Clinical Recognition

The onset of T1D can be insidious because the immune-mediated loss of β-cells is typically slow, occurring over several months to years before hyperglycemia is manifest. The earliest signs of hyperglycemia begin with polyuria, followed shortly by polydipsia. A typical scenario in children is that of a few weeks’ history of increasing fatigue, intermittent polyuria and polydipsia, a recent viral illness and/or travel followed by exacerbation of these symptoms. If not recognized at this stage, hyperglycemia further impairs β-cell function and insulin secretion, which eventually leads to increasing lipolysis to provide free fatty acids as an alternative substrate for energy generation. Oxidation of free fatty acids leads to accumulation of acetoacetic and β-hydroxybutyric acids (ketones). When the level of ketones exceeds the child’s capacity to buffer the acidosis, the blood pH begins to decrease to below 7.3. In addition, the osmotic diuresis caused by the hyperglycemia leads to dehydration and lactic acidosis which further contributes to the acidosis and to increasing insulin resistance, all leading to a vicious cycle and rapid worsening in the hemodynamic status and development of severe DKA. The severity of DKA is divided into mild (pH 7.2-7.3, or bicarbonate <15 mmol/L), moderate (pH 7.1-7.2, or bicarbonate <10 mmol/L), and severe (pH <7.1, or bicarbonate <5 mmol/L). The younger the child the faster the progression towards DKA, and the more severe the acidosis can be, with ensuing classic signs of dehydration, Kussmaul breathing, and potential obtundation and even coma.

Diagnosis

The diagnosis of new onset DKA relies on a high index of suspicion because most children presenting with new onset T1D have no family history of T1D. In addition, infants and toddlers may not have the classical series of symptoms that usually precede presentation with DKA and may present with non-specific symptoms such as increased irritability, difficulty sleeping, or poor feeding. Because the initial hyperglycemia can be exacerbated by a viral illness, these non-specific symptoms can be attributed to the viral illness and not to diabetes. Therefore, a careful review of the history of the illness and the presenting symptoms is essential for making the right diagnosis. Important clues include increased number of daily diapers or parental description of “heavy diapers especially in the morning”, the presence of diaper rash in infants or vaginal yeast infection in older girls, increased frequency of using the bathroom during school, nocturnal enuresis in a child who has already been trained, increased appetite yet continued weight loss, deterioration of performance in sports or school, and the presence of a sweet fruity smell from the child.

Once suspected, new onset T1D is easily confirmed by obtaining a basic metabolic panel which includes glucose and bicarb measurements. A glucose level >200 mg/dl, with symptoms of hyperglycemia confirms the diagnosis of diabetes, while a lower than normal bicarb level suggests the presence of DKA, which can be confirmed by measuring urine or serum ketone levels.

Treatment

Once diagnosed, new onset DKA in children is best managed if possible, in a pediatric specialty center with expertise in treating children with DKA. This is due to the fact that a) fluid replacement in children must be calculated with greater precision based on body weight and surface area, and be provided in a manner that minimizes the risk of rapid shifting in osmolality between intra- and extracellular spaces, which can occur more easily in children because of their relatively immature hemodynamic and cerebral autoregulatory processes. Rapid shifting of fluids can lead to cerebral edema, the most serious complication of DKA especially in younger children presenting with new onset T1D; b) children, especially pre-pubertal children, are far more sensitive to insulin, requiring much smaller doses than what is usually needed in adults; and c) even within the pediatric population, the approach to managing DKA in infants and toddlers is quite different than in older patients. Adolescents in peak puberty present a different challenge because of their often-severe resistance to insulin. For these and other reasons, we strongly recommend that children in DKA get transferred to a center with pediatric intensive care with the ability to provide close monitoring and management according to childhood specific treatment protocols. If initial stabilization of the child is required before transfer, it should be done in consultation with a pediatric intensivist and/or endocrinologist if possible.

The first steps in the treatment of DKA are shown in Table 1.

Follow-Up

After recovery from the DKA and normalization of pH and anion gap, the child can be transitioned from intravenous to subcutaneous insulin administration. It is essential to recognize that subcutaneous insulin takes time to begin and reach peak action, which means that intravenous insulin should be continued for a few hours after the first injection of insulin. Ideally, iv insulin should be continued until 1-2 hours after the first injection of SQ rapid acting insulin (Aspart or Lispro), or 4 hours after the first injection of long acting insulin (Glargine or Detemir).

Although it is obviously important to differentiate between children with new onset T1D and T2D because of the implications for long term therapy, the initial management of DKA in both populations should not be different. With increasing rates of obesity in children, more youth are presenting with T2D at younger ages. It is thought that children who develop T2D at a younger age do so because of more progressive beta cell failure than in adults. Thus, the initial DKA at presentation with T2D is physiologically and biochemically similar to DKA in new onset T1D, with the main targets of therapy being fluid and insulin replacement. Measuring pancreatic auto-antibodies and documentation of careful family history, will eventually aid in differentiating T1D from T2D, especially in children who are overweight or obese.

Clinical Recognition

While in the general population, a blood glucose (BG) level of <70 mg/dL is considered low (hypoglycemia) and results in clinical symptoms, children with diabetes spend significant time with BG levels above 200 mg/dL, thus shifting upward the brain threshold for exhibiting signs and symptoms of hypoglycemia. Conversely, recent episodes of hypoglycemia can shift downward the threshold for exhibiting and recognizing hypoglycemia. Recent consensus statements from the American Diabetes Association (ADA) and the International Society for Pediatric and Adolescent Diabetes (ISPAD) have defined hypoglycemia in a child with diabetes as any BG level that results in symptoms or signs of impaired cognitive function. These hypoglycemic levels frequently change as the range of BG levels shift up or down over time, even within short periods of time.

In the context of diabetes, any level of hypoglycemia (resulting in symptoms) can be considered an emergency because of the potential for the BG level to drop further within minutes. Therefore, any BG <70-80 mg/dL is generally considered a “hypoglycemia alert” and should be managed urgently. This is particularly true in children with diabetes because of their higher sensitivity to both insulin and physical activity, resulting in more rapid drops in BG levels.

The current consensus is that a true emergency is considered a BG <54 mg/dL (3 mMol/L), a level that indicates a clinically important hypoglycemia that is likely to be associated with defective counter-regulatory response and impaired cognitive function. At these levels, a child is at a much higher risk for more severe cognitive impairment, with or without loss of consciousness or seizure, and requiring external assistance (severe hypoglycemia).

Pathophysiology

By far the most common cause of hypoglycemia in children with diabetes is excess insulin. Most children are treated with intensive insulin therapy with a basal/bolus regimen, by multiple daily injections or via an insulin pump. Boluses of rapid acting insulin are determined for each meal based on current BG value at the time before the meal and on the amount of carbohydrates (carbs) to be consumed in that meal. This requires fairly accurate carb counting, followed by entry of the estimated carbs and the BG number into a dose calculator, which can be a simple sliding scale hard copy sheet, a smart phone app, or a smart insulin pump. This process involves multiple steps, which naturally presents opportunities for estimation and transcription errors, leading sometimes to over-dosing of insulin.

A common scenario, especially in young children, is refusal to eat or to finish a meal after a bolus had been given, or vomiting shortly after a meal. A history of repeated episodes of vomiting and/or repeated hypoglycemia after meals in an adolescent should alert the provider to the possibility of an eating disorder.

The second frequent cause of hypoglycemia in children is exercise. Patients and caregivers are trained on adjusting insulin dosing to compensate for the enhanced sensitivity to insulin during and after any physical activity. These include lowering doses of long acting insulin or rapid acting insulin, lowering a bolus amount for the meal before or after exercise, or consuming extra carbs which are not dosed for. For patients on insulin pumps, a temporary basal rate reduction for several hours beginning before the activity is planned is often necessary. Omission of such adjustments can lead to hypoglycemia which can occur during or up to few hours after the exercise.

Management

Most hypoglycemic episodes in children should be managed in a timely manner, at the patient location, such as home, school, or sports fields, to avoid extended brain deprivation of glucose and prevent acute and long-term sequelae. Parents of children and persons with diabetes who are taking insulin or insulin secretagogues (sulfonylureas), should be trained to recognize the signs and symptoms of hypoglycemia and how to manage hypoglycemia.

Once a child exhibits signs of hypoglycemia, treatment should be initiated after measuring the BG regardless of level. If the child is cooperative and able to take anything by mouth, simple and fast absorbing carbohydrates should be given. Examples include glucose tablets, clear juice, soda, regular sugar, cake frosting, and a variety of candies. In late adolescents, like in adults, 10-20 grams of carbs can be given to treat any hypoglycemia, and can be repeated 15 minutes later if needed. However, in smaller children, it is imperative to recognize that smaller amounts of carbs should be used to prevent a rebound hyperglycemia. As little as 2-4 grams are often sufficient in toddlers to raise the BG 30-60 mg/dL.

If a child is combative, unconscious, or seizing, oral treatment should not be attempted, as this carries the risk of aspiration or injury. Instead, glucagon should be given intramuscularly as soon as possible. For most children, a dose of 0.5 mg (half the amount provided in glucagon emergency kits) is effective in raising BG to >100 mg/dL, but up to 1.0 mg can be given to older adolescents. Although rare, a dose of glucagon can be repeated within 30 minutes if the BG level does not rise above 100 mg/dL.

Pathophysiology

HHS is typically initiated by severe hyperglycemia caused by both relative insulin deficiency and elevation of counter regulatory hormones, which cause a decrease in peripheral glucose utilization and increase glucose production, respectively. The resulting severe hyperglycemia leads to polyuria and severe dehydration, with subsequent decrease in glomerular filtration and glucose clearance, which further exacerbates the hyperglycemia and hyperosmolality. The absence of ketones in HHS is attributed to the relative but not absolute deficiency of insulin, and the higher insulin to glucagon ratio than that in DKA.

As in adults, HHS occurs in children with T2D, but it can also be the first presentation of new onset T1D, caused by use of beverages with high carbohydrates, such as regular soda or juice, to alleviate the accompanying polydipsia. Other common precipitating factors of HHS are infections, cystic fibrosis, and use of certain anti-psychotic medications.

Diagnosis

The progression of HHS is typically slower than DKA, resulting in delayed diagnosis and presentation with more severe hyperglycemia, dehydration, and altered mental status. Diagnostic criteria for HHS include a BG >600 mg/dL (33.3 mmol/L), absence of appreciable acidosis (pH>7.30 and bicarb >15), anion gap <12, and an effective serum osmolality >320 mmol/kg. Recent consensus guideline recommended calculating the effective serum osmolality as [2 (serum Na)] + [glucose in mmol/L]. This is based on the fact that altered mental status is usually manifest at serum Na >160 mmol/L, or calculated effective serum osmolality >320 mmol/L.

Treatment

The main objectives of treating HHS are very similar to treating DKA: restoration of circulatory volume and tissue perfusion; correction of hyperglycemia and electrolyte imbalance; and identification and treatment of the precipitating event(s). Because HHS is rare in children, most published guidelines are based on experiences with adults. Therefore, practical management of HHS in children follow the same guidelines as for DKA, including estimation of fluid deficit, careful replacement of the deficit after initial management of shock if present, keeping in mind that fluid administration results in significant decrease in BG concentration and drop in serum osmolality. Once osmolality stops declining, insulin infusion can be started while fluid replacement continues, with the goal of maintaining BG at 250-300 mg/dL.