Fluid Administration in the Management
of DKA and Cerebral Oedema
Journal Club
19th June 2014
Dr James West (ST7)
Background
• What is already known on this topic:
- Symptomatic cerebral oedema occurs in 0.5 - 1.0%
- Subclinical cerebral oedema demonstrated by DWI
Theory 1:
A rapid decline in
effective serum
osmolality
Factors associated with brain herniation in the treatment of
diabetic ketoacidosis
Duck SC. J Pediatr. 1988 Jul;113(1 Pt 1):10-4
• Retrospective review of 40 cases of brain herniation
• Rate of fluid administration was inversely correlated with
the time of onset of herniation (r = -0.32, p = 0.04)
• 4 of 40 cases occurred at fluid intakes less than or equal
to 4.0 L/m2/day
• The corrected Na had fallen significantly and was less
than 130 mEq/L in 33% of cases at the time of herniation
Minimizing the risk of brain herniation during treatment of diabetic
ketoacidemia: a retrospective and prospective study
Harris GD. J Pediatr. 1990 Jul;117(1 Pt 1):22-31.
• Retrospective review of 219 episodes showed Na failed
to rise in 18 (95%) of 20 complicated episodes (p < 0.01)
• Prospective study of 58 cases with deficit replaced over
48 hours, Na increased in 95% cases, no complications
• Conclusions:
- Na in serum should rise as glucose falls
- ‘expanded repair period’ may protect against brain
herniation
Theory 2:
• Cerebral edema may be related to cerebral
hypoperfusion before treatment, with subsequent
vasogenic edema occurring during DKA treatment as a
result of reperfusion of previously ischaemic brain tissue
Correlation of Clinical and Biochemical Findings with Diabetic
Ketoacidosis–Related Cerebral Edema in Children Using Magnetic
Resonance Diffusion-Weighted Imaging
Glaser NS et al. J Pediatr. 2008;153:541-546
• Measured the ADC during and after DKA treatment in 26
children and correlated with clinical and biochemical
variables.
• Mean ADC values were elevated during DKA treatment
compared with baseline
• Children with altered mental status during DKA had
greater elevation in ADC
• Multivariable analyses identified the initial urea nitrogen
concentration and respiratory rate as independently
associated with ADC elevation.
PICO Question
Population
Do children with DKA who are…..
Intervention
…..rehydrated with rapid infusions of fluid…..
Comparison
…..compared to slower infusions of fluid…..
Outcome
…..have a greater risk of developing cerebral oedema?
Subclinical cerebral oedema in children
with diabetic ketoacidosis randomized to
2 different rehydration protocols
Glaser NS et al. Pediatrics 2013 Jan;131(1):e73-80
Method
• Pilot study
• Single centre
• Patients randomly assigned to 1 of 2 protocols
• Clinicians and research personnel aware of assignment
Inclusion criteria
• Presented to ED between 2008 and 2011
• 8 to 18 years of age
• Type 1 diabetes
• DKA (glucose >300 mg/dL, venous pH <7.25, HCO3- <15
mEq/l, +ve urine ketones)
Exclusion criteria
• Dental hardware
• Cognitive deficits
• Transferred to study centre after starting DKA treatment
Protocols
Protocol A
IV fluid bolus
(0.9% saline)
Protocol B
20 ml/Kg
10 ml/Kg
Assumed fluid
deficit
10% of body wt
7% of body wt
Rate of deficit
replacement
Two-thirds over first 24 hrs; onethird over next 24 hrs
Evenly over 48 h
Half of urine vol replaced while
serum glucose level is > 250
mg/dL
None
0.9% saline while serum glucose
is >250 mg/dL, followed by 0.45%
saline
0.9% saline while serum
glucose is >250 mg/dL,
followed by 0.45% saline
Urine output
replacement
Fluid type
Treatment contd.
• Insulin begun after first fluid bolus @ 0.1 U/Kg/hour
• Potassium given as KCl and KPO43• Clinician could give further fluid boluses and adjust fluid
infusion rates
• Vital signs / GCS assessed hourly
• Electrolytes, venous pH, PCO2 measured 3 hourly
• Glucose measured hourly whilst insulin infusion running
Imaging
• DWI:
1. 3 to 6 hours after initiation of treatment
2. 9 to 12 hours after initiation of treatment
3. after recovery from DKA (>72 hours after
initiation of treatment)
• Apparent diffusion coefficient (ADC) recorded in basal
ganglia, thalamus, hippocampus and frontal white matter
• Single radiologist blinded to patients’ group assignment
• Mean brain ADC determined by calculating mean ADC
values in all 4 regions
Statistics / Outcomes
• Aimed for 10 patients in each arm, 80% power to detect
a 1.3 SD difference in ADC
• Effects of group assignment on ADC change after
adjusting for level of risk of cerebral oedema
• Compared rates of change of biochemical variables
CASP Analysis
• 1. Did the trial address a clearly focused issue?
Yes – DKA treatment protocols based around careful fluid
administration to avoid cerebral oedema
• 2. Was the assignment of patients to treatments randomised?
Yes - Randomisation by computer-generated random permuted
block sequence
3. Were all of the patients who entered the trial properly accounted
for at its conclusion?
• 20 DKA episodes (2 patients presented twice)
• Unable to perform MRI’s in 2 patients
4. Were patients, health workers and study personnel ‘blind’ to
treatment?
• Study personnel not blinded except radiologist
• Patients were blinded
5. Were the groups similar at the start of the trial?
• No – younger in Group A
6. Aside from the experimental intervention, were the groups
treated equally?
• No – additional fluid boluses given to both groups (Grp A
received 32 +/- 17 ml/Kg, Grp B received 19 +/- 10
ml/Kg)
7 & 8. How large was the treatment effect
and how precise was the estimate of the
treatment effect?
• Group A received 61 +/- 19 ml/Kg, Group B 42 +/- 7
ml/Kg (P = 0.01)
Mean brain ADC values in both treatment groups measured at 3 to 6 hours and
9 to 12 hours after beginning DKA treatment and after recovery from DKA.
Mean brain ADC values (average of 3- to 6-hour and 9- to 12-hour values)
during DKA treatment and after recovery.
Results contd.
• No significant difference in ADC change between
patients who received >50 versus <50 cc/Kg of IV fluid
in first 8 hours (36 +/- 31 vs 45 +/- 37 mm2/sec, P = 0.58)
• ADC changes greater in high-risk group (P = 0.04)
• In low-risk patients trend towards lesser ADC change in
those with more rapid rehydration (P = 0.09)
9. Can the results be applied in our population?
Yes – BUT small sample size!
10. Were all clinically important outcomes considered?
No - ?duration of treatment / hospitalisation (IV access,
monitoring)
11. Are the benefits worth the harms and costs?
No - continue to be cautious, especially in high-risk patients
Risk factors for cerebral oedema
• Younger age
• Newly diagnosed compared with known diabetes
• Severity of acidosis – pH and bicarbonate levels at
presentation
• Higher urea levels
• Lower paCO2 values
• Administration of bicarbonate
• Larger volumes of fluid given over the first 3–4 hours
• Administration of insulin within the first hour of fluid
treatment
How can cerebral edema during treatment
of diabetic ketoacidosis be avoided?
Wendy Watts and Julie A
Edge. Pediatric Diabetes.
June 2014, pages 271–276
Thanks!