Autonomic symptoms include sweating, intense hunger, palpitations, tremor,
tingling, and anxiety. Epinephrine is thought to mediate many of the neurogenic
Neuroglycopenic symptoms resulting from neuronal fuel deprivation (glucose)
include difficulty concentrating, lethargy, confusion, agitation, weakness, and
possibly, slurred speech, dizziness, and fainting. Profound behavioral changes,
seizures, and coma are more severe manifestations of neuroglycopenia. Prolonged,
severe neuroglycopenia ultimately results in death. Symptoms of mild, moderate,
severe, and nocturnal hypoglycemia are as follows:
Mild hypoglycemia: Symptoms include tremor, palpitations, sweating, and intense
hunger. Diminished cerebral function is not present, and patients are capable of
Moderate hypoglycemia: Moderate hypoglycemic reactions include
neuroglycopenic as well as autonomic symptoms: headache, mood changes,
irritability, decreased attention, and drowsiness. Patients may require assistance
in treating themselves because of the presence of impaired judgment or weakness.
Symptoms are more severe, usually last longer, and often require a second dose
Severe hypoglycemia: Symptoms of severe hypoglycemia include unresponsiveness,
unconsciousness, or convulsions. These reactions require assistance from another
individual for appropriate treatment. Approximately 10% of patients treated with
insulin experience at least one severe, disabling episode of hypoglycemia per
year that requires emergency treatment with parenteral glucagon or IV glucose.
Nocturnal hypoglycemia: Tingling of the lips and tongue is a common complaint of
patients who experience nocturnal hypoglycemia. These patients also may
complain of headache and difficulty arising in the morning, nightmares, or
154 Family members should be conscious of any unusual
sounds or activity while the patient is sleeping.
G.O. has mild-to-moderate hypoglycemic reactions, which he is able to self-treat.
These are likely caused by overinsulinization and insulin “stacking” (giving rapid- or
short-acting insulin injections too close together, so that the doses “stack” on top of
the other) with his rapid-acting insulin.
CASE 53-8, QUESTION 2: Evaluate G.O.’s overall control. What signs and symptoms in G.O. are
consistent with overinsulinization and insulin stacking? How should he be managed?
The following is a list of signs and symptoms of overinsulinization in G.O.:
A total daily insulin dose of more than 1 unit/kg. This dose is unusually high for a
patient with Type 1 diabetes, who should not be resistant to the action of insulin.
Weight gain in the past several months. This is secondary to the anabolic effects of
insulin as well as G.O.’s increased carbohydrate intake to match his high insulin
doses for treatment of hypoglycemia.
Frequent hypoglycemic reactions.
High glycemic variability (i.e., BG concentrations that fluctuate wildly between
hypoglycemia and hyperglycemia). In G.O.’s case, high BG concentrations may
represent reactive hyperglycemia or overtreatment of hypoglycemic episodes. His
low BG level may represent excessive rapid-acting insulin at bedtime and insulin
stacking of his rapid-acting insulin after lunch. At lunchtime, he is administering a
high-sugar correction dose of insulin glulisine too soon; his mealtime glulisine is
still likely at a peak action and working to lower his prandial BG. By
administering additional glulisine soon after the meal, the two insulin doses are
adding up, or stacking, causing hypoglycemia.
Near-normal A1C levels indicate mean BG concentrations that must be within the
normal range even though the patient has recorded numerous high BG
concentrations. Patients treated with intensive insulin therapy in the DCCT
experienced hypoglycemic episodes 3 times more often than patients treated with
29 A1C levels were approximately 7.2%.
G.O. should be managed by discontinuing his high-sugar corrections at bedtime
and after lunch. He should check his BG premeal, 1 to 2 hours after meals, and at
bedtime to obtain a better picture of his glucose patterns and insulin requirements. He
should avoid the large bedtime snack because one should not have to add food just to
avoid hypoglycemia (i.e., the insulin regimen should be adjusted). He should also
begin testing his BG at 2 or 3 AM to
assess whether he is still experiencing nocturnal hypoglycemia after stopping the
bedtime insulin glulisine. It will be important that he records the actual dose he
administers before each meal and brings the record to clinic so that his insulin doses
can be fine-tuned. Next, if he is capable, an algorithm for adjusting his preprandial
insulin glulisine doses should be provided to minimize hypoglycemic and
hyperglycemic reactions (see Case 53-2, Question 12), eventually he can transition to
counting carbohydrates (see Case 53-2, Questions 11 and 12).
CASE 53-8, QUESTION 3: How should G.O.’s hypoglycemic episodes be managed?
As G.O. illustrates, many patients with diabetes are frightened of hypoglycemia
and have a tendency to over-treat their reactions with, for example, large quantities
of juice or regular soda. This should be discouraged because overcorrection together
with glucose generated by counter-regulatory hormones ultimately results in
The key to successful management of hypoglycemia is recognition and prevention.
Because early warning symptoms of hypoglycemia vary from person to person, it is
important that G.O. learns to recognize and pay attention to his earliest warning
symptoms and treat early. Patients generally can recall prodromal symptoms after
recovery from a severe hypoglycemic reaction if they have not developed
hypoglycemic unawareness (see Case 53-9). As a caveat, occasionally patients
“feel” hypoglycemic after their BG concentrations have been normalized from very
high levels with intensive insulin therapy, owing to the amount of BG change.
Encourage patients to test their BG level any time they “feel unusual” to verify a low
BG concentration before treatment. G.O. should treat his symptoms only if he is truly
A second component of prevention is determining its cause and taking preventive
or corrective action. This entails assessment of his diet (did he skip or delay a meal
or change its content?), exercise pattern, time of insulin administration, insulin dose,
and accuracy of carbohydrate counting and dose administered. If hypoglycemic
reactions consistently occur at a certain time of day, he should determine whether this
corresponds with a mealtime dose of his rapid-acting insulin and reduces that insulin
dose by 1 to 2 units. If his FPG is running low, his insulin glargine dose can be
If a reaction occurs, G.O. should be instructed to treat it as follows (Table 53-12).
Most hypoglycemic reactions are managed readily with the equivalent of 10 to 20 g
of glucose (see Table 53-12 for examples of carbohydrate sources containing 15 g of
glucose). If the blood concentration remains low after 15 minutes, the patient should
ingest another 10 to 20 g of carbohydrate. This quick-acting source of glucose should
be followed by a small complex carbohydrate or protein snack (e.g., milk, peanut
butter sandwich) to provide a continual source of glucose if a meal is not scheduled
within the next 1 to 2 hours. An easy rule of thumb that can be used by patients is
“15-15-15”: 15 g of glucose followed by a second 15 g if the patient is still
Glucose tablets are available and have the added benefit of being premeasured to
prevent overtreatment of hypoglycemia. Glucose gels, liquid, or small tubes of cake
frosting are useful for children or patients who become uncooperative and combative
Moderate-to-Severe Hypoglycemia
Glucagon can be injected by the SC or IM (preferred) route into the deltoid or
anterior thigh region. Glucagon is used when a patient is unable to self-treat their
hypoglycemia caused by exogenous insulin. The dose of glucagon recommended to
treat moderate or severe hypoglycemia for a child younger than 5 years of age is 0.25
to 0.5 mg; for children 5 to 10 years of age, 0.5 to 1 mg; and for patients older than
10 years, 1 mg. Parents, spouses, or other close contacts should be taught how to mix,
draw up, and administer glucagon during emergency situations. Kits with prefilled
syringes containing 1 mg glucagon are available. Patients who are given glucagon
should be positioned so that their face is turned toward the floor to prevent aspiration
in the event of vomiting. As soon as the patient awakens (10–25 minutes), he/she
If glucagon is unavailable, the patient should be taken to the hospital’s emergency
department, where he/she can be treated with IV glucose (~10–25 g administered as
20–50 mL of 50% dextrose for 1–3 minutes) in preference to glucagon. After the
bolus injection of glucose, IV glucose (5–10 g/hour) should be continued until the
patient has gained consciousness and is able to eat.
breakfast, 10 units regular insulin before lunch and dinner, and 14 units NPH at bedtime.
Should his current insulin regimen be continued? How should he be managed?
effectively. He also is an example of a patient who should not have aggressive BG
targets because he does not feel the symptoms of a low blood sugar and has already
developed end-stage organ damage (proliferative retinopathy and nephropathy).
Neither is likely to be reversed with improved glycemic control. In fact, proliferative
retinopathy may actually worsen with intensive insulin therapy initially.
DCCT study, severe hypoglycemic reactions were 3 times more common among
patients treated with intensive insulin therapy, and nocturnal hypoglycemia accounted
for 41% of the total hypoglycemic episodes.
In patients with defective counterregulation,
the risk of severe hypoglycemia may be 25 times higher than in patients with
adequate counter-regulatory mechanisms treated with intensive insulin therapy.
M.M. is at great risk for death secondary to hypoglycemia.
M.M.’s lifestyle is erratic, he eats irregularly, and his reported BG concentrations
(80–140 mg/dL) do not correspond to his elevated A1C value. This may indicate that
M.M.’s technique is incorrect or that he simply fills in the log with fictitious numbers
before he comes to the clinic. Irregular entries in different colored inks and
bloodstains usually indicate authentic records.
As noted, the primary hormones that are secreted in response to a low BG
concentration are glucagon and epinephrine. In patients who have had Type 1
diabetes for longer than 2 to 5 years, a deficiency in glucagon secretion is a
relatively consistent finding, and these patients must rely on epinephrine to reverse
and this may be related to the development of autonomic neuropathy. Patients whose
diabetes is tightly controlled also have reduced counter-regulatory hormone
responses to hypoglycemia. As illustrated by M.M., patients with defective
epinephrine secretory responses also lose the warning signs and symptoms of
hypoglycemia. These patients are said to have hypoglycemia unawareness because
they have no awareness of BG concentrations less than 50 mg/dL. In these
individuals, loss of consciousness, seizures, or irrational behavior may be the first
objective sign of exceedingly low BG concentrations. The glycemic threshold for
symptoms also is lowered in patients on intensive insulin therapy whose glucose
concentrations have been lowered to normal or near-normal levels.
their hypoglycemic reactions may go unnoticed and untreated until they lose
consciousness. M.M. should be managed as follows:
Because his waking, sleeping, and eating patterns are highly irregular, M.M. should
be treated with an insulin regimen that addresses his lifestyle. For example, he
could be switched to a basal-bolus insulin regimen, in which he can give himself
a rapid-acting insulin just before he actually intends to eat. A dose of insulin
glargine or detemir could be given before his first meal to supply a basal level of
insulin between meals. Additionally, when switching to insulin glargine or
detemir MM should be provided this insulin in a pen formulation as to avoid any
dosing errors from drawing insulin into a syringe based on MM’s current
symptoms of visual impairment.
Because M.M. has no warning symptoms for hypoglycemia, the importance of
regular SMBG should be emphasized. When BG testing was reviewed with
M.M., it was discovered that his eyesight was so poor that he was unable to
distinguish between the right and wrong side of the glucose test strip.
Furthermore, because he had lost his depth of field, he was unable to apply the
drop of blood into the test strip. To address this situation, M.M.’s girlfriend was
taught how to perform BG testing. Also, a glucose monitor that requires a very
small blood sample and beeps with an adequate blood sample would be
M.M.’s girlfriend also was taught how to recognize and treat symptoms of
hypoglycemia and how to administer glucagon. Often, patients ignore early
warning symptoms and progress to a point that they lose the judgment needed to
treat the condition. If M.M. has not yet become combative, a quick-acting
carbohydrate source should be offered. If he has lost consciousness, glucagon
All of these maneuvers diminished the frequency of M.M.’s severe hypoglycemic
reactions. On the whole, his BG concentrations were maintained below 180 mg/dL,
and he remained relatively free of hyperglycemic symptoms. M.M.’s A1C using a
basal-bolus insulin regimen was 8.0%.
has been unable to eat, she has omitted her usual morning dose of insulin for the past 2 days. Her
gastrointestinal (GI) symptoms progressed, and she was brought to the emergency department when she
Laboratory results on admission disclosed the following:
White blood cell count, 15,000/μL with 3% bands (normal, 3%–5%), 70% polymorphonuclear neutrophils
(normal, 54%–62%), and 27% lymphocytes (normal, 25%–33%)
Serum ketones, moderate at 1:10 dilution (normal, negative)
The urinalysis showed the following:
Specific gravity, 1.029 (normal, 1.020–1.025)
No white blood cells, red blood cells, bacteria, or casts
Arterial blood gas results were as follows:
What supports the diagnosis of DKA in J.L.?
The fact that J.L. has Type 1 diabetes puts her at risk for developing ketoacidosis.
About 80% of DKA cases occur in patients older than 18 years of age with about
one-third of those occurring in patients older than 45 years of age.
absolute or relative insulin deficiency promotes lipolysis and metabolism of free
fatty acids to β-hydroxybutyrate, acetoacetic acid, and acetone in the liver. Excess
glucagon enhances gluconeogenesis and impairs peripheral ketone utilization.
Physiologic stress contributes to the development of DKA by stimulating release of
insulin counter-regulatory hormones including glucagon, catecholamines,
glucocorticoids, and growth hormone. Common stress factors include infection,
pregnancy, pancreatitis, trauma, hyperthyroidism, and acute MI.
J.L. presented with symptoms of nausea, vomiting, diarrhea, and chills, and these
are suggestive of an acute viral gastroenteritis.
Patients such as J.L. commonly discontinue their insulin in this setting, which can
rapidly precipitate the development of DKA (see Case 53-5) . Table 53-22 lists
patient education points with regard to DKA.
As illustrated by J.L., patients with DKA present with moderate-to-high serum
glucose concentrations secondary to decreased peripheral utilization and increased
hepatic production (Table 53-23). This increases serum osmolality, which initially
shifts fluid from the intracellular to the extracellular space. When serum glucose
concentrations exceed the renal threshold for reabsorption of about 200 mg/dL,
glucose “spills” over into the urine and causes an osmotic diuresis that depletes the
total body water and electrolytes. J.L. also has lost fluid and electrolytes from
vomiting and diarrhea. Eventually, as losses exceed input, the patient becomes
dehydrated (dry mucous membranes; dry skin; soft, shrunken eyeballs; increased
hematocrit), and intravascular volume becomes depleted (orthostatic BP and pulse
The finding of hyperkalemia in J.L. is also common in DKA because insulin
contributes to the intracellular shift of potassium.
156 The relative deficiency of insulin
in DKA results in an extracellular shift of potassium that is worsened by the acidosis
157 A finding of hypokalemia in DKA (<3.3 mg/dL) is uncommon
and is a marker of more severe disease. In the hypokalemic patient, the combination
of the extracellular shift of potassium and polyuria has led to excessive depletion of
total body potassium. Care must be used in these patients to replace potassium
intravenously before beginning insulin therapy, which will cause further hypokalemia
as potassium shifts back into cells.
Diabetic Ketoacidosis: Patient Education
Definition: DKA occurs when the body has insufficient insulin
Has insulin use been discontinued or a dose skipped for any reason?
the bottle of NPH look frosty?
Have insulin requirements increased owing to illness or other forms of stress (infection, pregnancy,
pancreatitis, trauma, hyperthyroidism, or MI)?
elevated blood glucose concentrations (>300 mg/dL)
Signs of acidosis: fruity breath odor, deep and difficult breathing
Signs of dehydration: dry mouth; warm, dry skin; fatigue
Others:stomach pain, nausea, vomiting, loss of appetite
Review “sick day management” (Table 53-20)
Test blood glucose ≥4 times daily
Test urine for ketones when blood glucose concentration is >300 mg/dL
Drink plenty of fluids (water, clear soups)
DKA, diabetic ketoacidosis; MI, myocardial infarction; NPH, neutral protamine Hagedorn.
Common Laboratory Abnormalities in Diabetic Ketoacidosis (DKA)
Serum osmolarity Variable, can be >320 mOsm/kg in presence of coma
Ketones Present in urine and blood
WBC count 15,000–40,000 cells/μL even without evidence of infection
aTotal body sodium is always low.
Evidence of excessive ketone production in J.L. includes ketonuria, ketonemia, and
the characteristic fruity odor of acetone on the breath. Elevated levels of these
organic acids increase the anion gap and decrease the pH and carbonate levels. The
respiratory rate is increased to compensate for the metabolic acidosis leading to
CASE 53-10, QUESTION 2: How should J.L. be treated?
Treatment of patients with DKA is aimed at expansion of intravascular and
extravascular volume, replacement of electrolyte losses, and cessation of ketone
Rapid correction of fluid loss is most crucial. The usual fluid deficit is difficult to
estimate in the absence of overt hypernatremia but approximates 5% to 10% of body
weight in most patients depending on the severity of the DKA. In the absence of
cardiac compromise, hypernatremia, or significant renal dysfunction, isotonic saline
J.L. has evidence of significant dehydration and intravascular volume depletion.
Based on body weight, if the patient has the typical 5% to 10% weight loss, that
would indicate approximately 3 to 6 L of fluid will be needed to fully replete (10%
of 60 kg = 6-kg loss and 1 L = 1 kg). It is recommended that fluids be replaced at the
rate of 15 to 20 mL/kg/hour during the first hour (~1 to 1.5 L in the average adult).
The subsequent choice for fluid replacement depends on the patient’s state of
hydration, serum electrolyte levels, and urinary output. If the corrected sodium is
normal or elevated, 0.45% NaCl infused at a rate of 4 to 14 mL/kg/hour is
appropriate. If the corrected serum sodium is low, 0.9% NaCl is preferred.
serum glucose concentrations approach 200 mg/dL, solutions should be changed to
D5W/0.45% NaCl. Glucose is added to allow the continuation of insulin therapy
without causing hypoglycemia (see Case 53-10, Question 5).
Management of Diabetic Ketoacidosis
Start IV fluids using normalsaline (0.9% NaCl) unless patient has cardiac compromise
Rate is 15–20 mL/kg body weight or 1–1.5 L during first hour
Use 0.9% NaCl if corrected sodium is low
Once serum glucose reaches 200 mg/dL, change to 5% dextrose with 0.45% NaCl at 150–250 mL/hour
Maintenance dose: 0.1 units/kg/h IV
If blood glucose level has not decreased by 50–75 mg/dL after 1 hour, double infusion rate
dextrose with 0.45% NaCl (do not stop insulin infusion)
When SC insulin can be initiated, administer dose 1–2 hours before discontinuing IV infusion
but <5.3 mEq/L, give 20–30 mEq in each liter of IV fluid to maintain K between 4 and 5 mEq/L
potassium phosphate salt, 20–30 mEq added to replacement fluid. Rarely needed
Replacement is controversial and may be dangerous
DKA, diabetic ketoacidosis; IM, intramuscular; IV, intravenous; SC, subcutaneous.
Total body sodium usually is depleted by 7 to 10 mEq/kg of body weight in patients
with DKA. In assessing serum sodium in these patients, it is important to remember
that falsely low values (i.e., pseudohyponatremia) may be the result of hyperglycemia
and hypertriglyceridemia. A corrected sodium value can be estimated by adding 1.6
mEq/L to the observed sodium value for every 100 mg/dL glucose in excess of 100
mg/dL. Sodium is replaced adequately with normal saline, which has a sodium
Potassium balance is altered markedly in patients with DKA because of combined
urinary and GI losses. Invariably, total body potassium is at least partly depleted;
however, the serum potassium concentration may be high, normal, or low, depending
on the degree of acidosis and volume contraction and severity of insulin deficiency.
Usual potassium deficits in this situation average 3 to 5 mEq/kg of body weight,
although they may be as high as 10 mEq/kg.
Thus, J.L. needs approximately 200 to 350 mEq of potassium to replenish her body
stores, assuming her normal weight is 70 kg. To prevent hypokalemia, potassium
replacement should be started after her serum potassium concentrations decrease to
less than 5.3 mEq/L (assuming an adequate urine output of 50 mL/hour). The addition
of 20 to 30 mEq/L is usually sufficient to maintain the serum potassium at greater than
4 mEq/L. In cases when serum potassium is low at presentation (<3.3 mEq/L),
potassium replacement should be initiated with fluid therapy, and insulin therapy
delayed until the potassium level is greater than 3.3 mEq/L to avoid severe
hypokalemia and the risk of cardiac arrhythmias and diaphragmatic weakness. In
these cases, initial IV solutions should contain 20 to 30 mEq/L of potassium chloride.
Phosphate is lost as the result of increased tissue catabolism, impaired cellular
uptake, and enhanced renal excretion. Like other electrolytes, serum levels initially
may seem normal, even though body stores are depleted. However, replacement can
result in hypocalcemia, and the use of phosphate in DKA has resulted in no clinical
156 Severe hypophosphatemia (<1.0 mg/dL) can cause cardiac and
skeletal muscle weakness as well as respiratory depression. To avoid this, phosphate
can be carefully replaced in patients with cardiac dysfunction or respiratory
depression when phosphate concentrations are less than 1.0 mg/dL. Potassium
phosphate can be added to the replacement fluids in the amount of 20 to 30 mEq/L.
CASE 53-10, QUESTION 3: What is an appropriate insulin dose and route of administration for J.L.?
Insulin therapy is the key to DKA management because it is what stops the
mild (pH 7.25–7.30) and uncomplicated, regular insulin by continuous infusion is the
treatment of choice. Once hypokalemia (K+ <3.3 mEq/L) is excluded or treated, an IV
bolus of regular insulin at 0.1 units/kg followed by a continuous infusion at a dose of
0.1 units/kg/hour should be administered. This should decrease the plasma glucose
by at least 10% in the first hour. If there is not at least a 10% reduction in the first
hour, then a second bolus of 0.15 units/kg should be administered. Once the plasma
glucose reaches 200 mg/dL, the insulin infusion can be decreased to 0.05
units/kg/hour. Alternatively, insulin can be switched to SC at a dose of 0.1 units/kg
every 2 hours. Regardless of the route of insulin therapy, serum glucose should be
maintained at less than 200 mg/dL.
156 At this point, the fluid should be changed to
D5W with 0.45% NaCl. Thereafter, the rate of insulin administration and the rate of
infusion of D5W with 0.45% NaCl are adjusted to maintain the glucose value at
around 200 mg/dL until the ketosis is resolved.
156 Resolution of ketosis is marked by
a serum bicarbonate level of at least 15 mEq/L, a venous pH greater than 7.3, and a
calculated anion gap of 12 mEq/L or less. Once any two of those three findings are
present, the patient can be converted to a longer-acting SC regimen.
For mild DKA (serum bicarbonate ≥15 mEq/L, anion gap <15), SC rapid-acting
insulin has been used with no differences in patient outcomes. The advantage is that
patients can be treated in a non-ICU setting, thus reducing hospital costs. The dosing
for rapid-acting insulin is included in Table 53-24.
questions. Laboratory and clinical data 4 hours after therapy are as follows:
Serum ketones, strongly positive at a 1:40 dilution
The assumption that ketosis is worse in J.L. is incorrect. In DKA, low levels of
insulin and elevated glucagon levels promote the metabolism of free fatty acids in the
liver to acetoacetate and β-hydroxybutyrate. The standard nitroprusside reaction test
for ketones measures only acetoacetate, even though β-hydroxybutyrate is the more
important ketone. The conversion of acetoacetic acid to β-hydroxybutyrate is coupled
closely with the reduced NADH:NAD ratio. If this ratio is high (as in the presence of
alcohol), so much β-hydroxybutyrate may be formed that acetoacetate is virtually
undetectable; thus, the absence of ketones in the serum does not rule out ketoacidosis.
Conversely, treatment with insulin begins to suppress lipolysis and fatty acid
oxidation; nicotinamide adenine dinucleotide is regenerated, shifting the reaction
back in favor of acetoacetate.
156 Thus, even though there seem to be higher
concentrations of ketones in the serum, J.L.’s declining BG concentration, improved
bicarbonate concentrations, and improved acid–base and cardiovascular responses
indicate that she is responding appropriately. Therefore, no change in the insulin dose
is indicated. It is important to emphasize that the glucose concentrations normalize
before ketones (4–6 hours vs. 6–12 hours) because the latter are metabolized more
slowly. For this reason, it is important to continue insulin to maintain suppression of
lipolysis until plasma and urine ketones have cleared.
The use of bicarbonate in patients with DKA has been controversial.
investigators discourage its routine use, reserving it for patients with severe
acidemia (pH <6.9) or those in clinical shock. Coma is correlated most closely with
BG concentrations (>700 mg/dL) and hyperosmolality (calculated osmolality >340
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