Staff at the Nottingham Children s Hospital. Guidelines process; paediatric endocrinology team

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1 Hypoglycaemia Title of Guideline Contact Name and Job Title (author) Hypoglycaemia in infants and children: aetiology, investigation and treatment Dr. Hoong-Wei Gan ST6 Paediatric Endocrinology & Diabetes Dr. Louise Denvir Consultant in Paediatric Endocrinology & Diabetes Directorate & Speciality Directorate: Family Health Children Speciality: ** Endocrinology: Date of submission of this one May 2018 Date when guideline reviewed May 2023 Guideline Number 1937 Explicit definition of patient group to which it applies (e.g. inclusion and exclusion criteria, diagnosis) Children and young people presenting with hypoglycaemia Key Words Paediatrics. Children. Hypoglycaemia Statement of the evidence base of the guideline has the guideline been peer reviewed by colleagues? 1a meta analysis of randomised controlled Put a cross (X) in the highest level of evidence. trials 2a at least one well-designed controlled study without randomisation 2b at least one other type of well-designed quasi-experimental study 3 well designed non-experimental descriptive studies (ie comparative / correlation and case studies) 4 expert committee reports or opinions and / or clinical experiences of respected authorities 5 recommended best practise based on the x clinical experience of the guideline developer Consultation Process Staff at Nottingham Children s Hospital via the Guidelines process; paediatric endocrinology team Target audience Staff at the Nottingham Children s Hospital This guideline has been registered with the trust. However, clinical guidelines are guidelines only. The interpretation and application of clinical guidelines will remain the responsibility of the individual clinician. If in doubt contact a senior colleague or expert. Caution is advised when using guidelines after the review date. Hypoglycaemia (H-W Gan, L Denvir) Page 1 of 13 May 2018

2 Document Control Version Issue Date Author V1 November 2014 V2 May 2017 Dr Zainaba Mohamed GRID Trainee in Endocrinology Dr Josephine Drew Associate Specialist Paediatrician V3 January 2018 Dr. Hoong-Wei Gan ST6 Paediatric Endocrinology & Diabetes Dr. Louise Denvir Consultant in Paediatric Endocrinology & Diabetes Summary of changes for new version: Clarification of definition of hypoglycaemia Clarification of definition of idiopathic ketotic hypoglycaemia Timing of investigations at presentation and discharge and update of sample requirements Responsibilities regarding blood glucose monitor training Statement of Compliance with Child Health Guidelines SOP This guideline has had only minor changes made and therefore this version has not been circulated to all for review. A previous version had been approved by circulation to senior team members. Maria Moran Clinical Guidelines Lead 16 May 2018 Hypoglycaemia (H-W Gan, L Denvir) Page 2 of 13 May 2018

3 Hypoglycaemia in infants and children: Aetiology, investigation and treatment Scope of Guideline This guideline is intended for term infants and children presenting to Nottingham Children s Hospital who do not have a diagnosis of diabetes or other established metabolic disorder. It must be noted that it is not normal to have persistent, severe or recurrent hypoglycaemia even in term infants in the perinatal period and early discussion with the endocrine team in all cases is advised. Definition Hypoglycaemia refers to the inadequacy of circulating levels of blood glucose and is defined as a laboratory blood glucose measurement of < 2.6 mmol/l 1-3. Note that this is different to the treatment threshold for hypoglycaemia in patients with a known diagnosis of diabetes or hyperinsulinism, where a bedside blood glucose of <4 mmol/l requires further action, Hypoglycaemia may be associated with clinical symptoms or be asymptomatic. Severe hypoglycaemia is defined as a documented hypoglycaemic episode resulting in collapse, coma or seizures, and/ or requiring someone else s assistance for treatment (e.g. with IV dextrose or IM glucagon). Background Hypoglycaemia in children beyond the neonatal period is relatively common. The majority of these will be in patients with known diabetes (see separate guideline). In children without diabetes, there is a wide range of causes. Prolonged or recurrent hypoglycaemia, especially when associated with symptoms and clinical signs can cause long term neurological damage or death. Thus, prompt recognition and treatment are essential. Hypoglycaemia (H-W Gan, L Denvir) Page 3 of 13 May 2018

4 Assessment The following are typical symptoms and signs of hypoglycaemia but please be aware that this list is not exhaustive and a blood glucose should be checked in any child who is unwell. Young Infant Pallor Sweating Jitteriness Tachypnoea Apnoea Hypotonia Feeding difficulties Irritability Abnormal cry Convulsions Older Infant Anxiety,tremor, Palpitations, weakness Nausea, vomiting Hunger, abdominal pain, headache Visual disturbance, seizures Confusion, coma The following are some of the important features to elicit from the history and examination. History Age Feeding history Birth history and weight Neonatal jaundice &/or hypoglycaemia Tolerance to fasting / illness Drug ingestion Family history and parental consanguinity Examination signs Features of sepsis, hepatomegaly, encephalopathy Optic atrophy, cataracts, nystagmus, failure to fix and follow Cleft palate and other midline craniofacial abnormalities Appearance of external genitalia Skin pigmentation (gums, scars, skin creases) The following table lists causes of hypoglycaemia presenting usually outside the immediate postnatal period. Endocrine Hyperinsulinism Adrenal insufficiency Hypopituitarism Growth hormone deficiency Hypothyroidism (very rarely) Metabolic Disorders of organic acid metabolism Disorders of gluconeogenesis Disorders of carbohydrate metabolism Disorders of fatty acid oxidation and carnitine transport Glycogen storage disorders Hypoglycaemia (H-W Gan, L Denvir) Page 4 of 13 May 2018

5 Other Causes Idiopathic ketotic hypoglycaemia (The most common cause for hypoglycaemia in children after the neonatal period is idiopathic ketotic hypoglycaemia. This is usually precipitated by a relatively mild illness. Biochemically it presents with a low or undetectable insulin/ C-peptide, and raised ketone bodies (beta-hydroxybutyrate) and free fatty acids indicating appropriate mobilisation of ketones) Drug Related: insulin, alcohol, aspirin, chemotherapy, sulphonylurea Liver failure Multi-organ failure Sepsis Gastroenteritis Fabricated/Induced Illness Investigations The best time to investigate hypoglycaemia is during the hypoglycaemic episode itself, prior to treatment. This potentially avoids the need for a re-admission for a prolonged diagnostic fast. Therefore, unless there is already an established cause, always aim to obtain blood and urine samples PRIOR to correcting the hypoglycaemic episode. In the event of samples not being obtainable (e.g. if patient is admitted after being treated in the community), blood and urine ketones may still be useful if taken immediately afterwards. If no suitable samples have been obtained, then the decision to proceed with further investigations will require discussion with the endocrine team. Generally, the more severe the episode(s), the greater the necessity for definitive investigations as opposed to community blood glucose monitoring. Hypoglycaemia (H-W Gan, L Denvir) Page 5 of 13 May 2018

6 The following table is a guide to help collect samples correctly for a hypoglycaemia screen 3. Be aware that bedside measures of blood glucose are not accurate at the lower range, therefore a lab sample must be sent to confirm glucose. Specimen Test Bottle Time taken for result Urine (total volume required 20ml for laboratory tests) Glucose Urine Dipstick Ketones Immediate Reducing substances Laboratory tests Ketones Reducing substances Amino acids & organic acids* Toxicology screen (If factitious illness/accidental ingestion suspected) Blood (total volume required 6ml) Glucose* Bedside Ketones* testing White cap sterile universal container N/A 24 hours 24 hours 24 hours 1-2hours Immediate result Glucose* Flu Ox 24 hours Free fatty acids* Flu Ox 4 days Ketone Bodies (Beta hydroxybutyrate)* Flu Ox 7 days Lactate Flu Ox 24 hours Cortisol* Li Hep 24 hours Insulin*& C-peptide* Serum 7 days Carnitine Li Hep 7 days Laboratory Ammonia tests (Must get to lab within 20 Li Hep 1 hour minutes of taking sample) Growth hormone Li Hep 7 days Amino acids Li Hep 7 days U&E Li Hep 1-2 hours LFT Li Hep 1-2 hours Alcohol Salicylates Li Hep Li Hep 1-2 hours ( Indicated only in children > 2 yrs or accidental ingestion/factitious illness suspected 1-2 hours () Indicated only in children > 2 yrs or accidental ingestion/factitious illness Blood Gas Capillary blood gas Immediate suspected) Microbiology Blood Culture hours *These tests must be taken at the time of hypoglycaemia 3 *Collect first urine passed immediately following hypoglycaemia (urine bag can be put on at the time of hypoglycaemia). Hypoglycaemia (H-W Gan, L Denvir) Page 6 of 13 May 2018

7 Number and type of bottles required for hypoglycaemia blood tests Remember: Minimum blood volume needed = 5 ml (2ml Li Hep green top and 2ml Flu Ox grey top bottles Maximum blood volume required = 8 ml (Bottles as below) 1 x 6 ml lithium heparin bottle, green top 1 x 0.6 ml serum bottle, yellow top 2 x 0.6 ml Flu Ox grey top bottle OR 5 x 0.6 ml lithium heparin bottle, green top. 1 x 0.6 ml serum bottle, yellow top 2 x 0.6 ml Flu Ox grey top bottle Hypoglycaemia (H-W Gan, L Denvir) Page 7 of 13 May 2018

8 5-15g Glucojuice** **Give 5-15g of Glucojuice for oral treatment of hypoglycaemia for age > 1 year (15g/60ml) < 4 years 20ml 4-12 years 40ml 13 years and over 60ml *Refer to appendix table 1 Discussion of all cases presenting with hypoglycaemia with paediatric Endocrinologist before discharge is advised. Hypoglycaemia (H-W Gan, L Denvir) Page 8 of 13 May 2018

9 Hypoglycaemia results log (Print and place in patient notes) Specimen Test Result Interpretation Urine Urine Dipstick/ Laboratory results Blood Glucose Ketones Reducing substances Amino acids and organic acids Toxicology screen Glucose Bedside Lab Low/absent in Fatty acid oxidation defect Hyperinsulinaemia Galactosaemia/ Fructosaemia Deranged in Urea cycle defect <2.6mmol/l - Hypoglycaemia Time taken for results Immediate/1 hour 24 hours 1-2hours Immediate/1hr Ketone Bodies (Beta hydroxybutyrate) Lactate Free fatty acids Bedside Lab Low/absent in Fatty acid oxidation defect Hyperinsulinism >1 suspect ketotic hypoglycaemia Raised in Metabolic liver disease Prolonged convulsion Glycogen storage disorders,sepsis Fatty acid oxidation defect if low Ketotic hypoglycaemia if raised Immediate/1hr 24 hours 3 days Bedside/ Laboratory results Carnitine/ Acylcarnitine e Ammonia Cortisol Insulin & C-peptide Growth hormone Guthrie Lab Fatty acid oxidation defect Raised in Organic acidaemias Tyrosinaemia Liver dysfunction Hyperinsulinism - Hyperammonaemia Syndrome Low levels Hypoadrenalism ACTH deficiency/hypopituitarism Abnormal if present even at normal laboratory levels in hypoglycaemia ie BG <2.6. If insulin raised but C- peptide low, consider exogenous insulin administration Low level- GH deficiency Pan hypopituitarism Isolated GH deficiency New-born Screening Centre hour 2 days 7 days 7 days Amino acids Deranged in aminoaciduria. 7 days U&E Low Na, high K Addison s disease 1-2 hours LFT Poisoning Deranged in Sepsis Liver disease Metabolic defects Alcohol, salicylates 1-2 hours 1-2 hours Other drugs eg sulphonylureas 1-2 weeks Hypoglycaemia (H-W Gan, L Denvir) Page 9 of 13 May 2018

10 Blood Gas Capillary blood gas Metabolic acidosis FAOD (MCAD,LCAD) Defects in ketogenesis Sepsis Glycogen storage disorders Organic acid disorders Immediate Microbiology Blood Culture Sepsis hours Prior to discharge please ensure the following have been completed: 1. It is advisable that the Consultant Paediatrician responsible for the child discuss the case with a paediatric endocrinologist before discharge, especially if a cause for the hypoglycaemia is still not known prior to discharge, or if not all results are back. 2. A reasonable time between feeds/meals (at least 4 hours) must be safely tolerated without blood glucose dropping below 3 mmol/l if ketones present, 4 mmol/l if ketones not present. A controlled fast may be required but if this is planned, the paediatric endocrinology team would like to be consulted about the patient by their own named paediatrician. The controlled fast should be performed pre-discharge if planned. 3. Ensure dietetic input to agree a written management plan for the parents to take home (see sample attached). 4. Check the family know how to treat hypoglycaemia with age appropriate treatment (*Refer to the appendix table 1). A template hypoglycaemia plan for families to follow is at the end of this guideline. NB GLUCOJUICE IS FOR IN-HOSPITAL USE ONLY AND IS NOT PRESCRIBED FOR DISCHARGE 5. Obtain blood glucose monitor (from the diabetic nurses cupboard Children s Assessment Unit or D33) and ensure the family have been trained in how to use it. The responsibility for training the family lies with the primary medical and nursing team as blood glucose monitoring is performed throughout the hospital. Blood glucose should be measured whenever the child is felt to be symptomatic and as a minimum once a day prior to food immediately post discharge for hours or until all results are back. If confirmed ketotic hypoglycaemia the advice would be to test only if symptomatic or unwell. 7. Prescribe any necessary medications, glucose strips and thin lancets needed to operate the blood glucose monitor 8. Provide a written discharge summary for the GP including the information about treatments and the blood glucose monitor supplies that will need to be provided on a repeat prescription by the GP. 9. Arrange an outpatient follow-up with the general paediatric team for ketotic hypoglycaemia and or other specialist teams dependent on the cause of the hypoglycaemia (discuss this with the appropriate specialist team first). Hypoglycaemia (H-W Gan, L Denvir) Page 10 of 13 May 2018

11 Summary 1. Hypoglycaemia is a common finding in paediatrics and should be investigated and treated promptly. 2. All unwell children should have a blood glucose level checked. 3. Children with a blood glucose reading <2.6mmol/l should be treated according to the above flow chart with appropriate investigationsideally performed prior to treatment.. 4. Care needs to be taken to monitor serum electrolyte levels as well as the glucose regularly. 5. Children with a reduced level of consciousness should not be given oral treatment or feeds. All children should be observed until they have achieved a period of stable normoglycaemia on their usual feed regime and are able to sustain a minimum length of fast (length dependant on age of child). 7. A cause for the hypoglycaemia MUST be known prior to dischargeand an appropriate post discharge plan MUST be in place. If unsure please discuss with the paediatric endocrine team before discharge. References 1. Anoki et al.j Trop Pediatr August ; 56(4): Lang et al. Ann Clin Biochem 2011; 48: National Metabolic Biochemistry Network Guidelines for the investigation of hypoglycaemia in infants and children. January pdf 4. Advanced Paediatric Life Support: The Practical Approach, 5th Edition. BMJ Books - Publisher: John Wiley & Sons (Wiley-Blackwell). ISBN: Corporate Author: Advanced Life Support Group. 5. Verrotti A, Fusilli P, Pallotta R, et al. Hypoglycemia in childhood: a clinical approach. J Pediatr Endocrinol Metab 1998; 11 Suppl 1:147 Hypoglycaemia (H-W Gan, L Denvir) Page 11 of 13 May 2018

12 Management Plan for Home management of low Blood Glucose Levels (BGL): This Management Plan is for : Low Blood Glucose levels Less than mmol/l Ideal Blood Glucose levels Usual symptoms are : Treatment to be given if Blood Glucose reading is low Recheck Blood glucose after If Blood Glucose still low If Blood Glucose level now normal What to do when unwell If your child is unconscious, fitting or not responded to above treatment, call 999 and ask for an ambulance. Hypoglycaemia (H-W Gan, L Denvir) Page 12 of 13 May 2018

13 Appendix 1 Table 1: Oral treatment options for hypoglycaemia in children. Hypoglycaemia treatment has changed recently in NUH From the 15 th May 2017 NUH have changed to using GlucoJuice as first line treatment for patients with hypoglycaemia who are co-operative and able to swallow. Lucozade should no longer be used due to the reduced sugar content. Dosing alterations are based on the current ISPAD recommendations. Alternative treatment options are included in the table below Age Carbohydrate GlucoJuice 15g/60ml bottle Under 4yrs Dextrose Tablets 3.3g per tablet Gluco Tabs 3.6g per tablet *Fruit Juice 10g/100ml 5g 20ml ml 4-12 years 10g 40ml ml 13 years and over 15g 60ml ml *Fruit juice does not work as quickly as the other sugar options at treating a hypo. Fruit juices will vary across manufacturers* 2. Calculation of glucose requirement Glucose Requirement Calculator & Maintenance Fluid Preparation Glucose rate/requirement(mg/kg/min) = % glucose solution x ml/hr Weight x 6 Final dextrose Add concentration required 10% glucose/0.9% sodium 50ml of 50% glucose to a 500ml bag of chloride glucose 5%/0.9% sodium chloride 12.5% glucose/0.9% sodium chloride 15% glucose CENTRAL ACCESS REQ 20% glucose CENTRAL ACCESS REQ 75ml of 50% glucose to a 500ml bag of glucose 5%/0.9% sodium chloride Available from Pharmacy. Does not contain sodium chloride (monitor U&Es closely) Available from Pharmacy. Does not contain sodium chloride (monitor U&Es closely) Hypoglycaemia (H-W Gan, L Denvir) Page 13 of 13 May 2018