluids Start IV fluids before insulin 0.9% saline with 40mmol/L KCl (if the child is PUing) Once sugar drops to ~12mmol/L change to 0.45/5 dextrose saline with KCl added

What rate should Hannah’s fluids be given? Deficit = weight (kg) x % dehydn x 10 = 1300ml or 5% of 26kg = 0.05 x 26 = 1.3L or 5 x 26000 = 1300ml Given over 48hrs 100 Maintenance = (100 x 10)+(50 x 10)+(20 x 6) = 1620ml per 24 hours Hourly rate = (1300/2) + 1620 = 2270 = 94.6ml/hr 24 24

What insulin? Actrapid or any fast acting analogue available (Humulin S, Humalog, Novorapid) 50 units in 50ml Normal saline Run at 0.1ml/kg/hour – only dose proven in literature to be effective at switching off ketosis.

Complications of DKA Cerebral oedema Other complication Gastric stasis Pancreatitis Complications of treatment Hypoglycaemia Hypokalaemia

Cerebral Oedema Typically occurs 4 -12 hrs after starting treatment Risk 7 / 1000 episodes of DKA 12 / 1000 episodes of DKA in new IDDM 24% morbidity 35% left with significant morbidity

What we do know about cerebral oedema… We don’t seem to be getting any better at preventing it - overall risk stable over last 20 years The sicker you are at presentation the more likely you seem to be to get it Not related to type of fluid HAS vs 0.9% saline Not always related to treatment Some develop it prior to reaching hospital

Why does it happen? No one really knows! Numerous mechanisms proposed Cerebral hypoxia Drop in plasma osmolality Generation of inflammatory mediators Disruption of cell membrane ion transport Aquaporin channels Generation of intracellular organic osmolytes causing influx water into brain cells

Risk factors for cerebral oedema Younger child at highest risk Newly diagnosed Diabetes Lower pH at presentation High urea Administration of insulin within 1st hour (OR 4.7) Administration of bicarbonate Administration of large volumes of fluid in the 1st 4 hours of treatment Edge 2005

Cerebral oedema Symptoms Signs Headache Drowsiness Incontinence Vomiting recurrence Signs Decreased LOC Bradycardia Rising BP Decreasing O2 sats Neurological signs Abnormal pupil responses Abnormal posturing

Treatment of cerebral oedema Mannitol 0.5g to 1.5g / kg (= 2.5 to 7.5ml / kg 20% Mannitol) over 30mins 3% saline

Case history… 24 hours later Hannah is feeling much better. What are the different SC treatments regimens available to Hannah and what are their pros & cons? How are you going to change her from IV to SC insulin?

Treatment options – Type 1 Insulin sub cut injection Fast acting Insulin mixes Long acting Pump (CSII) ? Inhaled insulin ? Stem cell transplant

Fast acting insulin Soluble insulin Insulin analogues Actrapid Onset of action 30 mins Peak 1-2 hours Lasts around 6 to 8 hours Insulin analogues Humalog, novorapid Onset of action within 15 minutes peak 30-70 mins Last around 2 to 5 hours

Insulin mixtures Until recently most commonly used insulin in children Convenient Mixtard 30 or M3– 30% fast, 70% intermed Mixtard 20 or M2 – 20% fast, 80% intermed Humalog 25 – 25% fast 75% intermed Etc.

Long acting insulin Isophane insulin (intermediate) Insulin analogue Insulatard, Humulin I onset of action 2 hours Peak 4 to 6 hours lasts 12 hours Insulin analogue Glargine (Lantus) – lasts 24 hours Detemir (Levemir) – lasts around 20 hrs

Glargine vs Detemir Glargine Detemir Once daily Lasts 24hrs Acidic injection which stings 5-10% Poor pen device Detemir Once / twice daily Lasts 20-24 hrs Evidence of reductn in nocturnal hypos Good pen

Insulin regimes – BD insulin mixes 12MN 8am 12MD 5pm 10pm 12MN inject inject

Insulin regimes – BD insulin mixes Advantages Convenient Well understood Lots of pens / mixes available Only 2 injections a day Disadvantages Lack of flexibility Have to be up & injected by 9am at latest Have to have 3 snacks a day & 3 meals a day

Insulin regimes – Basal Bolus with Glargine (Lantus) 12MN Breakfast lunch tea bed

Insulin regimes – Basal Bolus Advantages Much more flexibility Can alter doses according to size of meal Less need to have between meal snacks If child unwell & not eating can omit doses of fast insulin Disadvantages 4 injections a day Need injection at school Easier to manipulate insulin Need to have clear understanding of diabetes

Insulin pumps

Theory of Insulin Pump Therapy Low rate insulin pumped in 24 hr/day Background rate can be pre-programmed to change at different times during the 24 hours Extra insulin bolus given when anything is eaten

Is a insulin pump better than multiple injections of insulin? Control of sugars - Generally better on an insulin pump Incidence of severe hypoglycaemia (low sugars) - Much lower on an insulin pump Up to 50% reduction in severe hypos compared to having multiple injections of insulin (Bolland et al Diabetes Care 1999) Weight - No increase in weight on an insulin pump Quality of life - Increased flexibility in lifestyle

Advantages of CSII More flexible lifestyle & eating pattern Delivers insulin in more physiological way Can improve diabetes control Lessens the risk of hypoglycaemia Multiple injections a day replaced by insertion of cannula every 2 to 4 days Positive effects on quality of life

Disadvantages of CSII It is an intensive therapy and this can = hard work Pump is intelligent but still needs to be told what to do Not everyone wants to visible sign of their diabetes Concerns about wearing a pump during sport & sex Risk of skin infection at the cannula site Expensive (pump cost £2400 + ~£1500/yr consumables)

Are pumps safe? Modern pumps much more reliable Lots of alarms, safety checks & warning systems Can be programmed to have a maximum amount of insulin they’ll deliver in one go Pump can be locked Line blockages can cause problems

Are pumps safe? Risk of diabetic ketoacidosis (insufficient insulin leading to high sugars, ketones and acid in the blood) Higher in some clinical trials No deposits of long acting insulin under the skin Switching off insulin supply from the pump can lead to trouble within 1 or 2 hours Risk decreases with increased experience using the pump Need to measure sugars at least 3 or 4 times / day

Who is eligible for an insulin pump? N.I.C.E. 2004 Type 1 diabetes on multiple daily injections of insulin including Glargine or similar AND HbA1c above 7.5% Recurrent unpredictable hypoglycaemia (low blood sugars) or hypoglycaemia unawareness or night time hypoglycaemia Patient willing and able to use therapy safely & effectively

The future CSII…

Changing from IV to SC insulin Ensure the child is tolerating oral intake Give SC insulin prior to stopping IV insulin If starting a basal bolus regimen try to ensure the basal insulin (glargine / detemir) is given the night before stopping the IV

What other education will Hannah’s family need prior to discharge? Able to do injections & blood glucose monitoring Basic dietary advice Hypoglycaemia management Ketone monitoring if sugar levels high

Hypoglycaemia symptoms & signs hunger coma pins & needles anxiety abdominal pain headache palpitations weakness nausea & vomiting tremor blurred vision fainting dizziness abnormal confusion convulsions cry irritability apnoea hypotonia

Hypoglycaemia management Conscious 10g fast carbohydrate followed by starchy snack Conscious but unco-operative Glucogel followed by starchy snack Unconscious Glucagon then starchy snack if possible & hospital

Any questions