Transcript Diabetic Ketoacidosis in Children Keystone, July, 2008 Arleta Rewers MD, PhD Robert Slover MD.

Diabetic Ketoacidosis in
Children
Keystone, July, 2008
Arleta Rewers MD, PhD
Robert Slover MD
Overview
• Review the incidence and
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•
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pathophysiology of DKA
Define the role of patient selfmonitoring including blood ketones
testing and the healthcare
professional advice in preventing DKA
Describe current approaches to the
clinical diagnosis of DKA, including the
role of ketone body levels
List treatment options for DKA
Definition
• Hyperglycemia BG > 200 mg/dl (11 mmol/l)
(young or partially treated children, pregnant adolescents may
present with “euglycemic ketoacidosis”)
• Venous pH <7.3 and/or bicarbonate <15
mmol/L
– mild DKA pH <7.3 bicarbonate <15
– moderate pH <7.2 bicarbonate <10
– severe
pH <7.1 bicarbonate < 5
• Glucosuria and ketonuria/ketonemia (βHOB)
Incidence of DKA at onset
• Wide geographic variation in DKA rates at
diabetes onset: 15 -70%
• More common in developing countries
• DKA rates inversely related to incidence of
type 1 diabetes
Diabetic Ketoacidosis at Diagnosis of DM in
Youth:
The SEARCH for Diabetes in Youth Study
Incidence of DKA at the time of diagnosis
• SEARCH is multicenter study
• In 2002 began population-based ascertainment
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of incident cases of DM in youth younger than 20
years
Incidence:
Overall - 25.5% (CI 23.9-27.1)
Type 1 - 29.4 % ( CI 27.5-31.3%)
Type 2 - 9.7% ( CI 7.1-12.2)
Rewers A et al., Pediatrics, May 2008
Risk factors for DKA at onset
• Age <12 yrs
• No first degree diabetic relative
• Lower socioeconomic status
• High dose glucocorticoids, atypical
antipsychotics, diazoxide and some
immunosuppresive drugs
• Poor access to medical care
• Uninsured
Prevalence of hospitalization and DKA
at onset
Colorado children, 1978-2001
100%
p<0.00001
80%
60%
40%
% hospitalized
% with DKA
p=0.038
20%
0%
1978-82
n=305
1984-88
n=541
1998-01
n=606
Rewers et al., ADA 2003
DKA in children with established
T1DM
• The risk of DKA varies from 1:10 to 1:100
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/p-yr
Poor metabolic control or previous DKA 
risk
Adolescent girls
Children with psychiatric disorders,
including those with eating disorders
Lower socio-economic status
Lacking appropriate insurance
Inappropriate interruption of insulin pump
therapy
Predictors of Acute Complications in Children
With Type 1 Diabetes
A Rewers, HP Chase, T MacKenzie, P Walravens, M Roback
M Rewers, RF Hamman, G Klingensmith
2002;287:2511-2518
Cohort of 1,243 diabetic children from BDC
- age 0-19 years
- residence in the six-county Denver area
- outpatient visits between 1/1/1996 - 1/1/2001
Average follow-up
Total follow-up
DKA events
DKA incidence
3.2 years
4,000 person-years
320
8 / 100 person-years
Incidence of DKA in established
patients
BDC Cohort, 1996-2001
Incidence /100 p-yrs
15
p=0.0006
p=0.006
10
p=0.06
girls
boys
5
0
<7
7 to 12
>12
Age [years]
Proportion of Children with Recurrent
DKA
5%
• 60% of DKA
episodes occurred
in 5% of children
who had 2 or
more events
0
1
2+
# of DKA events
Diabetic KetoAcidosis (DKA)
1. 160,000 Admissions to private
hospitals/year
2. Cost = over 1 billion $ annually
3. 65% = <19 years old
4. Main cause of death in children with
diabetes (approximately 85%)
5. Cerebral edema in 69%
Cost of hospitalization of a diabetic patient
$12,000
$11,123
$10,000
$8,000
$6,055
$6,000
$4,000
$2,000
$0
w ith DKA
w /out DKA
*HCIA-Sachs, 1998 Claims Data Warehouse, represents 2.5MM lives and 150 health plans
Diabetes Care 2006 29:1150-1159
Signs of DKA
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Vomiting
Increased urination
Abdominal pain
Fruity odor to breath
Dry mouth and tongue
Drowsiness
Deep breathing
Coma
Death
Mortality in Children with DKA
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0.15% USA
0.18% Canada
0.31% UK
80% of deaths occurs in association with signs of
CE
Other causes:
– hypokalemia / hyperkalemia
– thrombosis
– intracranial bleeding, infarction
– sepsis and other infections, e.g., mucormycosis
– aspiration pneumonia
– pulmonary oedema, ARDS
Physical Exam
• Perfusion
• Vital Signs - including weight
• Hydration
• Mental Status
• Evidence for insulin resistance
Initial Laboratory Evaluation
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Glucose*
Ketones*
Sodium
Potassium
Chloride
HCO3
• Venous pH
• BUN
• Serum Osmolality
• Phosphorus
• Calcium
• Anion Gap
*Always perform in an ill child
Calculations
Serum Osmolality:
2[Na+K]+ (glucose/18) + BUN/2.8
Serum Na:
Corrected Na =
measured Na + (1.6)(glucose - 100)/100
Anion Gap:
[Na] – ([Cl]+[HCO3])
Normally 12+/-2 mmol/L
Cerebral Edema
Major cause of death in childhood DKA
– 20% with cerebral edema die
– 20% with mild to severe neurologic outcomes
• At risk:
– Initial pH < 7.1
– Baseline mental status abnormal
– Newly diagnosed, < 5 years old
– Rapid rehydration (> 50cc/ kg in first 4 hrs)
– Hypernatremia/ persistent hyponatremia
Age distribution of affected children
Timing of Onset of Cerebral Edema in DKA
16
14
12
# of 10
patients
8
6
4
2
0
0-2.9
3-5.9
6-8.9
9-11.9
12-14.9
12-15
>15
Time of onset of Neurological Compromise
(hours)
Muir A, et al, Diab Care. July 2004
Symptoms and signs of cerebral
edema
• Headache
• Decreased
or
worsening
level
consciousness
Slowing of the HR
Increase in BP
Sudden onset/return of vomiting
of
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• Warning signs occur before the onset of CE
Clinical Factors Associated with
Cerebral Edema
• Prolonged Illness
• Severe acidosis - low PA CO2
• Severe dehydration
• Bicarbonate therapy
• Persistent hyponatremia
• Excessive fluid admistration
Cerebral edema
• CE occurs in 0.3%- 1% of all episodes of
DKA
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Initial 24 hours of treatment
Younger children (< 4 yrs)
Delayed diagnosis
Greater dehydration and acidosis, lower
pCO2
• Insulin given before fluids
Etiology of CE
• Vasogenic - excessive accumulation of water
and solutes in the interstitial space, due to
dysfunction of the blood-brain barrier
• Cytotoxic - excessive accumulation of water
and solutes in the intracellular space, due to
dysfunction of cell-volume regulatory
mechanisms
• Both forms may co-exist
Excessive Free Water
• Corrected Na = Na(measured)+1.6
(glucose-100)/100
• Calculated sodium is low and falling in many
cases of cerebral edema
• ADH levels rise 5-50 times in DKA and
contribute to increase in free water and
hyponatremia
Cerebral Edema
• Know what to look for
– Altered mental status/ severe headache
– Recurrence of vomiting
– Changes in pupil size, seizures, bradycardia
– Clinical worsening despite improving lab
values
– CT/ MRI changes may not be seen in early
cerebral edema
Cerebral Edema Bedside Score
Caveat – note that patient needs to be significantly
affected to meet diagnostic criteria
Muir Diab Care 2004 27:1541-46
Timing of presentation of cerebral edema
Treatment of cerebral edema
– Mannitol: 1 gram/ kg IV over 30 minutes
– Elevate the head of the bed
– Decrease IVF rate and insulin infusion rate
– Pediatric ICU management
– Do not delay treatment until radiographic
evidence
Diagnosis and prevention of
DKA
in outpatients
Why do ketones develop?
No carbohydrate intake
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fasting
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gastroenteritis
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Atkins diet, neonates fed high-fat milk
Prolonged exercise, pregnancy
Lack of insulin activity
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onset of diabetes (insufficient secretion)
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interruption of insulin delivery in established pt
Increase in insulin resistance
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infection, illness, surgery, stress
Alcohol, salicylate ingestion, inborn metabolic errors
Treatment of Mild DKA to Prevent
Progression: Key: Early Detection
Check blood ketones (-OHB) for a person with
diabetes any time:
1) A SMBG is >300 mg/dL (16.7 mmol/L)
2) An illness or infection is present
3) Unusual symptoms are present
4) It is realized a shot/bolus was missed or bad
insulin
Old Paradigm: Check urine ketones
New Paradigm: Check blood -OHB
1) Blood -OHB tells you how you are doing at
the time of the test. (Urine may have been in
bladder for hrs)
2) Urine ketone levels may not accurately reflect
the severity of the ketonemia
3) A person may not be able to void
4) Some (teens) give false urine test results
Hand-held device
Abbott/MediSense
Disadvantages to Urine Ketone Testing
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The results are not real time
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The readings are qualitative: color comparisons indicating
high, medium or low levels
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Short shelf life (typically 90 days on opening a vial)
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Sulfhydryl drugs, including the ACE inhibitor, Captopril,
may cause false-positive results
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High doses of Vitamin C may cause false-negative results
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Method does not detect the major ketone body hydroxybutyrate
Interpretation of Blood -OHB
-OHB level (mmol/L):
< 0.6 = normal
>1.0 = hyperketonemia
0.6-1.0 = take extra insulin + fluids
1.0-1.5 = as above; recheck in 1 hr and, if no
improvement, call diabetes provider
1.5-3.0 = call diabetes provider STAT
> 3.0 & sick = KETOACIDOSIS > Go to ED
Sick Day Management:
A Randomized Clinical Trial
Laffel L, et al. Diabet Med 2005
• 123 participants, age 3–22 years
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61 randomized to home blood ß-OHB testing
–
62 randomized to home urine Ketostix® testing
• All participants trained on their sick-day guidelines
• Outcomes
– ER visits
– Hospitalizations
Patients who monitor blood ß-OHB test more often
than those who test for ketonuria
Laffel L, et al. Diabet Med 2005
Lower incidence rates of ER use/hospitalizations in
patients using blood ß-OHB monitoring vs. Ketostix
6-month follow-up
p = 0.05
Laffel L, et al. Diabet Med 2005
Use of Blood -hydroxybutyrate
Levels at the Bedside
During Treatment of DKA
ADA, June, 2007
Fat
Normal state
postprandial
glucose
acetyl CoA
pyruvate
Krebs cycle
oxaloacetate
citrate
Fat
Normal state
postprandial
lipase

fatty acids (+ glycerol)
fatty acyl CoA

glucose
-oxidation
acetyl CoA
pyruvate
Krebs cycle
oxaloacetate
citrate
insulin
Normal state
postprandial
Fat
lipase

fatty acids (+ glycerol)
fatty acyl CoA

-oxidation
acetyl CoA
Krebs cycle
acetoacetyl CoA

HMGCoA synthase
acetoacetate
1:1
acetone
-OHB
insulin
Ketosis in DKA
Fat
- alternative source
of energy
lipase
 fatty acids
glucose 
fatty acyl CoA
-oxidation
acetyl CoA
pyruvate
Krebs cycle

oxaloacetate
acetoacetyl CoA

HMGCoA synthase
acetoacetate
1:10
citrate
acetone
-OHB
glucagon
insulin
Is bedside β-OHB monitoring
using hand-held device as
accurate as reference laboratory
method ?
Correlation between venous whole blood β-OHB levels measured using
Precision Xtra™ and serum levels using Cobas Mira Plus (Roche)
Laboratory reference β-OHB [mg/dL]
Bedside meter β-OHB [mmol/L]
Rewers A et al. Diabet Technol Therapeutics,
2006;8:671
Bland-Altman plot showing good agreement between β-OHB levels
measured using Precision Xtra™ and Cobas Mira Plus (Roche)
Mean difference = 0.18 (C.I. -1.18-1.53)
Rewers A et al. Diabet Technol Therapeutics,
2006;8:671
also
Byrne H, et al. 2000; Wallace TM, et al. 2001
Ham MR, et al. 2004; Khan ASA, et al. 2004
CONCLUSION
Real-time bedside measurement of OHB is generally as accurate as
reference laboratory, especially at levels
up to 3.0- 4.0 mmol/L
Is capillary blood β-OHB
monitoring superior to testing
urine for ketones ?
Measurement of Ketones
• Urine ketone measurements use a “dip stick” method
based on a chemical reaction with acetoacetate. E.g.,
Chemstrip® from Roche; Clinistix®, Ketostix® ,
Keto-Diastix® from Bayer)
• Blood ketone testing that specifically measures ßhydroxybutyrate are available for use in the
laboratory (e.g., Sigma®, Cobos® from Roche) and a
hand-held meter (Abbott / MediSense)
Blood β-OHB testing is superior to
urine ketone testing in detecting ketosis
Sensitivity
Specificity
Positive
predictive value
Ketonuria
63%
100%
100%
72%
Capillary blood
β-OHB
80%
100%
100%
83%
Gold standard – plasma β-OHB by reference laboratory method
(KONE Delta Automatic Analyzer)
Guerci B , et al. Diabetes Care 2003
Similar data: Taboulet P et al. Eur J Emerg Med 2004
Negative
predictive value
Advantages Blood β-OHB vs.
Urine Ketone Testing
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-OHB is a better marker of ketosis than acetoacetate
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-OHB is ‘real-time’ while ketonuria is usually ‘old news’
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Ketonuria doesn’t accurately reflect severity of ketonemia
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A dehydrated person may not be able to void
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Some people are too ill or exhausted to do the urine test
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Some patients (teens) give false urine sample
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Urine ketone strips spoil after opened >6 months
-hydroxybutyrate is a better indicator of metabolic
status when detecting and treating DKA
Schade DS, Eaton RP Special Topics in Endo and Metab 1982;4:1-27
β-OHB in diagnosis of DKA
in ED
β-OHB helps to diagnose DKA in patients with
known or new diabetes seen in ER
N
Blood
β-OHB
BG>200, adults
139
>0.42
Diabetic children
55
>1.5
BG>250,
age>18
160
>1.8
91%
BG>200, age
>15
50
>2.0
>3.0
100%
100%
Patients
Study
Bektas, 2004
Ham, 2004
[mmol/L
]
Sensitivity Specificity PPV
72%
NPV
82%
85%
100
%
92%
86%
95%
85%
88%
60%
64%
100
%
100
%
Nauheim, 2006
Harris,2004
Capillary blood β-OHB vs. venous pH in 118 newly diagnosed children
no DKA
DKA
compensated
acidosis

3

0.5
7.25
Prisco F, et al. Pediatr Diabetes 2006

Can bedside β-OHB monitoring
replace repeat measurements
of pH, bicarbonate and pCO2
during treatment of DKA?
Correlation between baseline β-OHB and other
biochemical indicators in 68 children with DKA Pearson
correlation coefficients (p <0.05 for all)
Biochemical
indicator
pH
Bedside meter
-0.63
Reference
method
-0.74
Bicarbonate
-0.74
-0.80
pCO2
-0.55
-0.61
Glucose
0.57
0.63
BUN
0.35
0.42
Rewers A et al. Diabet Technol Therapeutics,
2006;8:671
Time series analysis showing that bedside β-OHB
levels correlated very closely with time-dependent
levels of venous blood gases
Biochemical
indicator
pH
Bedside meter
β -6.3 **
Reference
method
β -8.0 **
Bicarbonate
β -0.22 **
β -0.24 **
pCO2
β -0.04 *
β -0.05 **
* p<0.001; ** p<0.0001
Rewers A et al. Diabet Technol Therapeutics,
2006;8:671
CONCLUSION
While the initial measurement of pH,
bicarbonate and pCO2 is warranted, realtime bedside measurement of -OHB
may replace repeat measurements of
blood gases in treatment of DKA
Can bedside β-OHB monitoring
shorten duration
of
DKA treatment ?
In most newly-diagnosed children with ketosis,
capillary ketonemia resolves sooner than ketonuria
N =99
Prisco F, et al. Pediatr Diabetes 2006;
In children with DKA, capillary ketonemia resolves
on average 11 hours sooner than ketonuria
(n=40)
Example of an individual treatment profile
pH >7.3
β-OHB <1.0
pH >7.3
No ketonuria
i.v. insulin U kg/h
β-OHB
Noyes KJ, et al. Pediatr Diabetes 2007, confirming Vanelli M, et. Al. Diabetes Care 2003
CONCLUSIONS
Real-time bedside measurement of OHB may help to optimize treatment of
DKA and shorten the duration of
hospitalization
Initial Laboratory Evaluation
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Glucose*
Ketones*
Sodium
Potassium
Chloride
HCO3
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Venous pH
BUN
Serum Osmolality
Phosphorus
Calcium
*Always perform in an ill child
Treatment
Monitoring
• Management requires close attention to
detail
• Use a flowsheet to track vital signs labs,
rates of insulin, fluids, dextrose
• Neurological status
– consider neuro checks q 1 hr
– How does the patient look TO YOU?
• Assess, reassess and then assess again
Treatment
• Consider ICU admission for closer monitoring
if:
•
– Severe DKA (pH < 7.1 or < 7.2 in young child)
– Altered level of consciousness
– Under age of 5 years
– Increased risk for cerebral edema
Caution with meds that may alter mental
status
Fluid Therapy for DKA
• Assume 10-15% dehydration
• Begin with a 10-20 ml/kg bolus of NS
• Replace calculated deficit evenly over
•
36 hours - generally 1.5 x maintenance
for the next several hours is
appropriate
Do not exceed 40ml’s/kg in the initial 4
hours, or 4 L/m squared in 24 hours
DKA - Fluids
• Double bag system
– ¾ NS at 1.5 x M until glucose below 300 mg/dl
– D10 ¾ NS to be mixed with ¾ NS to achieve
desired glucose concentration
– K supplementation
20mEq/L K Acetate + 20mEq/L K Phosphate
– Ionized calcium is low, phosphorous should not
be given
– early replacement and frequent monitoring
– Bicarbonate therapy is rarely, if ever, indicated
Insulin Therapy for DKA
• IV infusion with basal rate 0.1 U/kg/hr
• No initial insulin bolus – it will decrease time to
correction of the glucose, but does not alter the time
to correction of acidosis
It may decrease the serum osmolality more rapidly
than desirable
• Ideal glucose decline is about 100 mg%/hr
• Continue insulin until urinary (blood) ketones are
cleared
Potassium
• Add potassium when K< 5 and with
urination
– K >5.5 – no potassium in IVF
– K 4.5 – 5.5 – 20 meq/L K+
– K <4.5 – 40 meq/L K+
Phosphate – the controversy
• Prevent depletion of RBC 2,3 DPG which
will improve tissue oxygenation as acidosis
is resolving
• May be useful in patients with anemia,
CHF, pneumonia, hypoxia
Use of Bicarbonate in DKA
• Bicarbonate should be used only when
there is severe depression of the
circulatory system or cellular
metabolism...
• Not recommended unless pH <7.0, not
even then, unless above true
DKA: Cases
• 12 year old admitted with:
– pH = 7.0
– Na= 136, K=3.8, glucose 583mg/ dl
– She is oriented and conversant on admission, you
follow the DKA protocol,
• 2 hours later she becomes difficult to arouse and
•
is responsive only to deep pain. - What do you
do?
Presume cerebral edema
– Decrease fluid infusion to insensible losses
– Give mannitol: 1 gm/kg
DKA: Cases
• 6 y/o boy is admitted in severe DKA. The
•
•
•
family has been traveling and he has been ill
for several days.
Initial pH=7.0, K+ = 3.7, glucose is
350mg%.
Despite replacement, his K+ now is 1.9
mg/dl - what do you do?
A “bolus” of potassium at TCH is actually an
infusion over an hour. An actual bolus of
potassium into a central vein may be lethal
DKA: Cases
• 16 year old boy is admitted in moderate to
•
severe DKA (pH=7.23), his weight is 230
lbs, his BG is 1400, serum osm is 360
mOsm/L, what do you do?
Monitor! Everything you can!
Successful Management
• Careful attention to detail
• Careful record keeping
– A detailed flow chart is essential
– Following the data recorded is also essential
• Repeated examination of the patient