Diagnosis and treatment of diabetic ketoacidosis in children and adolescents

Abstract

Diabetic ketoacidosis (DKA) continues to be a common presentation of both type 1 and type 2 diabetes in children and adolescents. Early recognition and treatment in patients with new-onset diabetes are essential to the prevention of this potentially life-threatening complication of diabetes. DKA management protocols for paediatric patients differ from adult protocols, and therefore, it is important to have clear written guidelines and that in-patient care occur in centres with experience in the management of paediatric DKA. The present article outlines recommendations regarding the diagnosis and management of DKA. It also discusses management guidelines for intercurrent illness, with a view to reducing the frequency of DKA in children and adolescents with established diabetes.

The diagnostic criteria for type 1 diabetes mellitus (T1DM) have been detailed elsewhere in “Canadian Diabetes Association 2003 clinical practice guidelines for the prevention and management of diabetes in Canada” (1). It is important to reiterate that a second test on another day is rarely required to make the diagnosis of diabetes in children. In fact, the delay may result in a more severe presentation with diabetic ketoacidosis (DKA). As such, a health care professional trained in the education and management of children and adolescents with diabetes should be contacted as soon as an elevated glucose level is discovered.

The guidelines presented in the present article are derived primarily from two sources. The first is the “European Society for Pediatric Endocrinology/Lawson Wilkins Pediatric Endocrine Society consensus statement on diabetic ketoacidosis in children and adolescents” (2). This was developed by an expert panel who convened in June 2003 to review the current literature on DKA. The second is the “ISPAD [International Society for Pediatric and Adolescent Diabetes] consensus guidelines for the management of type 1 diabetes mellitus in children and adolescents” (3) which provides more specific guidelines for the management of DKA.

DEFINITION OF DKA

The biochemical criteria for DKA include hyperglycemia (blood glucose [BG] higher than 11 mmol/L) with a venous pH of less than 7.3 and/or a bicarbonate (HCO₃) level of less than 15 mmol/L. The severity of DKA can be categorized as mild (pH 7.21 to 7.3, HCO₃ 10 mmol/L to 15 mmol/L), moderate (pH 7.11 to 7.2, HCO₃ 5 mmol/L to 10 mmol/L) or severe (pH of less than 7.1, HCO₃ level of less than 5 mmol/L).

EPIDEMIOLOGY OF DKA

The reported frequencies of DKA at diagnosis of diabetes range widely from 15% to 67% in North America and Europe occurs more commonly in children younger than four years of age, without a first-degree relative with T1DM and from families of a lower socioeconomic class (4,5). In contrast to the adult experience, up to one-third of children and adolescents with type 2 diabetes also present with DKA (6). In established T1DM, the DKA risk is 1% to 10% per patient per year (7–9), with a higher risk in peripubertal and adolescent girls and those with poorer metabolic control or previous DKA, psychiatric disorders and difficult family circumstances. It is estimated that 75% of such episodes are associated with insulin omission or treatment error (10).

Mortality rates from DKA range from 0.15% to 0.31% (11–14) and cerebral edema accounts for 57% to 8P7% of these deaths (15,16). There are many other possible causes of mortality and morbidity, some of the more common ones include hypokalemia, hyperkalemia, hypoglycemia and other central nervous system complications (2).

Cerebral edema

Based on population studies, cerebral edema in DKA (CEDKA) occurs in 0.46% to 0.87% of DKA episodes (12,15,16). This includes 0.46% in a Canadian study (12) performed through the Canadian Paediatric Surveillance Program. Reported mortality rates were 21% to 25%, with significant morbidity in 10% to 26% of survivors (12,15,16). The mechanism of CEDKA is not well understood, with evidence for both osmotic (17) and vasogenic edema (18). It typically occurs 4 h to 12 h after the onset of treatment, but can present before treatment has begun (12,15–19). Several potential risk factors for the development of CEDKA have been identified. These include demographic variables such as new-onset diabetes (12,14,20), younger age (19) and longer duration of symptoms (20). Risk factors on presentation and before the onset of treatment include the severity of acidosis (lower pH) (21) and dehydration (higher serum urea nitrogen) (16), and greater hypocapnia (16). Identified treatment risk factors include HCO₃ treatment (16,22) and failure of the serum sodium to rise during therapy (16,23,24), which could reflect the use of relatively hypotonic intravenous (IV) fluids. There is conflicting evidence regarding associations between CEDKA and the volume or content of IV fluids, or the rate of change in serum glucose (16,25).

Given that many of the risk factors for CEDKA are already there at presentation, the best way to prevent this devastating complication is the prevention of DKA, with early diagnosis and treatment in cases of new-onset T1DM.

MANAGEMENT OF DKA

General

Children with hyperglycemia and ketosis without vomiting or severe dehydration can be managed at home or in an outpatient setting, but the degree of illness needs to be re-evaluated frequently and supervised by an experienced diabetes team. Moderate to severe DKA should be managed in an inpatient setting, using clear written guidelines in centres with experience in the management of DKA and where neurovitals and laboratory results can be monitored frequently (2). Management should be directed by a specialist/consultant paediatrician with training in the management of paediatric DKA.

Monitoring

Hourly vitals, neurovitals and fluid balance are essential. Early warning signs of cerebral edema include headache, recurrent vomiting and a change in neurological status. Rising blood pressure and inappropriate slowing of the heart rate are late signs. The staff monitoring the child should be instructed to alert the physician at the first sign of any of these manifestations. Capillary BG should be monitored hourly. Venous blood work at every 2 h to 4 h should include glucose, blood gas, sodium, potassium and urea (2,3).

Fluids

Fluid administration should begin immediately with an isotonic solution, such as 0.9% normal saline (NS) to correct the fluid deficit over 48 h. The rate should not exceed 1.5 to two times maintenance (2). Protocols vary in their method of calculation, but most are in the range of 4 mL/kg/h to 6 mL/kg/h (3), with up to 10 mL/kg to 20 mL/kg over the first 2 h, depending on the patient’s clinical status and degree of dehydration (2). One example using the ISPAD guidelines is shown in Table 1. Shock with hemodynamic compromise is rare in DKA. Given the potential association of CEDKA with high fluid administration rates, fluid boluses are recommended only in the face of hemodynamic compromise and should be given as a minibolus of NS (10 mL/kg), which should be repeated if clinically indicated.

TABLE 1.

Management guidelines for diabetic ketoacidosis in children and adolescents

Monitoring
Hourly vital signs, assessment of neurological status and fluid balance
Capillary blood glucose every hour
Venous glucose, blood gas, electrolytes and urea every 2 h to 4 h
Initial fluids
Intravenous fluids should begin immediately with 0.9% normal saline (NS)
Rate based on weight
Weight <10 kg	6 mL/kg/h
Weight 10 kg – 20 kg	5 mL/kg/h
Weight >20 kg	4 mL/kg/h (maximum 250 mL/h)
Or calculate the replacement of deficit plus maintenance over 48 h, not in excess of 1.5 to two times the usual daily requirement
In the event of hemodynamic compromise, a fluid minibolus of 10 mL/kg should be administered over approximately 30 min and repeated as necessary
Ongoing fluids
Use solution with tonicity of ≥0.45% NS
Continue 0.9% NS until dextrose added, ie, once glucose is ≤14 mmol/L to 17 mmol/L, then change to 5% dextrose in water/0.45% NS or 10% dextrose in water/0.45% NS, based on glucose requirements
Insulin
Regular insulin 0.1 units/kg/h
Continue until correction of acidosis (pH >7.30; bicarbonate >15 mmol/L)
Compensate for decreasing blood glucose by addition of dextrose intra-venously
Potassium
Starting potassium concentration should be 40 meq/L with ongoing replacement based on potassium levels
Start potassium with the initiation of insulin therapy, or immediately if hypokalemic
If hyperkalemic, defer potassium until urine output is documented
Bicarbonate
Not recommended unless acidosis is profound

Subsequent fluid management should be with a solution higher than 0.45% NS, and this solution should be changed to one with dextrose once the BG falls to 14 mmol/L to 17 mmol/L or below. The most commonly recommended solutions are 5% dextrose in water/0.45% NS or 10% dextrose in water/0.45% NS (3) as needed to maintain glucose in the 10 mmol/L to 15 mmol/L range.

Insulin

Insulin therapy is essential to normalize the BG and suppress ketogenesis, and should be started by the end of the initial fluid resuscitation. Low dose IV insulin is the standard of care, although subcutaneous or intramuscular insulin may be used in cases of mild DKA. The insulin infusion should be prepared as 1 unit/mL in NS and administered using a syringe pump. Alternatively, it may be prepared as 1 unit/10 mL NS and included in the total fluids administered.

A bolus of insulin is not indicated in paediatric patients; instead, a continuous infusion of 0.1 units/kg/h is recommended until the acidosis is corrected (pH higher than 7.30; HCO₃ greater than 15 mmol/L) (2). A decrease in BG before correction of the acidosis should be compensated by the addition of dextrose into the IV drip, not by a reduction in the insulin infusion. The correction of acidemia invariably takes longer than the reduction of blood glucose.

Subcutaneous insulin should be started/resumed once the acidosis is corrected, but if it is several hours before a subcutaneous dose is required (ie, in the middle of the night), the insulin infusion rate may be decreased by approximately 25% at a time to maintain glucose levels in the desired range. The insulin infusion should be discontinued 15 min after subcutaneous injection of insulin analogues, such as insulin Lispro (Humalog, Eli Lilly, Canada) or insulin Aspart (NovoRapid, Novo Nordisk, Canada), and 30 min after a subcutaneous injection of Regular (R) insulin (Eli Lilly, Canada) or Toronto insulin (Novo Nordisk, Canada). Patients with established diabetes will generally resume their usual dose, while those with new-onset diabetes start with 0.3 units/kg/day to 0.6 units/kg/day divided into two doses (two-thirds before breakfast and one-third before supper). Each dose contains two-thirds neutral protamine Hagedorn (NPH) insulin and one-third Aspart/Lispro/Regular insulin (26). The nighttime dose may be split as Aspart/Lispro/Regular insulin before supper and NPH at bedtime.

Potassium

Measured serum potassium levels at presentation may be normal, increased or decreased, but a total body potassium deficit almost certainly exists and must be replaced. The administration of insulin and correction of the acidosis will drive potassium into the cells, decreasing the serum levels. Therefore, potassium supplementation should be started with the initiation of insulin therapy and earlier if the patient is hypokalemic. If the patients is hyperkalemic, defer potassium until the urine output is documented.

HCO₃

Even severe acidosis is reversed by insulin and fluid replacement. HCO₃ is no longer recommended in acute resuscitation protocols. Some studies (15,21) have shown an independent association between the administration of HCO₃ and the development of CEDKA. Some patients may benefit from cautious alkali therapy (2). This should be done only after consultation with a health care professional experienced in the management of DKA in children.

Treatment of cerebral edema

There is evidence to suggest that the outcome of CEDKA can be improved by early and aggressive intervention. The rate of fluid administration should be reduced. Intubation and ventilation may be necessary for airway protection but aggressive hyperventilation should be avoided (27). Mannitol 0.25 g/kg to 1 g/kg IV over 20 min may be given to patients with early signs of CEDKA before respiratory failure (2). Alternatively, hypertonic saline (3%) 5 mL/kg to 10 mL/kg over 30 min may be used (2).

Illness management and DKA prevention in T1DM

As discussed previously, insulin omission and improper management of intercurrent illness are the most common causes of DKA in patients with established diabetes. A multidisciplinary approach, including psychosocial intervention, re-education and adult supervision of insulin injections, may be helpful in the prevention of DKA due to intentional insulin omission. During times of illness, the telephone availability of the health care team is an essential resource for families.

There are many different protocols for the management of intercurrent illness and the following is just one example. If the patient is unable to eat, meals should be replaced with sugar-containing fluids. While many more precise recommendations exist, the volumes shown in Table 2 are easy for families to follow and generally maintain hydration and glucose control when coupled with regular BG monitoring.

TABLE 2.

Meal replacement during intercurrent illness^*

Age	Number of choices/meal†	Approximate rate for fluid choices (choice/h)
0–5 years	3 to 4	1.0
6–12 years	5 to 6	1.5
13 years and older	7 to 8	2.0

^*May be used in the event of anorexia, nausea and/or vomiting;

^†Fluid choices equivalent to 10 g of carbohydrate, ie, 75 mL (1/3 cup) apple juice, 125 mL (1/2 cup) orange juice or regular pop, 200 mL (3/4 cup) sports drink or Pedialyte (Abbott Laboratories, Canada), one-half or one stick of a regular popsicle or six Pedialyte (Abbott Laboratories) popsicles

BG and ketone levels should be monitored every 2 h to 4 h. In general, parents should take over and closely supervise blood sugar testing and injections of insulin. Families should be instructed never to miss a dose of insulin, even if children are not eating. In fact, when the BG is higher than 14 mmol/L, additional fast acting insulin (Regular/Toronto) or insulin analogues (Humalog/NovoRapid) may be needed. Table 3 shows one example of guidelines regarding insulin dosing during illness. The principle is to give an additional 10% to 20% of the total daily dose (TDD) of insulin every 4 h as needed, in addition to the usual dose of insulin, to maintain the BG below 14 mmol/L and to clear ketones. The TDD is calculated by adding the basic dose of NPH and Regular insulin or analogues. For example, if the usual breakfast dose is 12 units of NPH and 6 units Regular, and the supper dose is 8 NPH units and 4 Regular units, the TDD is 30 units.

TABLE 3.

Supplemental insulin dosing during intercurrent illness

Urine ketones	Negative to small (+)	Moderate (++)	Large (+++/++++)
Blood ketones (mmol/L)	≤0.6	0.7 to 1.5	>1.5
Supplemental insulin*†	10% of TDD	15% of TDD	20% of TDD
TDD (units)	Extra insulin (units)	Extra insulin (units)	Extra insulin (units)
5–15	1	1.5	2
16–25	2	3	4
26–35	3	5	6
36–45	4	6	8
46–55	5	7	10
56–65	6	9	12
66–75	7	10	14
76–85	8	12	16

^*Supplemental Regular (Eli Lilly, Canada), Toronto (Novo Nordisk, Canada), Humalog (Eli Lilly, Canada) or Novorapid (Novo Nordisk, Canada) insulin given every 3 h to 4 h as needed for blood glucose (BG) of higher than 14 mmol/L;

^†Given in addition to usual insulin (eg, if the total daily dose [TDD] is 30 units, BG is 17.2 mmol/L with negative ketones before breakfast and the usual morning dose is 12 units neutral protamine Hagedorn (NPH) and six units Regular, one would give 12 NPH units and 6+3=9 units Regular)

CONCLUSIONS

DKA is still a common presentation of both type 1 and type 2 diabetes in children and adolescents. Protocols in paediatric patients differ from many adult protocols in that they tend to use slower fluid infusion rates and no insulin bolus. While complete recovery is usual, DKA carries a significant risk of life-threatening complications including cerebral edema. The key to preventing such events is the prevention of DKA itself through early recognition and treatment of diabetes in those with new-onset diabetes and through support and supervision, as well as proper illness management in those with established diabetes. It is recommended that centres treating children and adolescents with diabetes and DKA have clearly written guidelines for the management of DKA.