Figure 4-1 Insulin action
Diabetic Ketoacidosis
Diabetes is a chronic disease defined by hyperglycemia caused by insulin deficiency. (Chapter 71 provides a detailed discussion of diabetes mellitus.). This may be the result of a lack of insulin production, as in type 1 diabetes mellitus (T1DM) or the body’s ineffective use of the insulin it produces, as in type 2 diabetes mellitus. The most common form of diabetes in children is T1DM.
The World Health Organization and
International Diabetes Foundation have established the diagnosis of diabetes as
meeting any of the following criteria: (1) fasting (≥8 hours) plasma glucose above 126 mg/dL; (2)
plasma glucose above 200 mg/dL 2 hours
after a glucose load as given by an oral glucose tolerance test; (3) any random
plasma glucose above 200 mg/dL along with the presence of symptoms of diabetes,
including increased thirst and urination or unexplained weight loss, or (4) a
hemoglobin A1C ≥6.5%.
Diabetes is one of the most common
chronic diseases in the United States. Approximately
8.0% of the U.S. population meets criteria for diabetes. It is estimated that
about 150,000 people in the United States younger than 20 years of age have
diabetes; about one in every 500 children and adolescents has T1DM. There is a
bimodal distribution of age at onset, with a peak age at presentation around
age 5 years and another at early puberty. This chapter focuses on the care of
acutely ill children with T1DM presenting with diabetic ketoacidosis (DKA), a
complication of T1DM in which hyperglycemia, dehydration, electrolyte
derangement, ketonemia, and acidemia result from absolute insulin deficiency.
DKA can be the presenting manifestation of T1DM in up to 25% of children; it is
also seen in children with known T1DM secondary to failure of or noncompliance
with insulin therapy.
ETIOLOGY AND PATHOGENESIS
T1DM is the result of an
inflammatory process within the pancreas. It is thought that children inherit a
susceptibility to the disease through specific genes. There is then a
triggering event, such as a viral infection, that is either directly toxic to
pancreaticβ-cells
or triggers a widespread generalized immune response. Affected individuals tend
to become symptomatic when 90% of β-cell mass is destroyed and carbohydrate intolerance occurs.
DKA is a result of insulin
deficiency. Insulin is a hormone that
responds to an increase in serum glucose via receptor- mediated utilization.
This includes stimulation of glucose uptake from the blood by peripheral
tissues; glycogen synthesis in the liver; and inhibition of processes that
increase serum glucose, such as gluconeogenesis and glycogenolysis (Figure
4-1). In the absence of insulin, blood glucose levels increase. There is
inability to store glucose that is absorbed through the gut, and because of the
absence of insulin’s suppression of these pathways, pro- duction of new glucose
via gluconeogenesis continues. This process is perpetuated by increased
production of hormones that increase blood glucose, including glucagon,
cortisol, and catecholamines. As blood glucose increases,
osmotic diuresis occurs, resulting in urinary losses of electrolytes. Because
the body cannot use the glucose that has been supplied, it responds as if in
the fasting state. Fat is then broken down into free fatty acids to be used as
fuel. Free fatty acids are converted to keto-acids, including β-hydroxybutyrate and acetoacetate, leading to metabolic acidosis (Figure 4-2).
The presenting signs and symptoms of
DKA reflect this progression. Initially, hyperglycemia and hyperosmolarity
cause osmotic diuresis leading to polyuria and compensatory polydipsia.
Progressive insulin deficiency leads to catabolism of protein and fat stores,
resulting in weight loss and fatigue. As production of counterregulatory
hormones increases, ketosis worsens, leading to acute symptoms of nausea,
vomiting, and abdominal pain. Progressive dehydration can lead to lethargy and
confusion. Ongoing metabolic acidosis stimulates respiratory compensation via
hyperpnea, leading to deep, sighing breaths known as Kussmaul respirations.
CLINICAL PRESENTATION
Patients with DKA typically present
with acute symptoms of nausea and vomiting. In patients presenting with T1DM
for the first time, there may be a history of polyuria, polydipsia, enuresis,
or weight loss. As ketosis progresses, patients may become obtunded and unable
to provide a history. Therefore, a glucose measurement should be obtained
quickly in any patient who presents with altered mental status. (Hypoglycemia
may also be manifested as altered mental status.) Ketosis may also result in
presence of a fruity breath, which can help direct the diagnosis. On physical
examination, patients generally show signs related to the degree of dehydration
from chronic hyperglycemia and osmotic diuresis. This may include tachycardia,
presence of dry mucous membranes, and delayed capillary refill. DKA should be
suspected in patients with signs of dehydration who maintain a high urine
output. Abdominal examination often reveals diffuse tenderness. It is important
to document a detailed neurologic examination at presentation because patients
who present with normal mental status may have an acute change in status with
therapy. DKA leads to physical examination findings affecting many systems
(Table 4-1).
Differential Diagnosis
The diagnosis of DKA can be
difficult because of the presenting signs and symptoms, which are similar to
those of other acute illnesses. The history of polyuria and polydipsia are also
signs of urinary tract infection or diabetes insipidus. The weight loss and
abdominal pain may be indicative of anorexia or inflammatory bowel disease.
Abdominal pain can also be a symptom of appendicitis or other acute surgical
problems in the abdomen. Vomiting may be a symptom of gastroenteritis. The
presence of hyperpnea may be concerning for pneumonia or an asthma exacerbation. In patients who are obtunded, DKA
may be confused with head trauma or central nervous system infection.
Laboratory testing can be both misleading and helpful in terms of narrowing the
differential diagnosis. Elevation of stress hormones, including epinephrine and
cortisol, in DKA may lead to leukocytosis,
suggestive of infection. In addition, infection may be a precipitating factor
in development of DKA, and patients may manifest with a chief complaint related
to the underlying infectious process. The best way to narrow the differential
diagnosis is by rapidly obtaining serum glucose, electrolytes, blood pH, and urinalysis. DKA is defined as blood
glucose above 240 mg/dL with the presence of ketones in the urine or blood and
pH below 7.3.
Figure 4-2 Ketoacidosis.
EVALUATION AND MANAGEMENT
The management of patients with DKA
focuses on correction of the dehydration, electrolyte loss, acidosis, and
hyperglycemia. This requires frequent monitoring and admission to the hospital.
Dehydration
Management begins with an initial
bolus of isotonic crystalloid fluid (hypotonic fluids should be
avoided), usually 10 to 20 mL/kg of normal saline
given over 1 hour. Initial fluid therapy is aimed at correcting the
cardiovascular compensation for the degree of dehydration. Patients who present
in shock may need more rapid fluid resuscitation. However, care must be taken
not to administer too much fluid initially because of the risk of potentially
fatal cerebral edema (see Complications). In general, the vital signs and
clinical status should be reassessed between boluses of 10 mL/kg to avoid fluid
overload. The goal is to gradually replace the fluid deficit over 36 to 48
hours.
Electrolyte Loss
DKA results in electrolyte loss,
specifically related to sodium, potassium, and phosphate. Sodium deficit at
presentation is attributable to hyperosmolarity resulting from hyperglycemia and osmotic shift of water into the
intravascular space, resulting in dilutional hyponatremia. Serum sodium is
reduced by 1.6 mEq/L for each 100-mg/dL increase in glucose;
thus, it is important to calculate the sodium concentration corrected for
hyperglycemia with the formula:
Corrected sodium = Measured sodium
([Serum glucose 100]/100) 1.6
It is important to follow the serum
sodium as treatment continues; an increase in sodium does not indicate a
worsening of the hypertonic state. In contrast, a failure of the sodium value
to increase may indicate overly rapid rehydration and increase the risk for
complications, namely cerebral edema. All children with DKA are total body
potassium depleted but the initial serum potassium concentration may be low,
normal, or elevated. Treatment of hyperglycemia with insulin and acidosis
correction will move potassium intracellularly, resulting in hypokalemia.
There-fore, except in cases of extreme elevation of serum potassium
concentration (e.g., >5mEq/dL) or when patients are anuric, potassium should
be added to rehydration fluids regardless of the initial serum potassium
concentration. The initial concentration of potassium added to intravenous (IV)
fluids should be 40 mmol/L if the initial serum potassium is in the “normal”
range. The concentration of potassium should then be adjusted based on frequent
reassessments of serum potassium. Generally, half of the potassium is given as
potassium chloride, and half is given as potassium phosphate. The phosphate
loss in DKA results in reduction in 2,3-diphosphoglycerate, which is important
in the affinity of hemoglobin for oxygen. As a result, less oxygen is available
to the tissues, resulting in increased anaerobic metabolism, production of
lactic acid, and worsening metabolic acidosis. It is important to recognize
that phosphate administration may result in hypocalcemia, so serum calcium
concentration should be monitored simultaneously. It is recommended to follow
electrolyte values every 2 hours during initial treatment for DKA.
Acidosis
In DKA, production of ketoacids and
bicarbonate loss results in acidosis. With correction of DKA, there is
replacement of intra-vascular fluids and improvement in peripheral perfusion,
which help to improve acidosis. In addition, with the administration of insulin
(see below), ketoacids are metabolized to produce bicarbonate and replace
bicarbonate losses. The administration of bicarbonate has been shown to worsen
cerebral edema and may cause exacerbation of hypokalemia; thus, it is not
recommended in the acute management of DKA. If it is believed that bicarbonate
is necessary (e.g., in cases of extreme acidosis, i.e., blood pH <7.0), it
should be given in small doses and over a slow infusion. Even with pH below
7.0, bicarbonate is not recommended in most cases.
Hyperglycemia
Because DKA results from insulin
deficiency, insulin administration is critical to correction. Insulin treatment
generally begins after the first hour of therapy, when the fluid bolus is
complete. Insulin is generally given as a continuous infusion at a rate of 0.1 U/kg/h. Hyperglycemia will be
corrected by insulin faster than the acidosis, and ketosis will resolve.
Therefore, as the serum glucose decreases, it is necessary to administer some
dextrose along with the insulin infusion until the acidosis resolves and the
ketones begin to clear. Generally, addition of dextrose-containing solutions
begins when the glucose has reached 300 mg/dL. Some institutions have adopted
the use of a “two-bag system” in which fluids of identical electrolyte content
and the presence or absence of dextrose are infused simultaneously (i.e., one
bag of normal saline without dextrose and one bag with 10% dextrose in normal
saline). With this method, the amount of dextrose provided can be gently
titrated based on hourly assessment of serum glucose, with the target blood
glucose range between 100 and 200 mg/dL. This helps to ensure a gradual decline
in serum glucose, with a goal of decreasing by 50 to 100 mg/dL/h.
Monitoring
Patients with DKA should be followed
closely to avoid and detect complications. Patients should not be allowed to
eat or drink by mouth until the acidosis has resolved. Serum glucose should be
tested every hour. Blood pH (via venous blood gas) and electrolytes need to be
followed at least every 2 hours until major abnormalities are corrected.
Urinalysis is also checked with each void to monitor for clearance of urine
ketones. Continuous electrocardiographic monitoring is recommended for patients
receiving high concentrations of potassium.
Complications
Cerebral edema is the complication
most associated with morbidity and mortality in DKA, occurring in approximately
1% of patients. The cause is not clearly identified, but current hypotheses
include cerebral hypoperfusion during DKA treatment and rapid fluid shifts
caused by rapid changes in osmolarity. Risk factors at presentation include pH
below 7.0, age younger than 3 years, low pCO2, high blood urea nitrogen,
treatment with bicarbonate, lack of increase in serum sodium during treatment,
corrected serum sodium above 155 mEq/L, and glucose above 1000 mg/dL. The
symptoms include headache, new findings on neurologic examination (abnormal
response to pain, posturing, cranial nerve palsy), a sudden decline in mental
status, and hypertension. Cerebral edema is a clinical diagnosis, and if it is
suspected, treatment should begin rapidly with infusion of IV mannitol at 0.25
to 1.0 g/kg, elevation of the head of the bed, and reduction in the rate of IV
fluids by one-third. When stabilized, an emergent cranial computed tomography
should be performed.
Resolution
When pH and bicarbonate have
normalized, ketones have decreased, and the patient feels well enough to begin
to maintain hydration by mouth, treatment can be switched to a regimen of
subcutaneous insulin. Because the half-life of IV insulin is several minutes, a
subcutaneous insulin injection should be given before the insulin infusion is
stopped. Management after DKA resolves is discussed in
Chapter 71.
When the patient is beyond the acute
stage of illness, it is important to determine what caused the patient to
develop DKA. Some patients present with diabetes for the first time and have
families that are unfamiliar with the signs and symptoms of DKA. For these
patients, it important to provide education about diabetes management and to
develop a good relationship with an endocrinologist for follow-up. For some
patients, acute illnesses can increase the need for insulin that is not met by
the current maintenance regimen. In these instances, identification and
treatment of the underlying illness is necessary.
In patients with known T1DM, it is
important to determine if DKA is the result of noncompliance with the demanding
insulin regimen of several injections per day or with failure of insulin pump
therapy (see Figure 71-2). Insulin pump therapy is designed to deliver
subcutaneous insulin continuously with bolus dosing on demand. In these
patients, it is important to emphasize compliance and education with current
equipment.
FUTURE DIRECTIONS
Although efforts to prevent or reverse T1DM have not met good results thus far, there have been significant developments in the management of patients with diabetes. Advances in glucose monitoring and ease of insulin delivery have made living with T1DM easier and less painful than in the past. While awaiting the next development in diabetes management, patients should be empowered to optimize control while living with a chronic disease.
