Cerebral Edema and Diabetic Ketoacidosis: Rebaked

Authors: Drs. Kendra Jackson and Rebecca Raffler

While we’ve gotten to snack on a Morsel on this subject before, new guidelines and research surrounding DKA and cerebral edema have come to light since the first go ‘round! Thankfully, Dr. Fox wasn’t too “salty” when we asked to rehydrate this topic. Rates of type 1 diabetes have increased since the COVID-19 pandemic. As a result, the rates of DKA and Hyperglycemic Hyperosmotic Syndrome are on the rise. Cerebral edema is the most feared emergent complication of pediatric diabetic ketoacidosis.  Children with moderate to severe DKA admissions have been shown to drop IQ points and it is theorized that cerebral edema is the culprit. To help us avoid this, let’s take a minute to review the current recommendations for Cerebral Edema and Diabetic Ketoacidosis.

Pediatric Diabetic KetoAcidosis: Basics

• To consider the diagnosis of diabetic ketoacidosis, there must be three major criteria:
  1. Hyperglycemia
  2. Ketone formation
  3. Metabolic acidosis

• The severity of DKA is categorized by the degree of acidosis
  • Mild: venous pH < 7.3 or serum bicarbonate between 11-17 mmol/L 
  • Moderate: venous pH < 7.2 or serum bicarbonate between 5-10 mmol/L 
  • Severe: venous pH < 7.1 or serum bicarbonate <5 mmol/L

• Treatment for DKA is centered around the following principles
  • Fluid resuscitate and rehydrate
  • Insulin, IV or subq, to counteract ketosis/acidosis
  • Giving glucose PRN to promote anabolism and avoid hypoglycemia (due to insulin therapy)
  • Correcting hypokalemia

• After initial fluid resuscitation with crystalloids, we need to provide insulin as safely and conveniently as possible.
  • The triple bag system was developed to easily adjust the glucose infusion rate as needed to avoid hypoglycemia and hypokalemia. 
  • Here are our three bags. Some intuitions refer to this system as the “Two-bag” system, but why leave out the most important bag? Insulin!

• We have a cheat sheet at our institution to provide weight-based titration protocols for our nursing colleagues. Take a peak…

Cerebral Edema and Diabetic Ketoacidosis

• Neuroimaging studies have shown that Cerebral Edema is not rare.
• Mental status abnormalities (GCS scores <14) occur in approximately 4%–15% of children treated for DKA and are often associated with mild cerebral edema on neuroimaging.
• The mortality rate for cerebral edema is 21%–24%. 
• Lesson = treat early!
• The exact mechanism is not known…
  • It was previously believed that it was due to rapid changes in serum osmolality during initial fluid resuscitation. 
  • However, new information tells us that the hyperinflammatory state in DKA with cerebral hypoperfusion may play a big role. 
• Clinically significant injury generally presents within the first 12 hours of treatment, but as long as 24-48 hours out
• The diagnosis is clinical! Neuroimaging is NOT required.

Debunked Risk Factors for Developing Cerebral Edema

• Generally, there is an absence of evidence that associates higher initial glucose levels, higher osmolality, or declines in these values during treatment and our risk for developing cerebral edema. 
• One study found no difference in frequency of mental status change and cerebral injury in kids who had a decline in sodium vs. kids who did not. 
• Cerebral edema CAN present prior to initiation of treatment for DKA, including in some children with diabetes who died at home.

Risk Factors that seem to stay consistent:

• Administration of Bicarb for correction of acidosis has been shown to be associated with cerebral edema and DOES persist after correcting for severity of DKA! 
• Kids < 5 years of age
• New onset of diabetes at presentation
• Longer duration of symptoms
• Severity of acidosis
• Elevated BUN
• Greater degree of dehydration and hyperventilation

Cerebral Edema and DKA: Diagnostic Considerations

• Early detection and treatment is the best means to prevent brain injury and death.
• Headaches can be common at initial presentation and are generally acceptable.
• They should provoke our increased vigilance – pay closer attention if they worsen after starting therapy.
• GCS score is not sensitive enough.

Muir et al published a Bedside Evaluation of Neuro State of Kids with DKA:

Diagnostic Criteria

• Abnormal motor or verbal response to pain
• Decorticate or Decerebrate posture
• Cranial Nerve Palsy (especially III, IV, or VI)
• Abnormal neurologic respiratory pattern (grunting, Cheyne-Stokes, etc)

Major Criteria

• Altered mentation, confusion, fluctuating level of consciousness
• Heart rate decelerations (decline of more than 20 bpm) not due to improved hydration or sleep
• Age-inappropriate incontinence

Minor Criteria

• Vomiting
• Headache
• Lethargy or being not easily aroused from sleep
• Diastolic BP > 90 mmHg
• Age < 5 yrs

Having either 1 Diagnostic Criterion, 2 Major Criteria, or 1 Major and 2 Minor criteria lead to 92% sensitivity and 96% specificity for recognition of Cerebral Edema early enough for intervention.

A critical MORSEL is that every child you treat for DKA needs to have an initial thorough neuro exam including cranial nerves and then frequent neuro reassessments… and document it (so your colleagues who take over care for the kid can know if there has been a change)!

Cerebral Edema and DKA: Treatment

• 3% hypertonic saline 3-5 mL/kg or 250 mL is preferred.
  • Alternately, Mannitol 1 g/kg over 20 minutes, but it is associated with worsening diaresis
  • Repeat dose after 30 minutes if no improvement
• Head of Bed at 30 degrees
• Consider Intubation
  • Reserve only for those with respiratory failure secondary to severe neurologic compromise
• AVOID giving bicarb… as stated above, this is associated with worse outcomes

Moral of the Morsel

• DKA – An actually USEFUL Abreviation! Is your patient hyperglycemic, acidotic, with ketonuria? Then we’ve likely got DKA.
• Triple bag, triple bag, triple bag! Insulin (in Bag #1) is for the Acidosis. Prevent the hypoglycemia is adding Glucose and use the other two bags to make timely adjustments of glucose infusion rate.
• You don’t need a CT or MRI for that! Cerebral edema is a clinical diagnosis – do NOT delay treatment of cerebral edema for imaging!
• Get Salty! If you are concerned for developing cerebral edema, consider using Hypertonic Saline over Mannitol.

References:

White PC, Dickson BA. Low morbidity and mortality in children with diabetic ketoacidosis treated with isotonic fluids. J Pediatr. 2013 Sep;163(3):761-6. PMID: 23499379. [PubMed] [Read by QxMD]

Rosenbloom AL. The management of diabetic ketoacidosis in children. Diabetes Ther. 2010 Dec;1(2):103-20. PMID: 22127748. [PubMed] [Read by QxMD]

Morales AE1, Daniels KA. Cerebral edema before onset of therapy in newly diagnosed type 2 diabetes. Pediatr Diabetes. 2009 Apr;10(2):155-7. PMID: 19261103. [PubMed] [Read by QxMD]

Lawrence SE1, Cummings EA, Gaboury I, Daneman D. Population-based study of incidence and risk factors for cerebral edema in pediatric diabetic ketoacidosis. J Pediatr. 2005 May;146(5):688-92. PMID: 15870676. [PubMed] [Read by QxMD]

Muir AB1, Quisling RG, Yang MC, Rosenbloom AL. Cerebral edema in childhood diabetic ketoacidosis: natural history, radiographic findings, and early identification. Diabetes Care. 2004 Jul;27(7):1541-6. PMID: 15220225. [PubMed] [Read by QxMD]

Marcin JP1, Glaser N, Barnett P, McCaslin I, Nelson D, Trainor J, Louie J, Kaufman F, Quayle K, Roback M, Malley R, Kuppermann N; American Academy of Pediatrics. The Pediatric Emergency Medicine Collaborative Research Commitee. Factors associated with adverse outcomes in children with diabetic ketoacidosis-related cerebral edema. J Pediatr. 2002 Dec;141(6):793-7. PMID: 12461495. [PubMed] [Read by QxMD]

Glaser N1, Barnett P, McCaslin I, Nelson D, Trainor J, Louie J, Kaufman F, Quayle K, Roback M, Malley R, Kuppermann N; Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. Risk factors for cerebral edema in children with diabetic ketoacidosis. The Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. N Engl J Med. 2001 Jan 25;344(4):264-9. PMID: 11172153. [PubMed] [Read by QxMD]

https://jamanetwork.com/journals/jama/fullarticle/2805461

Weiss A, Donnachie E, Beyerlein A, Ziegler A, Bonifacio E. Type 1 Diabetes Incidence and Risk in Children With a Diagnosis of COVID-19. JAMA. 2023;329(23):2089–2091. doi:10.1001/jama.2023.8674

Chase H, Garg S, Jelley D. Diabetic ketoacidosis in children and the role of outpatient management. Pediatr Rev. 1990;11:297-304

von Oettingen J, Wolfsdorf J, Feldman HA, Rhodes ET. Use of serum bicarbonate to substitute for venous pH in new-onset diabetes. Pediatrics. 2015;136(2):e371-e377.

Dunger D, Sperling M, Acerini C, et al. ESPE / LWPES consensus statement on diabetic ketoacidosis in children and adolescents. Arch Dis Child. 2003;89:188-194

https://www.ispad.org/page/ISPADGuidelines2022

Chapter 11: Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State. Nicole Glaser, Maria Fritsch, Leena Priyambada, Arleta Rewers, Valentino Cherubini, Sylvia Estrada, Joseph I. Wolfsdorf, Ethel Codner

Glaser, N, Fritsch, M, Priyambada, L, et al. ISPAD Clinical Practice Consensus Guidelines 2022: Diabetic ketoacidosis and hyperglycemic hyperosmolar state. Pediatr Diabetes. 2022; 23( 7): 835- 856. doi:10.1111/pedi.13406