Christina Kanaka-Gantenbein, MD, PhD
Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with Type 1 diabetes mellitus (T1D). Mortality is mainly related to the occurrence of cerebral edema, while only a minority of deaths are attributed to other causes.1,2 …
Diabetic ketoacidosis is attributed to the combination of absolute or relative insulin deficiency with excess of counter-regulatory hormones, including glucagon, growth hormone, catecholamines, and cortisol.1-3 It is well known that insulin is the only glucose-lowering hormone of the body, permitting the influx of glucose into the cells for energy production and facilitating lipid formation, while all other hormones, the so-called "counter-regulatory hormones" — growth hormone, glucagon, catecholamines, and cortisol — exert an opposing action, facilitating glucose formation through gluconeogenesis and glycogenolysis. The combination of low serum insulin with increased counter-regulatory hormones thus results in a catabolic state with increased glucose production and diminished peripheral glucose utilization, causing hyperglycemia and hyperosmolality and enhanced lipid oxidation, resulting in increased lipolysis and ketogenesis and ultimately leading to ketonemia and metabolic acidosis.3,4 The pathophysiology of diabetic ketoacidosis is illustrated in Figure 1.1. The combination of hyperglycemia, which drives water transport from the intracellular compartment to the intravascular one and finally through enhanced urinary perfusion leads to enhanced osmotic diuresis causing hyperosmotic dehydration, with metabolic acidosis, may be life-threatening if left undiagnosed and not adequately managed. The ketoacidosis may even be aggravated by supervening lactic acidosis, because of poor tissue perfusion, while the osmotic diuresis results in electrolyte losses that may cause further life-threatening disturbances such as cardiac arrhythmias.1-4
At presentation, the magnitude of specific deficits in the individual patient varies, depending on the duration and severity of symptoms and dehydration, until the individual patient comes to medical attention and receives adequate treatment.
The epidemiology, potential causes, and clinical manifestations as well as management of DKA presented in this chapter are based on the recent international consensus statements of the most appropriate scientific societies in this field such as the European Society for Pediatric Endocrinology (ESPE), the Lawson Wilkins Society for Pediatric Endocrinology (LWSPE), the American Diabetes Association (ADA), and the International Society for Pediatric and Adolescent Diabetes (ISPAD). The recommendations for the management of DKA were first published in both Pediatrics and Archives of Disease in Childhood in 2004,1,2 then as a consensus statement of the American Diabetes Association in 2006,3 and more recently in the Compendium of the ISPAD Clinical Practice Consensus Guidelines 2009 in Pediatric Diabetes in 2009.4
The consensus statements with their worldwide evidence-and expert-based recommendations on diabetic ketoacidosis in children and adolescents1–4 are greatly respected and are presented in detail here. Their management recommendations are summarized in Figure 2.1. It has to be noted, however, that although guidelines are considered to be useful for the majority of cases, individualization in decision making and treatment modalities may also be necessary.
DKA is usually the first manifestation in an undiagnosed case of Type 1 diabetes mellitus (T1D), especially in toddlers, while it may also occur in a poorly controlled Type 1 diabetic patient, either due to concurrent disease or insulin omission.3,4 Diabetic children and adolescents treated by continuous subcutaneous insulin infusion (insulin pump) are more prone to develop DKA if a technical problem in the pump supervenes, since there is no circulating long-acting insulin in the body and insulin deficiency leads quickly to metabolic decompensation.3–5
Most cases of DKA are therefore observed in T1D patients.4,6,7 However, the significant increase in childhood and adolescent obesity worldwide has led to an increase in Type 2 diabetes (T2D) incidence, especially during adolescence and more frequently in some ethnic groups such as African-Americans and less frequently in Hispanics, while it is still rare among Caucasian whites. In the ethnic minorities that present a high incidence of T2D, DKA may be the first manifestation of Type 2 diabetes in up to 25% of cases. Overall, however, only about 5% of T2D cases are first manifested by DKA.4,8,9
Figure 2.1 Algorithm for the monitoring and management of diabetic ketoacidosis. From Wolfsdorf J et al. Pediatric Diabetes 200910 (suppl. 12):128 , with permission.
There is a wide geographic variation in the frequency of DKA at diabetes onset, ranging from 10 to 70% of cases in Europe and North America. Rates of DKA were suggested to be higher in areas where T1D incidence is lower and therefore suspicion for the occurrence of T1D is weaker. However, recent epidemiological studies have documented a continuing high incidence of DKA among new-onset T1D patients, even in areas where the annual incidence of T1D has significantly increased during the last decades (Figure 2.2).4,6,7 Moreover, the frequency of DKA is higher among younger children, reaching an incidence of almost 60% among children younger than 2 years of age, and averaging 25% in those younger than 4 years of age worldwide, especially in areas where medical care is less accessible. Therefore, both older retrospective studies and recent prospective studies have revealed a high incidence of DKA among newly diagnosed T1D patients, especially in the very young, even in areas with an increased overall incidence of T1D.6,7,10,11
Figure 2.2 Frequency of diabetic ketoacidosis and its severity during a 13-year observation period — a multicenter analysis of 14,664 patients from 106 institutions. Frequency of DKA according to years. _, pH < 7.3; pH < 7.2; _, pH < 7. Copyright 2009 American Diabetes Association. From Diabetes Care, Vol. 32, 2009; 1647-1648. Reproduced by permission of The American Diabetes Association.
The diagnosis is mainly based on biochemical criteria, while clinical presentation may vary depending on the duration until the patient seeks medical assistance.4
The biochemical criteria for the diagnosis of diabetic ketoacidosis are:
- Hyperglycemia (blood glucose > 200 mg/dl [11 mmol/L])
- Acidosis (venous pH < 7.3 or bicarbonate < 15 mmol/L)
- Ketonemia and ketonuria.
Laboratory investigations may also reveal:
- Leukocytosis with a left shift
- Non-specific serum amylase elevation.
DKA is generally categorized by acidosis, varying from mild to severe:
- Mild: venous pH < 7.3 but still > 7.2 and bicarbonate concentration 10-15 mmol/L
- Moderate: venous pH ranging from 7.1 to 7.2 and bicarbonate concentration 5-9 mmol/L
- Severe: venous pH < 7.1 and bicarbonate concentration < 5 mmol/L.1–4
The clinical manifestations of diabetic ketoacidosis are:
- Rapid, deep sighing (Kussmaul respiration)
- Nausea, vomiting, and abdominal pain, mimicking an acute abdomen
- Progressive dizziness, lethargy, and loss of consciousness
- Fever, only when infection is present.
First of all, the patient should be clinically assessed to define the severity of dehydration, the level of consciousness, the presence of vomiting, etc.4
The level of consciousness can be assessed using the Glasgow coma scale (Table 2.1) although clinical common sense is usually adequate.
Clinical assessment of the severity of dehydration may quite often be inaccurate and imprecise.4,12,13 The three most useful signs to assess at least 5% dehydration and acidosis in young children are:
- Prolonged capillary refill time (normal capillary refill time is < 1.5-2 seconds)
- Abnormal skin turgor
- Sunken eyes
- Dry mucous membranes
- Absent tears
- Weak pulses
- Cool extremities.
Initial laboratory assessment
- Obtain a blood sample for determination of blood glucose, electrolytes (sodium, potassium, chloride) blood urea nitrogen, venous pH, PCO 2, HCO 2, anion gap, calcium, phosphorus, magnesium, complete blood count for determination of hemoglobin, hematocrit, leukocytes. It has, however, to be mentioned that phosphorus, calcium, and magnesium levels are less important for treatment.
- Obtain a urine sample to check for ketones and to ascertain diuresis.
- If clinically indicated, perform ECG monitoring to check for possible abnormalities as a response to electrolyte changes.
- If clinical suspicion of an intercurrent infection exists, obtain specific samples for culture, for example blood and urine specimens.
A child with diabetic ketoacidosis should be managed in a unit that has:
- Experienced nursing staff trained in monitoring and management
- Written guidelines for DKA management based on international guidelines
- Access to laboratories for frequent and timely biochemical measurements
- A specialist/consultant pediatrician with training and expertise in managing DKA in children, who should supervise initial inpatient management.
- A child with severe DKA or depressed level of consciousness may be managed in a pediatric intensive care unit, if enough expertise is available.
- Secure the airway, if necessary.
- A peripheral intravenous catheter should be sited for frequent venous sampling and two further intravenous routes should be placed to cover fluid and insulin administration.
- Cardiac monitoring may be necessary to check for changes due to potassium alterations.
- Oxygen administration may be needed.
- Antibiotic administration may be indicated in a febrile patient, after specific body fluid samples for culture have been obtained.
- Bladder catheterization is not usually indicated in a pediatric patient with DKA, but may be necessary when the patient is unconscious or urine output cannot otherwise be monitored.
Successful management of DKA requires meticulous and close monitoring.4 Monitoring of the patient should be documented on a flowchart, where clinical assessment and fluid and insulin administration should be registered hourly and laboratory results should be documented when available. Monitoring should include (Figure 2.1):
- Vital signs (pulse rate, blood pressure, respiratory rate): hourly
- Neurological observation for early detection of the occurrence of signs and symptoms of cerebral edema, the most serious complication of DKA (discussed in detail below): hourly
- Amount of insulin administered: hourly
- Accurate fluid input and, if indicated, output: hourly
- Capillary blood glucose measurement, verified by laboratory blood glucose measurement, since capillary readings may be inaccurate in extreme high or low glucose values and because of poor peripheral circulation: hourly
- Biochemical laboratory tests for determination of plasma electrolytes, blood glucose, blood urea nitrogen, calcium, magnesium, and phosphorus, as well as blood gases and hematocrit: every 2 hours at the beginning, or more frequently in severe cases, and gradually monitored less frequently upon stabilization of the patient
- Urine ketones: until cleared. (con’t)
- Dunger DB, Sperling MA, Acerini CL, et al. European Society for Paediatric Endocrinology; Lawson Wilkins Pediatric Endocrine Society. European Society for Paediatric Endocrinology/Lawson Wilkins Pediatric Endocrine Society consensus statement on diabetic ketoacidosis in children and adolescents. Pediatrics 2004; 113: e133-40.
- Dunger DB, Sperling MA, Acerini CL, et al. ESPE; LWPES. ESPE/LWPES consensus statement on diabetic ketoacidosis in children and adolescents. Arch Dis Child 2004; 89: 188-94.
- Wolfsdorf J, Glaser N, Sperling MA; American Diabetes Association. Diabetic ketoacidosis in infants, children, and adolescents: A consensus statement from the American Diabetes Association. Diabetes Care 2006; 29: 1150-9.
- Wolfsdorf J, Craig ME, Daneman D, et al. Diabetic ketoacidosis in children and adolescents with diabetes. ISPAD Clinical Practice Consensus Guidelines 2009 Compendium. Pediatr Diabetes 2009; 10 (Suppl 12): 118-33.
- Hanas R, Lindgren F, Lindblad B. A 2-year national population study of pediatric ketoacidosis in Sweden: predisposing conditions and insulin pump use. Pediatr Diabetes 2009; 10: 33-7.
- Neu A, Hofer SE, Karges B, et al. DPV Initiative and the German BMBF Competency Network for Diabetes Mellitus. Ketoacidosis at diabetes onset is still frequent in children and adolescents: a multicenter analysis of 14,664 patients from 106 institutions. Diabetes Care 2009; 32: 1647-8.
- Schober E, Rami B, Waldhoer T; Austrian Diabetes Incidence Study Group. Diabetic ketoacidosis at diagnosis in Austrian children in 1989-2008: a population-based analysis. Diabetologia 2010; 53: 1057-61.
- Sapru A, Gitelman SE, Bhatia S, et al. Prevalence and characteristics of Type 2 diabetes mellitus in 9-18 year-old children with diabetic ketoacidosis. J Pediatr Endocrinol Metab 2005; 18: 865-72.
- Zdravkovic V, Daneman D, Hamilton J. Presentation and course of type 2 diabetes in youth in a large multi-ethnic city. Diabet Med 2004; 21: 1144-8.
- Rewers A, Klingensmith G, Davis C, et al. Presence of diabetic ketoacidosis at diagnosis of diabetes mellitus in youth: the Search for Diabetes in Youth Study. Pediatrics 2008; 121: e1258-66.
- Hekkala A, Reunanen A, Koski M, et al. Finnish Pediatric Diabetes Register. Age-related differences in the frequency of ketoacidosis at diagnosis of Type 1 diabetes in children and adolescents. Diabetes Care 2010; 33: 1500-2.
- Fagan MJ, Avner J, Khine H. Initial fluid resuscitation for patients with diabetic ketoacidosis: how dry are they? Clin Pediatr (Phila) 2008; 47: 851-5.
- Koves IH, Neutze J, Donath S, et al. The accuracy of clinical assessment of dehydration during diabetic ketoacidosis in childhood. Diabetes Care 2004; 27: 2485-7.
Professor of Internal Medicine
Athens University Medical School
Evgenideion Hospital and Research Laboratory ‘Christeas Hall’
Associate Professor of Pediatric Endocrinology and Diabetology
First Department of Pediatrics, University of Athens
Agia Sofia Children’s Hospital
Consultant in Internal Medicine and Diabetology
Laiko General Hospital
Assistant Professor of Internal Medicine and Diabetology
Athens University Medical School
Laiko General Hospital
Assistant Professor of Internal Medicine and Diabetology
University of Athens
Laiko General Hospital