1. Fluid Administration in the Management of DKA and Cerebral Oedema Journal Club 19th June 2014 Dr James West (ST7)

2. Background What is already known on this topic: - Symptomatic cerebral oedema occurs in 0.5 - 1.0% - Subclinical cerebral oedema demonstrated by DWI

3. Theory 1: A rapid decline in effective serum osmolality

4. 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

5. 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

6. 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

7. 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.

8. PICO Question PopulationDo 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?

9. 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

10. Method Pilot study Single centre Patients randomly assigned to 1 of 2 protocols Clinicians and research personnel aware of assignment

11. 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, HCO 3 - <15 mEq/l, +ve urine ketones)

12. Exclusion criteria Dental hardware Cognitive deficits Transferred to study centre after starting DKA treatment

13. Protocols Protocol AProtocol B IV fluid bolus (0.9% saline) 20 ml/Kg10 ml/Kg Assumed fluid deficit 10% of body wt7% of body wt Rate of deficit replacement Two-thirds over first 24 hrs; one- third over next 24 hrs Evenly over 48 h Urine output replacement Half of urine vol replaced while serum glucose level is > 250 mg/dL None Fluid type0.9% saline while serum glucose is >250 mg/dL, followed by 0.45% saline

14. Treatment contd. Insulin begun after first fluid bolus @ 0.1 U/Kg/hour Potassium given as KCl and KPO 4 3- Clinician could give further fluid boluses and adjust fluid infusion rates Vital signs / GCS assessed hourly Electrolytes, venous pH, PCO 2 measured 3 hourly Glucose measured hourly whilst insulin infusion running

15. 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

16. 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

17. 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

18. 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

19. 4. Were patients, health workers and study personnel ‘blind’ to treatment? Study personnel not blinded except radiologist Patients were blinded

20. 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)

21. 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)

22. 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.

23. Mean brain ADC values (average of 3- to 6-hour and 9- to 12-hour values) during DKA treatment and after recovery.

24. 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 mm 2 /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)

25. 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

26. 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

27. How can cerebral edema during treatment of diabetic ketoacidosis be avoided? Wendy Watts and Julie A Edge. Pediatric Diabetes. June 2014, pages 271–276

28. Thanks!