Evidence Based

Guidelines for
Management of
Diabetic
Ketoacidosis

Azza Shaltout
FRCP FRCPCH
 What is evidence-based medicine?
• Evidence-based medicine (EBM)
has been defined as "the
conscientious, explicit, and
judicious use of current best
evidence in making decisions
about the care of individual
patients”.

Sackett D, et al. " BMJ 199312,(7023)

 What is evidence-based medicine?

“ Integration of best research

evidence with clinical expertise
and patient values ”

Sackett D, et al. Evidence-Based Medicine:

How to Practice and Teach EBM (New York:
Churchill Livingstone, 2000)
 ADA evidence grading system
Levels of evidence
A . Clear evidence with well conducted , randomized
controlled trials that are adequately powered
. Multicentre trials
. Meta analysis incorporating quality ratings
B . Supp. evidence from well conducted cohort studies
C . Supp. evidence from poorly controlled or
uncontrolled studies , or conflicting evidence with the
weight of evidence supporting the recommendations
E . Expert consensus opinion or clinical experience
 European Society for Paediatric
Endocrinology/Lawson Wilkins
Pediatric Endocrine Society

•Consensus Statement on
DKA in Children and
Adolescents

Dunger D et al. Pediatrics. 2004; 113: 133 - 140.

 Introduction
 DKA is the leading cause of morbidity
&
mortality in children with TIDM.

 Mortality is predominantly related to

the occurrence of cerebral edema ; only
a minority of deaths in DKA are
attributed to other causes.

 Cerebral edema occurs in 0.3% to

1% of all episodes of DKA , & its
etiology, pathophysiology & ideal
method of treatment are poorly
understood
 The risk of DKA in
established TIDM

• is 1% to 10% per
patient per year
 Epidemiology of DKA
• Accounts for 65% of admissions in
children with diabetes < 19 years
•  15% to 67% of newly onset type 1
diabetes in Europe and North America
present with DKA
•Correlates inversely with the incidence,
socioeconomic status and presence of other
family members with diabetes
 Incidence and severity of ketoacidosis in
childhood-onset diabetes in Kuwait
• The annual incidence of childhood onset diabetes for
Kuwaiti children 1992-1993 was 15.4 per 100,000
243 children <15 years were identified.
• Nearly half of the children (49%) presented in
ketoacidosis.
• In 23.5% it was severe (venous pH < 7.1 and/or
plasma bicarbonate level < 10 mmol/l).
• All children recovered completely without
major complications

Al-Khawari M ., Shaltout A et al Diab Res Clin Pract. 1997;35:123-

8.
 Risk is increased in:
• Children with poor metabolic control or
previous episodes of DKA
• Peri pubertal and adolescent girls
• Children with psychiatric disorders
(including those with eating disorders)
• Difficult family circumstances
• Inappropriate interruption of insulin-pump
therapy also leads to DKA.
 Risk
 Children whose insulin is administered by a
responsible adult rarely have episodes of DKA

(C)

 75% of episodes of DKA beyond diagnosis

probably are associated with insulin omission

or treatment error.
 Diagnosis of DKA
Hyperglycemia (blood glucose: >11 mmol/L
[ 200 mg/dL]) with a venous pH <7.3 and/or
bicarbonate <15 mmol/L.

DKA can be classified as:

• mild (pH: < 7.3 ; bicarb : <15 mmol/L)
• moderate (pH: < 7.2 ; bicarb: <10 mmol/L)
• severe (pH: < 7.1 ; bicarb: < 5 mmol/L).
 Insulin Deficiency &
Counter Regulatory Hormone Activity
Lipolysis proteolysis Glycogenolysis Peripheral glucose
Fat, Protein Synthesis Gluconeogenesis utilization

Gluconeogenic
substrates HYPERGLYCEMIA
(FFA,alanine)

DKA Absolute deficiency

FFA oxidation OSMOTIC DIURESIS
Ketogenesis

KETOACIDOSIS VOL CONTRACTION ELECTROLYTE LOSSES

 Usual losses of fluids and electrolytes in DKA
and normal maintenance requirements
Average losses/kg Maintenance
(range) requirements/ m2
• water 70 mL (30–100) 1500 mL/m2
• Sodium 6 mmol (5–13) 45 mmol
• Potassium 5 mmol (3–6) 35 mmol
• Chloride 4 mmol (3–9) 30 mmol
• Phosphate (0.5–2.5) mmol 10 mmol
 Goals of therapy

• Correct dehydration
• Restore blood glucose to near normal
levels
• Correct acidosis and reverse ketosis
• Avoid complications of treatment
• Identify and treat the precipitating event
• Avoiding cerebral edema
 Management of DKA

• Fluid and salt

• Insulin
• Potassium
• Phosphate
• Acidosis
• Cerebral Edema
 Assess degree of dehydration

Infants Children
• Mild : 5% • Mild : 3%
• Moderate: 10% • Moderate : 6%
• Severe : 15% • Severe : 9%
 Water and salt replacement
• Immediate 0.9% saline 10-20 ml/kg/hr (or balanced
salt solution such as Ringer Lactate) for volume
expansion. The volume and rate depends on
circulatory status (E)
• Use crystalloid (A)
• Subsequent fluid replacement should be > 0.45%
saline with added potassium(E)
• Rate and volume: rehydrate over 48 hours (E)
• Do not exceed 1.5 to 2 times the normal fluid
requirements for age , weight or body surface area (E)
Correction of Insulin Deficiency
 Insulin IV 0.1 U/kg per hour (A) at least
until resolution of ketoacidosis (pH: >7.30;
HCO3: >15 mmol/L and/or closure of anion gap).
 Glucose should be added to the IV fluid
when the plasma glucose falls to 14 to 17
mmol/L (250–300 mg/dL) (B).
 In unusual circumstances in which IV
administration is not possible, the IM or SC
route of insulin administration has been used
effectively (C).
 IV bolus is not necessary ( C )
 POTASSIUM
•Replacement therapy should be based on serum
•
potassium measurements (E).

Start potassium replacement immediately if the patient is

hypokalemic; otherwise, start potassium concurrent with
starting insulin therapy. If the patient is hyperkalemic ,
defer potassium until urine output is documented (E).
Starting potassium concentration in the infusate should be
40 mmol/L (E), and potassium replacement should
continue throughout IV fluid therapy (E).
 PHOSPHATE

• There is no evidence that replacement has

clinical benefit (A).
• Severe hypophosphatemia should be treated
(C).
• Potassium phosphate salts may be used as an
alternative to or combined with potassium
chloride/acetate (C).
• Administration of phosphate may induce
hypocalcemia (C).
 ACIDOSIS
In DKA, there is an increased anion gap.
The major retained anions are ß-OHB and acetoacetate.

•Anion gap=[Na+]-( [Cl-]+[HCO3-] ):normally 12+ 2mmol/L

• Corrected K = measured K- 6 (7.4- measured pH)
•Corrected Na = measured Na + 1.6 ( Glucose – 5.6 )
5.6
• Osmolality = (2  serum Na ) + glucose + serum urea(mmol)
 ACID BASE
• Protocols no longer recommend bicarbonate
administration unless the acidosis is "profound" and
“ likely to affect the action of adrenaline/epinephrine
during resuscitation" (A).
• Fluid and insulin replacement without bicarbonate
administration corrects ketoacidosis (A).
• Bicarbonate confers no clinical benefit (B).
• Repair fluids containing various buffering agents
(bicarbonate, acetate, and lactate) have been used (C).
The efficacy and safety of these agents have not been
established.
 Alkali Therapy
• Bicarbonate therapy may cause
Paradoxical CNS acidosis
• Rapid correction of acidosis by bicarbonate will
result in Hypokalemia and
• May accentuate sodium load and contribute to
Serum hypertonicity.
• Alkali therapy may increase hepatic ketone
production, thus slowing the rate of recovery
from the ketosis.
Evolution of acidosis in a 14 months’ old infant with severe DKA

t=0 Hr 6 Hr 15 Hr
pH 6.96 7.16 7.28
PaCO2 ( mmHg) 7.3 15.9 23
Bicarbonate (mmol/L) 1.6 5.7 10. 6
Base excess -28.4 -22.9 -16.0
Sodium (mmol/L) 126 130 134
Potassium (mmol/L) 4.18 3.46 3.73

No Need for NaHCO3 regardless of pH!

 Bicarbonate therapy
• Patients with severe acidemia (arterial pH <6.9)
,with decreased cardiac contractility &
peripheral vasodilatation impaired
tissue perfusion
• Life-threatening HYPERKALEMIA.
• Severe acidosis is (arterial pH ≤ 6.9) plus
hypotension , shock, or an arrhythmia.
• 1 to 2 mmol/kg or 40 to 80 mmol/m2 of
NAHCO3 is infused over 2 hours and the
plasma bicarbonate level is rechecked.
Pediatric Clinics of North America
Volume 52 • Number 4 • August 2005
 Evaluation and treatment of DKA
Replete
History Replace
Insulin R
LAB
exam IV K+
volume 0.1U/kg/h
Glucose Stop IV
PPT Use 0.9% Insulin ECG
ABG Factors ONLY after
Na enquiry
saline acidosis follow
K resolves labs
BUN When •Give SC
Cr Assess GLU Insulin
PO4 IV Falls 30 min
volume <250mg/dL prior
CBC Use 0.45% to stopping
Saline in D5%W
Urine insulin drip
 Complications of DKA
Other possible causes of mortality and morbidity include(C):
CNS complications :( hematoma ,thrombosis )
Sepsis, infections ( Aspiration pneumonia, pulmonary
edema )
Adult respiratory distress syndrome
( pneumomediastinum & subcutaneous emphysema
and rhabdomyolysis )
Late sequelae relate to cerebral edema and other CNS
complications include( C ):
Hypothalamopituitary insufficiency
Isolated growth hormone deficiency, and
Combined growth hormone and thyroid-stimulating
hormone deficiency.
 Complications of therapy

• Inadequate rehydration
• Hypoglycemia
• Hypokalemia
• Hyperchloremic acidosis
• Cerebral edema
Prominent U waves after T waves in hypokalemia
 Cerebral Edema in DKA

Cerebral edema accounts for between 57% and 87% of all

DKA deaths.

The incidence of cerebral edema has been fairly consistent

between national population-based studies: 0.46%

(Canada), 0.68% (United Kingdom), and 0.87%

(
 Cerebral edema
When does it occur?
• Cerebral edema typically occurs 4 to 12 hours
after treatment is activated but can be present
before treatment has begun ( C) or may develop
any time during treatment for DKA( B)

• Preliminary imaging studies in children with DKA using

ultrasound, CT or MRI, indicate that some degree of cerebral

edema may be present even in patients without clinical evidence

of raised ICP
 Pathophysiology
Several hypotheses reported in the literature.
• Too rapid correction of the osmotic disequilibrium between
neurons and extracellular fluid mediated by “idiogenic
osmols”;
• A syndrome of inappropriate secretion of ADH as a
contributor to the shift of sodium into neurons;
• Hypoxemia caused by dehydration and contraction of the
extracellular space with decreased cerebral blood flow;
• Overzealous bicarbonate administration [1]

American Journal of Emergency Medicine

Volume 23 • Number 3 • May 2005

 Risk Factors
There is evidence that
• 61 children with CE complicating DKA were
identified in 10 centres in the US were
identified between 1987-1992.
• Children with DKA who had
a) low partial pressures of arterial carbon dioxide (C )
b) high serum urea nitrogen concentrations at
presentation and
c) treated with bicarbonate (C) were at increased risk
for cerebral edema.
Glaser et al N Engl J Med 2001;344:264-269
 Risk Factors
There is evidence that
Relative Risk

 Low PaCO
2
3.4 for each PaCO
2
7.8 mm Hg )

 Elevated s. urea nitrogen 1.7 for each of 9 mg/dl

Treatment with bicarbonate 4.2

Glaser et al N Engl J Med 2001;344:264-269

 Risk factors for cerebral edema
An attenuated rise in measured serum
sodium concentrations during therapy
for DKA( C )

Cerebral edema in DKA may be related

to brain ischemia with cerebral
hypoperfusion resulting from hypocapnia
and circulatory volume depletion

Glaser et al N Engl Med 2001;344:264-269

 Na-K-Cl cotransporter in cerebral microvascular
endothelial cells and astrocytes
are stimulated by :
• HYPOXIA
• VASOPERESSIN
• ENDOTHELIN-1
• Ketoacids acetoacetate and ß-
hydroxybutyrate
Bumetanide Reduces Cerebral Edema Formation in Rats With DKA
Diabetes 2005 54:510-516,
 Monitoring for symptoms and signs of
Cerebral Edema

Hourly or more-frequent neurologic observations for

warning signs and symptoms of cerebral edema:
.
Headache
. Inappropriate slowing of heart rate
. Recurrence of vomiting
. Change in neurologic status (restlessness,
irritability, increased drowsiness, or incontinence),
or specific neurologic signs (eg, cranial nerve palsies
or pupillary response)
. Rising blood pressure
. Decreased oxygen saturation
 Bedside evaluation of neurologic state of
children with diabetic ketoacidosis
DIAGNOSTIC CRITERIA
• Abnormal motor or verbal response to pain
• Decorticate or decerebrate postures
• Cranial nerve palsy (especially III, IV, and VI)
• Abnormal neurogenic respiratory pattern (eg, grunting,
tachypnea, Cheyne-Stokes respiration, apnoea)

MAJOR CRITERIA
• Altered mentation/fluctuating level of consciousness
• Sustained heart rate deceleration (decrease >20
beats/min) not attributable to improved intravascular
volume or sleep state
• Age-inappropriate incontinence
 Bedside evaluation of neurologic state of
children with diabetic ketoacidosis

MINOR CRITERIA
• Vomiting
• Headache
• Lethargic or not easily arousable
• Diastolic blood pressure more than 90 mm Hg
• Age younger than 5 years

• One diagnostic criterion, two major criteria, or one

major and two minor criteria have a sensitivity rate of
92% and a false-positive rate of 4% .

Muir et al Diabetes Care 2004 ;27:1541-1546

 Cerebral Edema
Treatment
• Treatment should be initiated as soon as the
condition is suspected.
• The rate of fluid administration should be
reduced.
• IV mannitol should be given (0.25–1.0 g/kg over
20 minutes) in patients with signs of cerebral
edema before impending respiratory failure (C,
E).
• Repeat in 2 hours if there is no initial response.
• Hypertonic saline (3%), 5 to 10 mL/kg over 30
minutes, may be an alternative to mannitol (C).
 Cerebral Edema
Treatment
• Intubation and ventilation may be necessary.
Aggressive hyperventilation has been associated
with poor outcome in one retrospective study of
DKA-related cerebral edema;
• Detrimental effects have been reported in
numerous other conditions such as head trauma
and high-altitude exposure.
• There are no data regarding glucocorticoid use
in DKA-related cerebral edema.
 Prevention
• High levels of public awareness (E ),
• A school and physician awareness
campaign(B)
• Studies of the effects of comprehensive
diabetes programs and telephone help lines
report a reduction in the rates of DKA
from 15–60 to 5–5.9/100 patient-years (B).
• Access to a 24-hour diabetes telephone help
line (A).