Diabetic ketoacidosis and cerebral edema: The story so far

Abstract sent 20th International Congress of Pediatrics Teheran

J Puliyel

1. The Enigma of Death in DKA
Death among children being treated for diabetic ketoacidosis (DKA) is something of an enigma: The deaths occur during treatment and has not declined in spite of the use of better human insulins and continuous infusions with accurate syringe pumps.

2. Overestimation of dehydration in DKA
At an annual meeting of the British Pediatric Association an elegant paper was presented that suggested that iatrogenic over-hydration was perhaps responsible.

The authors retrospectively studied the patients admitted with DKA in their hospital. They looked at the admission weight and the weight of children after rehydration - a couple of days later. From this they calculated the quantum of dehydration.

They looked at this against the treating doctors assessment of dehydration at admission. The doctors had consistently overestimated the dehydration. Those with mild dehydration were classified as moderate dehydration and those with moderate dehydration were considered as having severe dehydration. Fluids were prescribed accordingly and it was speculated that this over-hydration could result in cerebral edema and death in this manner.

Grove LM, Noble-Jamieson CM, Barnes ND, Challenger J. Assessment of dehydration, fluid balance and insulin requirements in diabetic ketoacidocis. Proceeding of the British Pediatric Association 7th annual meeting Abstracts 1995;67:27(pg 10)

3. Hypertonic dehyration the cause of overestimation of dehydration?
I was present at this presentation and asked myself the question: Why would experienced pediatric doctors who estimated dehydration all the time in the context of gastroenteritis, consistently make this error when estimating dehydration in DKA?
I developed a hypothesis that it was probable that children with DKA had hypertonic dehydration and that was the reason doctors were misled. Hypertonicity caused children to have parched dry tongues and associated with the acidosis of DKA they were judged to have severe dehydration when their fluid deficits were not so bad.

I decided to test the hypothesis. We studied prospectively the serum osmolality (using the depression of freezing point method ) of children with DKA and found that the mean osmolality was indeed 318mOsm/kg (SD12.9 Range 297-337). This could result in over estimation of dehydration. The paper was presented at the 2nd European Pediatric Congress in Berlin

Puliyel JM, Puliyel MM, Hincliffe R. Hypertonicity may contribute to overestimation of dehydration in diabetic ketoacidosis. 2nd European Pediatric Congress Berlin Germany. Abstract Book 1996 Endocrine and Metabolism 2

4. Hyperosmolity in DKA due to unmeasured substances like ketone bodies
Having proved that DKA is associated with hypertonicity, we did a follow-up study to understand what caused the hypertonicity. We found the calculate osmolality [2 (Na + K) + Urea + Glucose] was within the normal range (275-295) but the measured osmolality (freezing point method) was above 300 in 22 of the children (55% cases). In 3 children measured osmolality was greater than 310mOsm/kg. We found that the main cause of increase osmolality was the presence in DKA of unmeasured substances like ketone bodies. This finding was presented at the International Symposium on Diabetes in Chaing Mai.

Puliyel J, Puliyel M, Hincliffe R. Hypertonicity in diabetic ketoacidosis: Unexpected biochemical correlates and clinical implications. Prioceedings of International Symposium on Diabetes.
Chaing Mai Thailand, 1997; 26-29

5. Lancet suggests that ketone bodies add to osmolality but not to osmotonicity of serum and so it cannot cause fluid shifts and cannot be responsible for hypertonic dehydration and thereby it cannot explain the overestimation of dehydration by doctors.

Van der Meulen JA, KlipA, Grinstein S: Possible mechanism for
cerebral oedema in diabetic ketoacidosis. Lancet, 1987; ii: 306-8

Paradoxically our study of increased osmolality due to unmeasured compounds contradicted our ‘hypertonicity causes overestimation’ theory.
If hypertosmolality was due to ketone bodies it could not cause hypertonicity because according to an article in the Lancet ketone bodies are like urea and it moves across cell membranes freely and it cannot to produce fluid shifts.

6. A simple study that proves the assertion in the Lancet wrong
Although the article in the Lancet asserted that ketone bodies do not exert osmotonicity no empirical evidence of this was provided.
We there for devised a simple test to see if ketone bodies were osmotonic.

A modified erythrocyte fragility test was used to check the osmotonic and osmoprotective effects of the ketone body. Red blood cells were suspended in different test tubes containing distilled water, normal saline, glucose, urea and acetoacetic acid (lithium salt C4H5O3Li). All
solutions (except the tube with distilled water) were made to match the osmolality of plasma.
We hypothesized that solutions in which red cell hemolysis does not take place have greater tonicity than the tonicity of 0.45% saline.

Results: Spectrophotometry showed that there was no hemolysis in the solutions of normal saline or solutions containing glucose or acetoacetate. Complete hemolysis was demonstrated in the
tube with plain distilled water and also in the solutions containing urea.

Conclusion: This study shows that acetoacetate is functionally similar to glucose in that it contributes to increased osmotonicity. The drop in ketone body levels can produce a drop in the osmolar tonicity of plasma and precipitate cerebral edema.

Puliyel JM. Osmotonicity of acetoacetate: possible implications for cerebral edema in diabetic ketoacidosis. Med Sci Monit 2003;9:BR130-3.

7. We recommended estimation of ketone bodies (or measured osmolality) and its gradual reduction in treating DKA
We recommended that we measure real osmolality by the freezing point depression technique rather than calculated osmolality as this left out unmeasured substances like ketoacids that could cause fluid shifts.

Puliyel JM, Bhambhani V. Ketoacid levels may alter osmotonicity in diabetic ketoacidosis and precipitate cerebral edema [letter]. Arch Dis Child 2003;88:366.

This is impractical, as most centers do not have the equipment to measure osmolality.

8. Cerebral odema if serum sodium at admisson is less than 135mMol/L
Excess ketones may drive down serum sodium making low sodium the marker of risk.

Hoorn et al suggest that blood glucose must be brought down slowly.

Hoorn E, Carlotti A, Costa L, et al. Preventing a drop in effective plasmaosmolality to minimize the likelihood of cerebral edema during treatment of children with diabetic ketoacidosis. J Pediatr 2007;150:467-73.

A study of their data suggests a simple way to avoid cerebral odema. No child with a serum sodium greater than 135mMol/L at admission developed cerebral edema. We speculate that ketoacids drive the serum sodium levels down. The message now is to be careful if the child has serum sodium less than 135mmol/L. They are the ones that perhaps have high ketone levels and so susceptible to cerebral edema when the ketone levels come down with treatment.

Akatoli Sema, Jacob M. Puliyel Cerebral edema in diabetic ketoacidosis with serum
sodium <135 mEq/L Pediatr. 2008 Jan;152(1):145-6