Diabetic Ketoacidosis (DKA):
Treatment Guidelines
Arlan L Rosenbloom, M.D.1
Ragnar Hanas, M. D. 2
Summary: Diabetic ketoacidosis (DKA), resulting from severe insulin deficiency, accounts for
most hospitalization and is the most common cause of death, mostly due to cerebral edema, in pediatric diabetes. This article provides guidelines on management to restore perfusion, stop ongoing
ketogenesis, correct electrolyte losses, and avoid hypokalemia and hypoglycemia and the circumstances that may contribute, in some instances, to cerebral edema (overhydration, rapid osmolar
shifts, hypoxia). These guidelines emphasize the importance of monitoring glycemia, electrolytes,
hydration, vital signs, and neurologic status in a setting where response can be rapid if necessary
(e.g., mannitol for cerebral edema). Most important is the prevention of DKA in established
patients by close supervision of those most likely to omit insulin, or during illness, and a high index
of suspicion for diabetes to prevent deterioration to DKA in new patients, particularly those under
age 5, who are at greatest risk of complications.
Introduction
Diabetic ketoacidosis (DKA) is
the most common cause of hospitalization of children with diabetes and of death in the pediatric years in this group. Most
deaths can be attributed to intracerebral crises.1 From 20 to 40%
of newly diagnosed patients are
admitted in DKA, depending on
the adequacy and availability of
medical services to diagnose the
diabetes early. Recurrent DKA
in established patients has been
reduced in frequency by the
intervention of multidiciplinary
teams.2,3 Unfortunately, there is
no evidence of a decrease in case
fatality below the 1-2% achieved
by the early 1970s, despite
improvements in fluid and insulin therapy and more careful
monitoring.1,3 Thus, a major
goal of diabetes management is
to prevent DKA by a high index
of suspicion with early symptoms of diabetes and close supervision of established patients.
ten for all circumstances and for
rigid adherence. It should be
obvious that a diagnosis does not
carry with it the assumption that
either the patient or the treatment
regimen will follow the book.
This article is a supplement to,
not a substitute for, clinical judgment.4
This article provides guidelines
to serve as a checklist and
reminder, particularly for those
who do not regularly treat DKA
or hyperosmolar coma in diabetes. Guidelines cannot be writ-
DKA is always caused by insulin
deficiency, either relative or
absolute. Many previously undiagnosed patients have been seen
in physicians offices or emergency rooms where an adequate
history and laboratory study
could have made the diagnosis
before they became critically ill.
A high index of suspicion is particularly important for infants
and young children. An interesting phenomenon is the occasional marked delay in diagnosis
seen in medical families and in
Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL; and
Department of Pediatrics, Uddevalla Hospital, S-451 80 Uddevalla, Sweden.
Reprint requests and correspondence to: Arlan L Rosenbloom, M.D.,
Department of Pediatics, University of Florida College of Medicine, PO Box
100296, Gainesville, FL 32610-0296.
Scanned and reprinted for publication on Internet with permission.
MAY 1996
Cause
CLINICAL PEDIATRICS
261
the siblings or offspring of people with diabetes, reflecting
denial. A simple urine test may
turn out to be lifesaving by preventing the initial episode of
ketoacidosis, particularly in the
high-risk infant and preschool
child.1
In the established patient, DKA
results from:
blood glucose level very high
(often referred to as hyperosmolar nonketotic coma); this occurs
typically in very young patients,
in those with brain disorders that
may affect thirst responses, and
in older adolescents with
new-onset noninsulin-dependent
diabetes. These treatment guidelines also apply to these variants.
Coma: Results from hyperosmolality, not acidosis; calculated osmolality greater than
320 mosm/L is associated with
coma (8).
Hyperosmolality: Largely due
to hyperglycemia; calculated as
Na (mmol/L) x 2 + glucose (mg/dL)
18
+ BUN (mg/dL)
2.8
Presentation
Failing to take insulin, the most
common cause of recurrent
DKA, particularly in adolescents.5
Acute stress, which can be
trauma, febrile illness, or psychological turmoil, with elevated counterregulatory hormones (glucagon, epinephrine,
cortisol, growth hormone).
Poor sick-day management,
typically not giving insulin
because the child is not eating
or failing to increase insulin for
the illness, as dictated by blood
glucose monitoring. Home testing of urine for ketones with
test strips may be misleading
and result in delayed institution
of sick-day management; the
strips can deteriorate and give
false-negative readings. Nitroprusside tablets are less convenient but very stable and reliable (6).
Definition
The combination of hyperglycemia (greater than 12 mmol/L),
hyperketonemia (large serum
ketones-acetone or betahydroxybutyrate) or large ketonuria, with
acidosis (venous pH <7.3 or
serum bicarbonate <15 mmol/L).
Occasionally, DKA can occur
with normoglycemia when there
is vomiting, reduced intake of
carbohydrate, and continued
insulin therapy.7 There are also
pediatric instances of coma in
which ketosis is mild but the
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CLINICAL PEDIATRICS
Hyperglycemia: Insulin deficiency results in decreased glucose uptake with tissue starvation resulting in proteolysis and
lipolysis providing amino acids
and glycerol for gluconeogenesis, enhanced by counterregulatory hormone response to both
the precipitating and tissue
starvation stress; in the liver,
insulin deficiency results in
glycogenolysis and enhanced
gluconeogenesis, also stimulated by counterregulatory hormones.
Dehydration
and
thirst:
Results from osmotic diuresis
due to hyperglycemia and
hyperketonemia, hyperventilation, and vomiting as part of
the primary precipitating illness or resulting from the ketosis; since dehydration is usually
hyperosmolar and mostly intracellular, dehydration may be
underestimated by clinical
examination.
Acidosis: Due to ketonemia
from
overproduction
of
ketones, which cannot be
metabolized in the absence of
insulin, and lactic acidosis
from tissue hypoperfusion.
Rapid deep respiration (Kussmaul):
Compensatory
response to the metabolic acidosis, contributing to dehydration.
or
Na (mmol/L) x 2 +
glucose (mmol/L) + urea (mmol/L)
Hyperlipidemia:
Due
to
counter-regulatory-hormonestimulated
lipolysis
and
hypoinsulinemia.
Electrolyte disturbances: Spuriously low Na level due to
osmolar dilution by glucose
and sodium-free lipid fraction.
Corrected Na (i.e., for normal
glucose level) can be estimated
as measured
Na + (glucose in mmol/L-5.6)
2
Na deficit is estimated at 10
mmol/kg body weight. Potassium may be spuriously normal
because of acidosis-related exudation from tissues and obligatory urinary losses; estimate total
K deficit at 5 mmol/kg. Potassium deficits in newly diagnosed
patients may be greater than in
established patients because of
the longer duration of polyuria
before admission.
Other Findings
BUN: elevated as a result of
dehydration.
Creatinine: may be falsely elevated due to interference in the
autoanalyzer
methodology
from ketones.
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Serum ketones: dilutions for
nitroprusside testing of no
value;
betahydroxybutyrate
will be most abundant and is
not measured by nitroprusside,
but betahydroxybutyrate assay
is available in many laboratories.
Elevated WBC with shift to the
left is a stress response that is
not helpful for diagnosing
intercurrent infection.
Elevated serum amylase level
is salivary, not pancreatic;
acute pancreatitis may occasionally be seen with DKA, in
which case serum lipase level
will also be increased.
Abdominal pain and tenderness, with ileus, are usually
nonspecific and improve with
improvement of the metabolic
state (if not, these need to be
evaluated as with any other
acute abdominal problem).
Increased blood pressure and
heart rate are due to constricted
circulatory volume and stress
state.
Retrosternal or neck pain with
dysphonia, dyspnea, or subcutaneous emphysema can occur
from pneumomediastinum due
to alveolar rupture from hyperventilation or retching. Typically, however, pneumomediastinum is asymptomatic (9).
Treatment
Basic rules in dealing with DKA
are:
1. Admit patients only to a unit
in which neurologic status and
vital signs can be monitored
frequently and blood glucose
level measured hourly.
MAY 1996
2. Personally evaluate the patient
early on admission and frequently thereafter.
3. Keep good records, including
rationalization for decisions,
and a flow sheet.
4. Develop a relationship with a
pediatric diabetes specialist
you trust and call him or her
with any questions, including
whether the patient needs to
be transferred to a specialized
unit.
The patient who does not have
persistent vomiting, with a pH
>7.25, can be treated and
observed in the emergency room
over a few hours without hospital admission.
The goals of treatment are:
1. Restore perfusion, which will
increase glucose use in the
periphery and reverse the progressive acidosis.
2. Stop ketogenesis by giving
insulin, which will reverse
proteolysis and lipolysis, and
stimulate glucose uptake and
processing,
normalizing
blood glucose concentration.
3. Correct electrolyte losses.
4. Avoid the complications of
treatment insofar as possible,
including intracerebral complications, hypoglycemia, and
hypokalemia.
Fluid Therapy
Can generally assume 10%
dehydration (100 mL/kg), up to
15% in infants.
Provide 20 mL/kg 0.9% NaCl
in first one to two hours to
restore peripheral perfusion.
In the patient with shock or
preshock give 5% albumin,
20-25 mL/kg, as initial hydration.
Calculate
maintenance
in
usual fashion (e.g., 1,000 mL
for first 10 kg + 500 mL for
next 10 kg + 20 mL/kg over 20
kg).
Calculate remainder of replacement after the loading dose
based on 10% dehydration, and
maintenance for administration over the subsequent 22 to
23 hours.
If osmolality (calculated or
measured) is >320 mosm/L,
correct in 36 hours and if >340
mosm/L, correct in 48 hours.
After initial 0.9% NaCl bolus,
continue rehydration/maintenance with 0.45% NaCl. Some
prefer to continue with
Ringers lactate or acetate solution; however, hyperosmolar
patients should be changed to
0.45% NaCl after the initial
bolus of 0.9% NaCl. During
rehydration the measured Na
can increase to the level of the
corrected Na as glycemia
declines and then decline to
normal levels if the corrected
level was elevated.
Provide K (20-40 mmol/L or
up to 80 mmol/L as needed) as
half KCL, half KPO4 (to
replenish low phosphate levels
and to decrease the risk of
hyperchloremia) or as half
KPO4 and half K acetate
(which, like lactate, is converted to bicarbonate to help
correct acidosis) after serum K
reported as less than 6 mmol/L
or urine flow is established.
Bicarbonate is rarely indicated. There is no evidence that
bicarbonate facilitates metabolic recovery. It should be
CLINICAL PEDIATRICS
263
given when there is absence of
hyperventilation; never give
bicarbonate by push, for this
can
produce
dangerous
hypokalemia. Safe administration to avoid risk of hypokalemia is to give 1-2 mmol/kg
body weight or 80 mmol/m2
body surface area over 2
hours.10 Reduce NaCl concentration in the fluids to allow for
added Na ion unless Na level in
the serum is subnormal.
Insulin
Insulin can be started immediately at the time of the initial
fluid expansion or it can be
held until the fluid expansion is
completed for a more realistic
starting glucose level.
The most widely used system
is 0.1 U/kg hourly as a continuous infusion, using a pump.
It may be more convenient in
some settings to administer 0.I
U/kg IV and 0.1 U/kg IM with
subsequent doses of 0.1 U/kg
IM or SC hourly. In adults,
there did not seem to be any
difference whether insulin was
administered
intravenously,
intramuscularly, or subcutaneously after the first couple of
hours of treatment.11
There is no evidence that
low-dose insulin as currently
used results in any less frequency
of
hypoglycemia,
hypokalemia,
or
cerebral
edema than the earlier treatment with much higher doses.
The principal advantages of
low-dose therapy given as continuous IV or hourly injections
are that there is frequent contact with the patient and hourly
blood glucose determinations
are done.
During initial fluid expansion,
a high blood glucose level may
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CLINICAL PEDIATRICS
drop 10-15 mM/L, even without insulin infusion.
High blood glucose levels
should drop 3-8 mmol/L/hr
(but not > 12 mmol/L/hr), and
if they do not, the dose should
be increased. This is rarely necessary.
When the blood glucose level
falls to 15 mmol/L or >12
mmol/L/hr, 5-10% dextrose
should be added to the intravenous fluids.
If the blood glucose level falls
below 8 mmol/L with 10%
dextrose solution running, the
insulin dose should be reduced
to 0.05 U/kg/hr.
Do not stop insulin or reduce it
below 0.05 U/kg/hr, for a continuous supply of insulin is
needed to prevent ketosis and
permit continued anabolism.
Monitoring
A flow sheet is essential to
record the measures noted in
Table 1 at hourly intervals.
The nursing personnel must
have clear guidelines on when
to call the attending physician,
such as findings listed in Table
2.
ECG monitoring should be
done and hourly potassium
measurements made if the initial potassium level is <3 or >6
mmol/L.
Mannitol in quantities sufficient to give 1-2 g/kg body
weight should be kept at the
bedside for the first 36 hours
Table 1
MONITORING TREATMENT OF DKA
Clinical
Interval
Vital signs
20-30 minutes
Coma score (e.g., Glasgow)
20-30 minutes
Laboratory
Glucose
Hourly bedside; in the laboratory
with electrolyte assay, or 1-2 hourly
if outside bedside monitor range
Potassium
Hourly if abnormal (<3 or >6 mM/L)
Sodium, potassium, CO2 or HCO3,
venous pH, osmolality
Admission, 2, 6,10, 24 hrs. (or 2-4
hourly until osmolality normal)
BUN
Admission, 12, 24 hrs.
Betahydroxybutyrate (if available)
Admission, 6,12, 24 hrs.
Ketonuria
Admission, 4-6 hourly
Calcium, phosphorus (optional)
Admission, 12, 24 hrs.
Fluids
Type and rate
Intake (include oral and reduce IV intake accordingly)
Output
Insulin
MAY 1996
Table 2
SIGNS AND SYMPTOMS OF INTRACEREBRAL CRISIS
DURING TREATMENT OF DKA
handling of hydrogen ion as a
result of an episode of renal
hypoperfusion.
Hypokalemia
Decreasing sensorium
Extracellular K concentrations
fall as a result of treatment,
with potassium reentering
cells.
Sudden and severe headache
Incontinence
Vomiting
Combativeness; disorientation; agitation
Change in vital signs (hypothermia, hypotension or hypertension, tachycardia or bradycardia or arrhythmia, gasping respirations, or periods of apnea)
Ophthalmoplegia
Pupillary changes (asymmetry, sluggish to fixed)
If initial serum K <3 mmol/L,
K must be put into the initial
expansion fluids without waiting for demonstration of renal
function and insulin should be
delayed or stopped until after
the initial bolus fluids are
infused.
Papilledema
Intracerebral Complications
Posturing; seizure
(see below under complications).
Resist the convenience of catheterization for monitoring output. The occasional older
patient may have bladder atony
while ketoacidotic and require
initial catheterization, but it is
rare to need an indwelling catheter.
Failure of measured serum Na
level to rise with falling blood
glucose concentration or an
actual decrease in serum Na
may indicate impending cerebral edema. Hydration should
continue slowly and with 0.9%
NaCl solution.
produce ketosis and nausea
with vomiting, particularly in
children.
Persistent Acidosis
Defined as persistence of a
bicarbonate value less than 10
mmol/L after eight to ten hours
of treatment.
Usual cause is inadequate insulin effect, indicated by persistent hyperglycemia. Check
insulin dilution and rate of
administration, consider inadequate absorption if insulin is
being given by subcutaneous or
IM injection or resistance due
to unusually high counterregulatory hormones, as with concomitant febrile illness.
Complications
Infrequent with hourly blood
glucose monitoring.
May need to switch to IV
administration if patient is not
receiving insulin IV. If receiving IV insulin, solution should
be changed every six hours.
With the presence of an intravenous line, severe hypoglycemia is best treated with intravenous glucose. Glucagon can
Extremely rare causes are lactic
acidosis due to an episode of
hypotension or apnea or inadequate renal competency in the
Hypoglycemia
MAY 1996
Intracerebral complications comprise the most serious and frequent complications of DKA and
can occur despite adherence to
the guidelines above. There is no
evidence for reduction in the frequency of intracerebral complications with the advent of
low-dose insulin use by continuous infusion or the shift to more
isotonic initial fluids. Although
the classic picture is one of metabolic and clinical improvement
with sudden deterioration, there
may be up to several hours of
decreasing
sensorium
and
change in vital signs, as noted in
Table 2, and some children will
be admitted in coma and not
recover. An occasional patient
will develop intracerebral complications even before treatment, raising the suspicion of
cerebral thrombosis.
In more than half of patients who
develop intracerebral complications, there is a sufficient warning period to permit administration of mannitol to reduce edema
and, if indicated by respiratory
distress, intubation/hyperventilation to reduce intracerebral blood
flow. When this is accomplished
CLINICAL PEDIATRICS
265
before respiratory arrest, there is
a greater than 50% chance of
survival in the normal state or
with disability that does not preclude independence.l Computerized tomographic (CT) scans
should not be depended upon to
determine the need for intervention; this decision should be
made on clinical grounds. Initial
CT scans, even after respiratory
arrest, often appear normal or
show only localized basilar
edema. The dose of mannitol is I
g/kg body weight intravenously,
over 15 minutes, repeated as
necessary.l3
Particularly susceptible to intracerebral complications are previously undiagnosed patients and
children under 5 years of age.
Mucor Infection
Opportunistic infection with
mucormycosis is a rare and frequently fatal complication of
recurrent ketoacidosis, involving the respiratory tract and
sinuses with erosion into the
brain.l2
Transition
IV fluids can be stopped l-2
hours after substantial consumption of oral fluids without
vomiting.
Subcutaneous insulin injection
can be started when the patient
no longer needs IV fluids.
Wait until the presupper or prebreakfast time to restart intermediate-acting insulin. Until
then, give regular insulin 0.25
U/kg subcutaneously (sc) every
~6 hours and do not stop the
insulin infusion until 60-120
minutes after first sc dose.
-Give the established patient
the usual morning or afternoon insulin dose unless this
266
CLINICAL PEDIATRICS
was inappropriate. The infusion can be stopped an hour
later if still running.
-The new patient can be given
0.5 U/kg intermediate-acting
insulin and stop infusion an
hour later. If blood glucose
level is >220 mg/dL, can combine this with 0.1 U/kg of regular. Various other starting
regimens are used.
Do not keep patient in the hospital simply to adjust insulin
dosage, for food, activity, and
psychosocial environment are
not normal.
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Heller DR, et al: Regional services for children and youth with
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Brouhard BH, Schreiner BJ, eds
Diabetes Mellitus in Children
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PA:
WB
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Dreyer N. Ketotic hyperosmolar
coma. Lancet 1973;ii:63639.
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Conerly AW. Rhinocerebral
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edema in diabetic ketoacidosis
in children. Lancet. 1990;2:64.
Additional reading:
Krane EJ. Diabetic ketoacidosis.
Bio chemistry, physiology, treatment and prevention. Pediatr
Clin
North
Am.
1987;34:935-960.
Mortensen HB, Bendtson I: Diabetic ketoacidosis: diagnosis
and initial emergency management. Diabetes in the Young.
1993;29:4-8.
5) Malone JI, Root AW. Plasma
free insulin concentrations: keystone to effective management
of diabetes mellitus in children.
J Pediat. 1981;99: 862-867.
6) Rosenbloom AL, Malone JI.
Recognition
of
impending
ketoacidosis delayed by ketone
reagent strip failure. JAMA
1978;240:2462-2464.
7) Munro JF, Campbell IW,
McCuish AC, Duncan LJP. Euglycemic diabetic ketoacidosis.
Br Med J. 1973;2:578-580.
MAY 1996