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Diabetic Ketoacidosis

Author: William H Lamb, MBBS, MD, FRCP(Edin), FRCP, Clinical Lecturer, Department of Child Health, The General Hospital, Bishop Auckland, UK
Contributor Information and Disclosures

Updated: Dec 11, 2008

Introduction

Background

Diabetic ketoacidosis (DKA) is a metabolic derangement caused by the absolute or relative deficiency of the anabolic hormone insulin. Together with the major complication of cerebral edema, diabetic ketoacidosis is the most important cause of mortality and severe morbidity in children with diabetes, particularly at the time of first diagnosis. Early recognition and careful management are essential if death and disability are to be avoided.¹

Pathophysiology

Insulin is the pivotal hormone of blood glucose regulation, increasing peripheral glucose uptake, switching off hepatic gluconeogenesis, while stimulating glycogen synthesis and peripheral fat deposition.

Insulin deficiency exaggerates the normal response to fasting, which is to increase liver production of glucose by gluconeogenesis from fat and protein together with breakdown of liver glycogen stores by glycogenolysis. Peripheral glucose uptake is impaired and levels of the main counter-regulatory hormones (ie, glucagon, cortisol, catecholamines, growth hormone) increase. Various metabolic consequences follow.²

Hyperglycemia

Glucagon stimulates glycogenolysis and gluconeogenesis, doubling liver glucose production. Hyperglycemia further impairs peripheral glucose uptake and inhibits any residual insulin synthesis. Blood glucose levels rise above the renal threshold for glucose reabsorption, causing an osmotic diuresis.

Fluid and electrolytes

Fluid losses can be considerable, typically 3-10% of body weight. Most water is lost by osmotic diuresis, with important contributions from hyperventilation and vomiting. The diuresis also leads to significant urinary losses of potassium, sodium, phosphate, and magnesium ions.

Ketoacidosis

Insulin inhibits the lipolytic action of cortisol and growth hormone; thus, insulin deficiency increases circulating levels of fatty acids. These are oxidized in the liver, producing the acidic ketone bodies beta-hydroxybutyrate and acetoacetate, from which acetone spontaneously forms. The resulting acidosis primarily is due to circulating ketone bodies, with additional contributions from excess fatty acids and lactic acidosis, as a consequence of poor tissue perfusion.

Eventually, hyperventilation no longer can compensate for the metabolic acidosis, which, together with dehydration, leads to renal failure and circulatory collapse followed by coma and death.

Frequency

United States

Exact figures for the incidence of diabetic ketoacidosis are not available; but several population based studies report that around 25% of new cases of type I diabetes present with ketoacidosis, giving an approximate incidence of 4 per 100,000 children annually. Rates are highest in younger children at diagnosis but tend to increase with age in children with established diabetes.^3,4,5

International

As in the United States, few data are available. A large European multicentre study showed widely varying rates of diabetic ketoacidosis at diagnosis (26-67%), with rates inversely related to the overall incidence of childhood diabetes.⁶  Diabetic ketoacidosis rates in children with established diabetes widely vary; in a United Kingdom national prospective study, 60% of all cases occurred in patients with known diabetes.⁷  Diabetic ketoacidosis at the time of diagnosis is more likely in the most deprived communities.

Mortality/Morbidity

Diabetic ketoacidosis is the most common cause of diabetes-related death in childhood. Without insulin therapy, the mortality rate is 100%, but current mortality rates are around 2-5%.^8,9,10

• Treatment for diabetic ketoacidosis may cause life-threatening, predictable, and avoidable acute complications such as hypokalemia, hypoglycemia, hyponatremia, and fluid overload. Other complications, such as cerebral edema, are not as predictable but are very important.
• Cerebral edema is the most serious complication of diabetic ketoacidosis. Its causes are not known, but associated factors include duration and severity of diabetic ketoacidosis before treatment, overaggressive fluid replacement, the use of sodium bicarbonate to treat the acidosis, too early an introduction of insulin therapy, cerebral anoxia, and degree of hyperglycemia.^{11,12,13,14,15} Cerebral edema is the most important cause of mortality and long-term morbidity with diabetic ketoacidosis.
• Other rare complications of diabetic ketoacidosis include acute respiratory distress syndrome (ARDS) with pulmonary edema,^16,17 mediastinal pneumothorax, rhabdomyolysis, and acute renal failure.

Race

Race alone does not appear to have any influence on the likelihood of developing diabetic ketoacidosis.¹⁸

Sex

Although no difference in diabetic ketoacidosis rates between the sexes is observed at diagnosis and during early childhood, adolescent girls with diabetes are twice as likely to develop diabetic ketoacidosis as adolescent boys.¹⁹

Age

Infants and children younger than 5 years are at greatest risk of presenting with diabetic ketoacidosis because the diagnosis of diabetes in younger children is more difficult and is more likely to be delayed.²⁰ Adolescents are more likely to develop diabetic ketoacidosis after diagnosis of diabetes.

Clinical

History

When diabetic ketoacidosis (DKA) occurs as a first presentation of diabetes, symptoms are likely to develop over several days with progressive dehydration and ketosis. In a small child wearing diapers and with naturally high fluid intake, polyuria and polydipsia are easily missed. When diabetes is developing, the stress and symptoms of another illness may precipitate diabetic ketoacidosis, as well as mask the underlying problem.

Diabetic ketoacidosis can develop very rapidly in a patient with established diabetes, particularly when insulin therapy has been forgotten, deliberately omitted, or disrupted, as with children on continuous subcutaneous insulin infusions (CSII) or using the newer analogue insulins. Under these circumstances, diabetic ketoacidosis may present with relatively normal blood glucose levels (ie, 250 mg/dL, 15 mmol/L) or less.

• Symptoms of hyperglycemia
  • Increased volume and frequency of urination (polyuria)
  • Polydipsia: Thirst is often extreme, with children waking at night to consume large quantities of any available drinks.
  • Nocturia and secondary enuresis in a previously continent child
  • Weight loss, which may be dramatic due to breakdown of protein and fat stores
  • Muscle pains and cramps
• Symptoms of acidosis and dehydration
  • Abdominal pain that may be severe enough to present as a surgical emergency. For children with a failure of CSII, this may be the first presenting sign, along with vomiting.
  • Shortness of breath that may be mistaken for primary respiratory distress
  • Confusion and coma in the absence of recognized head injury²¹
• Other symptoms
  • Vomiting
  • Signs of intercurrent infection (eg, urinary tract infection, respiratory tract infection)
  • Weakness and nonspecific malaise that may precede other symptoms of hyperglycemia

Physical

• Dehydration may be observed.
  • The degree of dehydration is often reported to be approximately 5-10% but easily can be overestimated. Clinical signs, such as dry mouth, sunken eyes, and decreased skin turgor, are present from about 3% dehydration.
  • When the dehydration is estimated from comparing current against previous known weights, allow for the loss of protein, fat, and glycogen stores, which otherwise would exaggerate fluid losses. Table 1. Clinical Assessment of Dehydration

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    Table

    	Mild <3%	Moderate 3-10%	Severe 10% and Shock 15%
    Appearance	Thirsty, alert	Thirsty lethargic	Drowsy, cold
    Tissue turgor	Normal	Absent	Absent
    Mucous membranes	Moist	Dry	Very dry
    Blood pressure	Normal	Normal or low	Low for age
    Pulse	Normal	Rapid	Rapid and weak
    Eyes	Normal	Sunken	Grossly sunken
    Anterior fontanelle	Normal	Sunken	Grossly sunken

    	Mild <3%	Moderate 3-10%	Severe 10% and Shock 15%
    Appearance	Thirsty, alert	Thirsty lethargic	Drowsy, cold
    Tissue turgor	Normal	Absent	Absent
    Mucous membranes	Moist	Dry	Very dry
    Blood pressure	Normal	Normal or low	Low for age
    Pulse	Normal	Rapid	Rapid and weak
    Eyes	Normal	Sunken	Grossly sunken
    Anterior fontanelle	Normal	Sunken	Grossly sunken

• Blood pressure is usually normal until terminal stages of illness.
• Tachycardia may be present.
• Capillary refill is initially maintained, but a combination of increasing acidosis and dehydration cause poor tissue perfusion.
• Kussmaul breathing or deep sighing respiration is a mark of acidosis. These symptoms may be mistaken for status asthmaticus, pneumonia, and even hysterical hyperventilation.
• Patient may have a smell of ketones on the breath. (Many people cannot detect this smell.)
• Impaired consciousness occurs in approximately 20% of patients.
• Coma may be present in 10% of patients.
• Abdominal tenderness may occur.
  • Tenderness is usually nonspecific or epigastric in location.
  • Bowel sounds may be reduced or absent in severe cases.

Causes

Twenty-five percent of patients with diabetes present with diabetic ketoacidosis; a missed diagnosis of diabetes is the most common cause, especially in young children.

• In children with established diabetes, the causes of diabetic ketoacidosis vary with age. Infection is the most likely precipitant in the prepubertal child; missed injections or emotional upset are more usual in the older teenager.
• Failure to administer prescribed insulin is the most common cause of diabetic ketoacidosis in adolescents.^22,23 Children with high glycosylated hemoglobin (HbA1c) levels (a measure of control over an 8-12 wk period) may be receiving only a third or less of the prescribed insulin dose.²⁴ Total insulin deficiency obviously leads to diabetic ketoacidosis, but inadequate doses render the child more liable to decompensate with other stresses such as infection, emotional turmoil, or food bingeing.²⁵ .
• Children on CSII are at particular risk of diabetic ketoacidosis if the device fails or if insulin delivery is disrupted because they have no effective depot of insulin and become insulin-deficient very quickly. Diabetic ketoacidosis is most likely to occur in the first months after commencing CSII. Children with diabetic ketoacidosis often present with vomiting and abdominal pain, symptoms that are mistaken for gastroenteritis or food poisoning.
• Children using only analogue insulins are also at risk of rapid-onset diabetic ketoacidosis. Omitting an evening dose of long-acting insulin may result in insulin deficiency through the night and typically leads to the child waking up vomiting.
• Some children have repeated episodes of diabetic ketoacidosis (so-called brittle diabetics). These children usually have major emotional disturbances relating to home, school, or relationships with their peer group. They may repeatedly present in a critical condition but invariably deny any failure of compliance. Helping these children is extremely difficult.
• Alcohol and drug abuse, particularly with amphetamine derivatives and their analogues, are other precipitants of diabetic ketoacidosis.²⁶
• In the developing world, infection and the lack of available insulin are the most important causes of diabetic ketoacidosis.

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