Thursday, January 30, 2014

DKA and Cerebral Edema. Are Fluids to Blame or is it Shock?

It's almost the end of the month and I am again behind schedule. But today I have something controversial and very interesting... Pediatric DKA. In particular the issue about fluid administration and risk for cerebral edema.

Pedi DKA is scary, dangerous and subject of heated debate when it comes to fluid administration. Most of the treatment protocols in pediatrics are very stingy when it comes to fluid administration. In severe cases, kids arrive in shock, hypotensive, tachycardic, severely vasoconstricted, and many of them comatose; the protocol says to give them just 10 ml/kg bolus and correct remaining deficits over 48 hrs. This doesn't make  sense to me. If you are in shock, you are not perfusing! Why would I want to drag the treatment of someone in shock? I have seen my fare share of sick pedi DKA's and the ones in the severe end of the spectrum look just like that, awful. In England you cannot give a 20 ml/kg initial bolus to a DKA kid in shock without being called to the medical director office and ordered to memorize the protocol and recite it the next day in front of everyone to hear.  The notion that rapid fluid administration is the cause of cerebral edema in severe DKA is so engraved in all the treatment protocols, but there is no solid evidence to support this idea, except for observational studies and consensus recommendations. I was really bothered by this and tried to find the science behind and found that it is not the fluid rate what is associated to the risk of cerebral edema, is the level of dehydration, acidosis with hypocapnia, hyperglycemia and brain hypoperfusion what causes all the problems. The kids who are going to develop cerebral edema are in the sickest end of the spectrum, probably arrive with cerebral edema and will become clinically obvious regardless of the fluid infusion rate. 

Last year, in the journal of Pediatrics ( there was a RCT of 18 kids (I know is a small number, but this is randomized human data rather than rat studies). One group received 20 ml/kg bolus with correction of dehydration over 24 hrs. The second group received a 10 ml/kg bolus and correction of dehydration over a 48 hr period. The results showed no difference in MRI cerebral edema parameters at different treatment stages between the rapid fluid replacement approach compared with the slower infusion rates approach; and more importantly, MRI findings were consistent with vasogenic edema and were worse at the beginning of treatment compared with after-treatment in both groups. This suggests that sick DKA kids already have cerebral edema before initiation of therapy and edema improves after treatment independently of fluid infusion rates. Those who support the idea that rapid fluid infusion is the cause of cerebral edema in DKA treatment, say that it is due to rapid osmotic changes (we all have heard that), and there is probably some true about that. However, one important distinction to make here, is that osmotic cerebral edema and vasogenic cerebral edema are not the same. The TBI research ( that vasogenic cerebral edema is due to blood-brain barrier disruption resulting in extracellular water accumulation. In the other hand, osmotic cerebral edema is caused by osmotic imbalances between blood and brain tissue. These kids who got MRI early, all had vasogenic edema. How is that different by MRI? - I have no idea, but I am sure the radiologist have.

In regards to the factors that predict the development of cerebral edema, there is a great article from the NEJM from 2001, comparing 265 children with severe DKA. This study puts it all together very nicely. ( Some children developed cerebral edema and some did not. Analysis of other biochemical markers showed something very interesting. "Although osmotic factors and other mechanisms may play a part in the development of cerebral edema, our data lend support to the hypothesis that cerebral edema in children with diabetic ketoacidosis is related to brain ischemia. Both hypocapnia, which causes cerebral vasoconstriction, and extreme dehydration would be expected to decrease perfusion of the brain. In addition, bicarbonate therapy causes central nervous system hypoxia in laboratory animals with diabetic ketoacidosis. Hyperglycemia superimposed on an ischemic insult increases the extent of neurologic damage, blood–brain barrier dysfunction, and edema formation. This interaction might help to explain the occurrence of neurologic damage in association with minor degrees of cerebral hypoperfusion. Blood–brain barrier dysfunction and vasogenic edema may occur several hours after an ischemic insult as a result of the release of vasoactive substances and mediators of inflammation. The occurrence of cerebral edema several hours after the initiation of therapy thus correlates well with the hypothesis that the basis of this complication is ischemia. Finally, the more frequent occurrence of cerebral edema in children than in adults may be explained in part by the fact that children's brains have higher oxygen requirements than adults' brains and are thus more susceptible to ischemia".

A good while ago, Canadians also found that low CO2 and high BUN had the strongest association with cerebral edema ( Again.. these are sick DKA kids. This was a case control study, after adjusting for variables, found not association between the occurrence of cerebral edema in DKA and treatment factors. The authors conclude that the presence of cerebral edema before treatment of DKA and the association with severity of illness suggest that prevention of DKA is the key to avoiding this devastating complication. 

Summarizing... Here are the strongest associations with their respective OR's, CI and P values

  • Initial BUN (per increase of 9 mg/dl): 1.8 (95% CI: 1.2-2.7); p value 0.008
  • Initial partial pressure of arterial carbon dioxide (per decrease of 7.8 mm Hg): 2.7 (95% CI: 1.4-5.1); p value 0.002
  • Treatment with bicarbonate: 4.2 (95% CI 1.5-12.1); p value 0.008 (Don't do it!)
  • Rate of increase of serum sodium concentration (per increase of 5.8 mmol/l/hr):0.6 (95% CI: 0.4 - 0.9); p value 0.01
- Cerebral edema in the setting of DKA is more related to the severity of the primary disease process rather than the rate of fluid treatment. The pathophysiology is complicated, but hypoperfusion leading to cerebral ischemia along with damage to the blood-brain barrier all result in vasogenic edema. 
- Pedi DKA in shock -> Treat shock !  Their brain needs perfusion. However, be cautious and don't flood this kids with fluids, just restore tissue perfusion. Some guidelines (mostly from the U.S.) suggest an initial bolus of 20 ml/kg is a reasonable start point in shocky kids, with the option to repeat if there is no improvement in hemodynamics. However, a maximum of 30-40 ml/kg in the first 4 hrs of treatment is recommended with early consideration of sepsis if no response. This is when being a good clinician is so important. 
- Don't give bicarbonate, don't give bicarbonate and don't give bicarbonate. Is that clear enough?
- Having a healthy skepticism and questioning the old dogmas may get us closer to the truth about what is the right thing to do. 

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