Diabetic ketoacidosis in children : diagnosis and management

DKA is most frequent in children less than 5 years old and becomes less common with increasing age. In a carefully analyzed cohort of paediatric patients who had new onset diabetes mellitus (DM) with DKA, 23% of the children presented with DKA. Thirty six percent of children below 5 years of age presented with DKA as the initial diagnosis compared to 16% of children older than 14 years of age. In children with established DM, the risk of DKA is 1-10% patients per year 3 .

Definition 2 The biochemical criteria for diagnosis of DKA are: • Hyperglycaemia ( blood glucose >11mmol/L or >200mg/dL ) • Venous pH <7.3 or bicarbonate < 15mmol/L • Ketonaemia and ketonuria DKA is most frequent in children less than 5 years old and becomes less common with increasing age.In a carefully analyzed cohort of paediatric patients who had new onset diabetes mellitus (DM) with DKA, 23% of the children presented with DKA.Thirty six percent of children below 5 years of age presented with DKA as the initial diagnosis compared to 16% of children older than 14 years of age.In children with established DM, the risk of DKA is 1-10% patients per year 3 .
Although DKA is commonly associated with Type 1 DM (TIDM), there has been an increased incidence of DKA reported among patients with type 2 DM (T2DM), associated with increased rate and severity of obesity, in some centres now accounting for as much as one half of newly diagnosed patients in children 4 .
A family history of DM reduces the risk whereas vulnerability increases with poor metabolic control, peripubertal girls and those with difficult family and social circumstances (social class 3-5 increases risk)._________________________________________ 1

Consultant Paediatrician, Base Hospital, Avissawella
The majority of DKA episodes are thought to be due to insulin omission or treatment error.The other causes include inadequate insulin therapy during intercurrent illness, alcohol, and technical errors, e.g. a malfunctioning pen, leaking cartridge or insulin pump failure 5,6 .

Pathophysiology
DKA results from absolute or relative deficiency of circulating insulin and the combined effects of increased levels of counter regulatory hormones viz.catecholamines, glucagon, cortisol, and growth hormone 7,8 .
Insulin is required for the active movement of glucose into cells as a source of energy.In the absence of insulin, the body goes into a catabolic state with breakdown of glycogen, protein and fat in muscles, liver, and adipose tissue.Counter regulatory hormones stimulate glycogenolysis, gluconeogenesis, proteolysis, lipolysis and ketogenesis in an attempt to provide more fuel to cells.Despite an excess of extracellular glucose, the cells sense a deficiency of fuel for metabolic needs 9 .
An impaired peripheral glucose utilization results in hyperglycaemia and hyperosmolality, increased lipolysis and ketogenesis causing ketonaemia and metabolic acidosis.Hyperglycaemia that exceeds the renal threshold and hyperketonaemia causes osmotic diuresis, dehydration, and obligatory loss of electrolytes, often aggravated by vomiting.These changes stimulate further stress hormone production, inducing more severe insulin resistance and worsening hyperglycaemia and hyperketonaemia 10 .
Ketoacidosis may be aggravated by lactic acidosis secondary to anaerobic glycolysis from poor tissue perfusion or sepsis.Lactic acidosis shifts acetoacetate towards beta-hydroxybutyrate, reducing the body's ability to eliminate ketoacids by the acetone route 9 .The ketone bodies are weak acids that dissociate completely and give rise to a large hydrogen ion load that rapidly exceeds normal buffering capacity.
Kussmaul respiration develops and despite this effort metabolic acidosis ensues 1 .If this cycle is not interrupted with exogenous insulin, fluid and electrolyte therapy, fatal dehydration and metabolic acidosis will ensue.

Clinical presentation and evaluation
The cardinal symptoms of diabetes (thirst, polyuria and weight loss) are often not complained of by patients and families.They are much more likely to complain about vulvo-vaginitis or balanitis, secondary enuresis, vomiting and abdominal pain.It is always helpful to ask about thirst, polyuria and weight loss directly to avoid any delay in diagnosis 11 .
The length of history is very important in determining the severity of DKA, particularly with respect to the symptom of deep breathing, drowsiness, and vomiting.Symptoms that suggest a precipitating cause, such as infections, should also be sought.Examination should focus on signs that help to determine the severity of DKA, and those that suggest a precipitating cause.The typical child who has DKA is about 5-10% dehydrated 12,13 .
Assessment of the degree of dehydration can be difficult with a tendency to overestimate the severity, probably because weight loss precedes dehydration.Most of the time degree of dehydration is estimated based on physical findings which are based on extracellular fluid volume.However, the extracellular fluid volume is maintained by plasma hyperosmolality till the last moment and it is not a very accurate measurement 9 .
DKA is characterized by severe depletion of water and electrolytes from both the intra-and extracellular fluid compartments; the range of losses is shown in Table 1.At presentation the magnitude of specific deficits in an individual patient varies depending on the duration and severity of illness, the extent to which the patient was able to maintain intake of fluids and electrolytes and content of food and fluids consumed before seeking medical attention 14 .
Early Kussmaul breathing can be easily missed as it is the depth rather than the rate of breathing that is striking.The level of consciousness needs to be assessed by using the Glasgow Coma Score (Table 2) and fundi need to be examined.The patients have to be screened for possible sepsis as a precipitating cause, both clinically and with the help of laboratory investigations.Fever is an unreliable indicator of infection as it is commonly absent in DKA.Its presence, however, is indicative of infection.Overall, it is wise to have a low threshold to treat very sick patients with antibiotics 1 .

Table 2 Glasgow Coma Scale
It is also very important to weigh patients if possible, even if they are very sick.This allows accurate calculations for fluid and insulin administration.
The severity of DKA is categorized by the degree of acidosis 15 .
• Mild : venous pH< 7.3 or bicarbonate <15mmol/L • Moderate: pH <7.2,bicarbonate <10 mmol/ L • Severe : pH <7.1, bicarbonate <5 mmol/L It is also important to recognize that overlap between the characteristic features of hyperglycaemic hyperosmolar state (HHS) and DKA may occur.Some patients with HHS, when there is severe dehydration, have mild to moderate acidosis, conversely some children with type I DM may have features of HHS if high carbohydrate containing beverages have been used prior to diagnosis 16 .
The criteria for HHS 16 are: Management of DKA (Figure 1) 17   Breathing: Give 100% oxygen via face mask.This should be given to all and should be continued during the first hour of management, even if oxygen saturation is 100% in air.This is important because patients with DKA suffer intracellular phosphate depletion and changes in serum phosphate.This may result in reduced levels of 2, 3-DPG in red cells.This results in a shift of the oxygen-haemoglobin dissociation curve to the left, causing reduced oxygen availability to the tissues 1,18 .
Circulation: Monitor BP, pulse volume and rate, skin turgor, capillary refill.Insert at least two IV cannulae and take blood samples for blood glucose, serum electrolytes, blood urea nitrogen, calcium, magnesium, phosphorus, blood gas, lactate, white cell count (leukocytosis is a feature of DKA and not always suggestive of an infection), haematocrit, Hb%, HbA1C, blood ketones (if available more superior) 19 and urinary ketones, serum osmolality.These should be repeated two hourly for the first 12 hours.
In addition, the following should be done.

Conscious level
An hourly neurological observation including Glasgow Coma Score (Table 2) should be monitored for early recognition of cerebral oedema as this can cause death.

Fluid calculation (Table 1)
No treatment strategy can be definitively recommended as being superior to others based on evidence.The principles described below were developed after a comprehensive review of the literature and were accepted by Lawson Wilkins Paediatric Endocrine Society, (LWPES) the European Society for Paediatric Endocrinology (ESPE) and ISPAD 2,22 .There are no data to support the use of colloid in preference to crystalloid in the treatment of DKA.
100 ml/kg for first 10kg 50 ml/kg for second 10kg 20ml/kg for subsequent kilograms Deficit (litres) = % of dehydration x body weight in kg Add calculated maintenance (for 48 hours) and estimated deficit, subtract the amount already given as resuscitation fluid, and give the total volume evenly over 48 hours 1,17,26 .

Type of fluid
Initially use 0.9% saline with 20 mmol KCL in 500ml, and continue this for at least 12 hours until blood glucose falls to 12mmol/l, then if plasma sodium level is stable change to 500ml bags of 0.45% saline /5%glucose/20mmol KCL.If the plasma corrected sodium level falls during treatment, then continue with normal saline with or without added dextrose depending on blood sugar level 17 .
Corrected sodium = measured Na + (2 x (blood glucose-5.5)/5.5) Serum sodium usually rises as the blood glucose falls and this may be associated with increased risk of cerebral oedema.Theoretically serum sodium should rise by 2mmol for every 5.5 mmol fall in blood glucose 10 .
During initial fluid resuscitation if plasma glucose concentration falls steeply >5mmol/L/h, consider adding glucose even before plasma glucose has decreased to 12mmol/L 27 .In addition to clinical assessment of dehydration calculation of osmolality may be valuable to guide fluid and electrolyte therapy.

Insulin therapy
Once dehydration fluids and potassium are running, blood glucose levels will start to fall.Therefore do not start insulin until intravenous fluids have been running for at least an hour.There is now evidence that too early insulin treatment has been found to be a risk factor for the development of cerebral oedema 28 .However, insulin therapy is essential thereafter to correct hyperglycaemia, inhibit lypolysis, ketogenesis, and glycogenolysis and to counteract the excessive levels of stress hormones 29 .
Continuous low dose intravenous infusion is the preferred method.Because insulin is adsorbed to the plastic IV tubing, a volume (about 50ml) of infusion should be run through the tubing before initiating therapy.There is no need for an initial bolus.Make up a solution of 1 unit per ml, of human soluble by adding 50 unit (0.5ml) insulin to 50ml of 0.9% saline in a syringe pump.Do not add insulin directly to the fluid bag.The solution should then run at 0.1unit/kg/hour.There are some who believe that 0.05unit/kg/hour is an adequate dose.There is no firm evidence to support this .The aim of treatment is to achieve a gradual fall in blood glucose, which does not exceed 5mmol/l/h.If blood glucose falls too rapidly insulin dose can be reduced to 0.05U/kg/h 17 .
Once blood glucose reaches 12mmol/l, the intravenous fluids should be changed to 0.45% saline and 5% dextrose.It is very important that insulin is not stopped and the dose is not reduced below 0.05U/kg/h because only insulin can switch off ketone production.Some suggest also adding glucose if the initial rate of fall of blood glucose is greater than 5-8 mmol/l per hour, to protect against cerebral oedema.There is no good evidence for this practice, and blood glucose levels will often fall quickly purely because of rehydration 17 .If blood glucose falls below 4mmol, give a bolus of 2 ml/kg of 10% dextrose and increase the glucose concentration of the infusion.If needed, solution of 10% glucose wit 0.45% saline can be made up by adding 50ml of 50% glucose to a 500ml bag of 0.45% saline /5% glucose with 20mmol KCL.
If biochemical parameters of DKA (pH, anion gap) do not improve, reassess the patient, review insulin therapy, and consider other possible causes of impaired response to insulin; e.g.
• Insufficient insulin to switch off ketones.
In circumstances where continuous IV administration is not possible, hourly or two hourly SC or IM administration of short or rapid acting insulin analog (insulin lispro or insulin aspart) is safe and may be as effective as IV regular insulin infusion [30][31][32][33][34][35] but should not be used in subject whose peripheral circulation is impaired.Initial dose SC: 0.3unit/kg, followed one hour later by SC insulin lispro or aspart at 0.1 unit/kg/h or 0.15-0.2units/kg every two hours.

Potassium replacement
Total body potassium is always substantially depleted in DKA, and the major loss is from the intracellular pool as a result of hypertonicity, insulin deficiency and exchange for hydrogen ions with in the cell.Intravenous fluids and insulin administration will drive potassium back into the cells resulting in a rapid fall in serum potassium.Therefore potassium replacement should be started as soon as resuscitation is completed provided anuria is not reported by the family and the ECG does not show elevated T waves.Ensure that every 500ml bag of fluid contains 20mmol KCL and check BUN and electrolytes 2 hourly after initial resuscitation 1 .

Bicarbonate
There is no evidence that bicarbonate treatment is either necessary or safe in DKA and it should not be used in the initial resuscitation.Bicarbonate should only be considered in children who are profoundly acidotic (pH 6.9) and shocked with circulatory failure due to decrease cardiac contractility and peripheral vasodilatation resulting in further impairment of tissue perfusion.Dose if decided to treat is 1-2mmol/kg over 60 minutes 17,36 .

Phosphate
There is no evidence in adults or children that phosphate replacement has any benefit.Phosphate administration may lead to hypocalcaemia 17,37 .

Introduction of oral fluids and regular SC insulin
Oral fluids should only be introduced when substantial clinical improvement has occurred and change over to subcutaneous insulin once blood ketone levels are below 1.0 mmol/l, although urinary ketones may not have disappeared completely.
The most convenient time to change to subcutaneous insulin is just before a mealtime.To prevent hyperglycaemia the first SC injection should be given 60 minutes before discontinuing the insulin infusion if using soluble or long acting insulin or 10-15 minutes before with rapid acting insulin.(Novorapidor Humalog ) 20,38 .

Thrice daily administration
Before breakfast: two third of TDD (1/3 as rapidly acting insulin; 2/3 as intermediate acting insulin) Before lunch: One third to one half of the remainder of the TDD as rapid acting insulin.Before dinner: One half to two thirds of the remainder of the TDD as intermediate-acting insulin.
Blood sugar should be monitored two hourly to prevent hypoglycaemia or hyperglycaemia.Supplemental rapid acting insulin is given at four hourly intervals to correct blood glucose levels that exceed 200mg/dl 9 .
Or Subcutaneous insulin should be started according to local protocols for newly diagnosed diabetes or child should be started back on to their usual insulin regimen at an appropriate time 17 .

Complications
Cerebral oedema, hypoglycaemia, hypokalaemia, infections and aspiration pneumonia are the main complications.

Cerebral oedema
The signs and symptoms are: • Headache and slowing of heart rate and rising blood pressure -late sign Management 17,39,40 Inform senior staff immediately and arrange transfer to PICU.
4. Intubation and ventilation may be required whilst awaiting transfer to PICU. 5. Repeat dose of mannitol may be required after 2 hours if no response.6. Documentation of all events in medical records is important.
Continuing abdominal pain is common and may be due to liver swelling, gastritis, bladder retention, ileus.A raised serum amylase is common in DKA 41 .

Prevention
Increasing public awareness of the symptoms and signs of diabetes is the most important way to achieve early diagnosis.Patients with established diabetes and their families need clear guidelines for management of illness and high blood glucose.

Figure 1 :
Figure1: Algorithm for the management of DKA17

Table 1 10 Losses of fluids and electrolytes in DKA and maintenance requirements in normal children Fluid/Electrolyte Average (range) losses per kg 24-hour maintenance requirements
Sodium and potassium concentrations are expressed in mEq/L and glucose and BUN are expressed in mg/dl.In a typical child who has DKA, glucose is elevated just above 400 mg/dl, and the BUN is elevated by about 15mg/dl 9 . 17 Perform clinical evaluation to confirm diagnosis.Always consult with a more senior doctor on call as soon as you suspect DKA even if you feel confident of your management.Remember that children can die from DKA. Secure airway.If the child is comatose insert an airway.If consciousness is reduced or child has recurrent vomiting, insert nasogastric (NG) tube, aspirate and leave on open drainage.