A Well-Grounded Myth? The Association of IV Fluids with Cerebral Edema in Pediatric DKA

Author: Brit Long, MD (@long_brit, EM Attending Physician at SAUSHEC, USAF) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital)

A 5-year-old little girl presents with vomiting, polyuria, and polydipsia. She has a history of type 1 diabetes on insulin. Her mom called her endocrinologist, who recommended they come in to the ED. Her vital signs demonstrate tachycardia and hypotension, and she appears ill. You order a VBG, urinalysis, CBC, renal function, and lactate, and while you consider your rehydration strategy, the endocrinologist calls and asks you to do maintenance therapy only. The patient looks ill, with hemodynamic abnormalities.

What’s the literature behind cerebral edema (CE) and fluid rehydration in pediatric DKA? This post will evaluate this topic and more.

Type 1 and 2 diabetes mellitus is a common chronic disease among children.^1-5 A major complication is DKA with a 25% incidence.^3-8 Almost 1/3 of patients have DKA at the time of initial diabetes diagnosis.^3-7 Younger age, smaller body mass index, delayed treatment, infectious trigger, and lack of health insurance are risk factors for DKA.^1,2,8  Even type 2 diabetics may experience DKA, with 5-25% of patients in DKA at time of diagnosis of type 2 diabetes.^4,8,9 Insulin omission and infection are the most common sources for DKA.^1,2

How is pediatric DKA diagnosed?

Pediatric DKA consists of hyperglycemia (serum glucose greater than 200 mg/dL), anion gap metabolic acidosis, and ketonemia.^1,10-14 DKA is due to absolute or relative deficiency in insulin and excess counterregulatory hormones, with dehydration and electrolyte abnormalities. Rehydration with fluids, insulin, and potentially potassium repletion are treatment mainstays.^10-14

Cerebral Edema

CE is a life-threatening complication in 0.5-1% of patients with DKA.^2,14-17 CE mainly causes death through herniation.  Mortality can reach 40%, and 1/4 of survivors suffer permanent neurologic deficits.^1,2,14-18 Though we classically view CE as the patient presenting with focal deficit or altered mental status, it may be asymptomatic or subtle.^19-22 Two thirds of patients are diagnosed within the first 7 hours of treatment, with 1/3 diagnosed 10-24 hours after treatment initiation.^15,16,23-25

The diagnosis is clinical, as close to 40% of patients with CE display normal neuroimaging.^1,2,22,26,27 There are actually criteria for diagnosis (sensitivity 92%, specificity 96%), and as you can see, there a variety of conditions that could mimic these findings.²⁶  If CE is diagnosed, mannitol is a common first line therapy at 1 g/kg IV, though hypertonic saline (3%) 5-10 ml/kg IV is an option.^1,2,10-13

So, let’s get to it…

One of the first descriptions of the disease was in 1936,²⁹ and many studies have tried to discover the cause of CE in pediatric DKA. Before we look at these factors, let’s begin with the first myth.

Myth #1: Cerebral edema in pediatric DKA is always easy to diagnose.

Edema isn’t always easy to diagnose, as it is usually subtle. In fact, clinical overt CE is rare.^20-23,30 Neuroimaging (computed tomography or magnetic resonance imaging) in children with DKA often shows CE before DKA treatment with fluids is initiated.^{14,15,23,31,32} Abnormal findings on neuro exam are associated with higher frequency of MRI changes.^16,22,26,33 However, Krane et al. obtained CT in patients with DKA and found signs of edema in 6 patients, though none had clinical signs of CE.²² CE is likely not rare in DKA. However, the severe form is rare.

The Bottom Line: Cerebral edema occurs along a spectrum in pediatric DKA and is likely fairly common, though the severe form is rare.

Myth #2: The mechanism of cerebral edema is well-known.

There are many proposed mechanisms for development of CE including vasogenic edema from blood-brain barrier (BBB) destruction, osmotic edema due to fluid therapy, and cytotoxic edema from ischemia.

A) Vasogenic edema is due to damage of the CNS vascularendothelial layer. This causes breakdown of the blood-brain-barrier, which allows diffusion of fluid into the CNS.^16,19,34,35 MRI can demonstrate abnormal diffusion of fluid into the brain in pediatric DKA.^16,19,34,35 Despite hypocapnia in DKA, CNS oxygen and blood supply often increase, suggesting vasogenic edema is a factor.^34-36 Vasogenic edema may be a component, though the studies promoting this mechanismare small, including patients without CE.

B) A change in serum osmolarity is another potential mechanism for CE. CNS osmolyte accumulation can occur in the hyperosmolar state of DKA, and with IV fluid resuscitation, it is thought a rapid decrease in the extracellular osmolar state causes brain swelling.^17,37,38 This is one of the major theories behind the recommendation for fluid repletion over 48 hours, rather than bolus.^39-42 Though this hypothesis seems bulletproof, data is lacking to support this mechanism.^39-42 One study suggests patients receiving replacement over 12 hours vs. 48 hours demonstrate no higher risk of CE.⁴³ Large osmotic shifts occur in all patients with DKA; however, clinically apparent cerebral edema develops in a small percentage of patients with DKA.^1,2,15,16,43 This mechanism may contribute, but it is not the primary reason for CE.

C) CNS hypoperfusion also contributes. Cerebral blood flow is decreased in DKA due to hypoperfusion, which may result in cytotoxic edema due to ischemia.^{15,19,30,44,45} CE may be a consequence of this hypoperfusion during DKA, similar to ischemic stroke. One study with neuroimaging at the initial time of neurologic decline found no radiologic evidence of injury, though patients demonstrated severe symptoms clinically.²⁶ CT completed hours to days later showed evidence of CE, including hemorrhage or cerebral infarction in several patients.^26,46-50 Several studies suggest hypoperfusion during severe DKA results in neurologic decompensation.^15,19,46-50

The Bottom Line: The mechanism of cerebral edema is complex and not associated with just one factor, and hypoperfusion during severe DKA is likely a contributor to cerebral edema.

Myth #3: Cerebral edema is definitively due to greater rates of intravenous fluid infusion or larger fluid boluses.

Unfortunately, a paucity of well-constructed, controlled trials exists evaluating the association of fluids and CE.^27,28 Most studies are poorly controlled and retrospective, with no comparison groups. A study in 1971 was one of the first suggesting an association, though this was an observational study with cerebrospinal fluid pressure measured during treatment.⁵¹ Authors state treatment raised CSF pressure, though no cases of CE were found.⁵¹ A study in 1988 (review of 42 cases of DKA) found increased IV fluid rate to be associated with decreased time to cerebral herniation.³⁹ This is one of the primary studies that suggests increased fluid infusion is associated with CE, though no comparison group was used.³⁹

Glaser et al. in 2001 conducted one of the first higher-quality studies.¹⁵ This retrospective study evaluated patients under age 18 years with CE in 10 U.S. hospitals, though investigators did not use specific criteria for CE diagnosis.

– Investigators compared 61 cases of CE with 174 control cases of DKA, defined by low pH or bicarbonate with ketonuria and serum glucose > 300 mg/dL.

– Authors randomly selected patients with DKA but no cerebral edema and then matched another group of patients in terms of age, onset of diabetes, initial serum glucose, and initial venous pH.

– Authors evaluated IV fluid administration by the volume infused per kg of weight per hr.

– Adjusted relative risk for IV fluid was 1.1 (95% confidence interval (CI) 0.4-3.0). Lower initial partial pressures of arterial CO2 (RR 3.4 for each decrease by 7.8 mm Hg, 95% CI 1.9-6.3), higher BUN (RR 1.7 for each increase of 9 mg/dL or 3.2 mmol/L, 95% CI 1.2-25), and bicarbonate therapy (RR 4.2, 95% CI 1.5-12.1) were associated with CE.^15,27,28

Lawrence et al. in 2005 conducted a case-control study, including patients less than 16 years with DKA and cerebral edema.³¹

– Authors evaluated 17 cases of CE and 28 controls with DKA, defined by low pH or bicarbonate with ketonuria. Cerebral edema was present initially in 19% of patients, though no specific definition was utilized for cerebral edema diagnosis.

– Investigators evaluated IV fluid through the volume infused per kg per hr.

– Lower initial bicarbonate, higher serum BUN, and higher initial glucose were associated with CE. Rate of fluid infusion was not associated with CE (though adjusted RR or OR were not reported).^27,28,31

Edge et al. in 2006 utilized a case-control study to identify 43 cases of cerebral edema in 2940 patients with DKA, defined by low pH or bicarbonate with ketonuria.³² This study measured infused volume without correcting for patient weight, unlike studies by Glaser and Lawrence.

– Investigators selected 169 patients as control subjects.

– CE was defined by deterioration of mental status with associated signs of increased intracranial pressure (hypertension and bradycardia, blurred disc margin, abnormal motor posturing, squinting, respiratory abnormalities).

– Investigators evaluated the total amount of IV fluid (divided into tertiles of total IV fluid administered, not based on weight).

– The study excluded a large number of cases and control patients due to misclassification, creating a large number of unmatched patients.

– Investigators performed a conditional analysis (consisting of only appropriately matched cases) restricted to a small subset of patients with complete sets of data. Analysis of all patients suggest an association of higher infusion volumes with CE within the first three hours of treatment (OR 7.3; 95% CI 1.51-35.12) and within 4 hours (OR 6.55; 95% CI 1.38-30.97). Analysis of only matched patients suggested similar results, though CI’s were larger.

– Importantly, authors did not utilize BUN in matching or adjusting for their analysis. This is a vital point, as dehydration severity is associated with BUN, and in this study, patients with severe dehydration were given larger boluses of IV fluids.^27,28,32

Marcin et al. retrospectively evaluated 61 patients under the age of 18 years with DKA and cerebral edema.⁵⁴

– Investigators utilized an ordinal logistic regression analysis, finding 17 patients died or survived in a vegetative state, 8 were mildly to moderately disabled, and 36 experienced no sequelae.

– Factors with poor outcome in CE included neurologic depression at the time of diagnosis of cerebral edema, high BUN, and intubation with hyperventilation to PCO2 < 22 mm Hg.⁵⁴

Several other studies suggest no relation between IV fluid rehydration and CE. Rosenbloom et al. found no association between fluid infusion and CE (2 episodes of CE occurred in patients with oral rehydration only),²⁵ and a second study by Rosenbloom found similar results.²⁴ A 20 year retrospective study evaluating two different fluid rehydration protocols found no difference in CE with fluid replacement rates, with one case in the group with replacement over 6 hours and the other over 24 hours.⁵² Hale et al. found no association of IV volume amount and CE.⁵³  Hoffman et al. evaluated head CTs in several patients with DKA and found no difference in findings on CT before treatment and after resuscitation.²¹ A 1997 study found evidence of edema on CT before fluid resuscitation was started, though these patients were toxic appearing.⁵⁵

The Bottom Line: The literature suggesting higher IV fluid infusion rates or larger fluid boluses is weak. IV fluid is likely not associated with cerebral edema.

What is associated with CE?

Several components consistently are associated with CE in pediatric DKA, shown below. However, these studies are mostly retrospective with no control groups.^{14,18,24,25,39,52,54,57} Studies by Glaser et al., Lawrence et al, and Edge et al. are more rigorously designed with comparison groups.^15,31,32  Bellos found declining sodium to be a poor prognostic finding, though fluid rate was not associated.⁵⁶ Glaser et al. found treatment with bicarbonate, higher serum BUN, and lower partial pressures of arterial CO2 to be related to CE.¹⁵ These results suggest toxic patients in the initial stages of DKA demonstrate higher rates of CE. Studies arguing association of CE with greater infusion rates also state younger age and new diagnosis of diabetes are associated, though these studies did not utilize controls.^{14,18,24,25,39,52,54,57} The CNS of younger patients may be more susceptible to metabolic and vascular changes in DKA.^1,2,15,16 The main takeaway is that patients who are sicker are at higher risk for CE, and dehydration may contribute.

Assessing hydration status – It isn’t easy…

Classically, patients with 5%-7% dehydration have moderate DKA, while those with 10%-14% are classified as severe DKA.^1,2,12,13,16 Examination findings such as reduced skin elasticity, dry mucosal membranes, tachycardia, and hyperpnea were thought to be associated with 5% dehydration, while 10% dehydration was assumed if capillary refill greater than 10 seconds was found with sunken eyes.^16,62,63

Studies suggest dehydration is often overestimated.^64-68  Exam findings such as reduced skin turgor, capillary refill, dry membranes, and sunken eyes are not reliable in predicting hydration status.^64-67 Tachypnea can result in dry mucous membranes, and vasoconstriction can lead to cool extremities. Metabolic acidosis can result in tachypnea, vasoconstriction, and dry mucous membranes (remember those Kussmaul respirations?).^65,68  DKA’s hyperosmolar state can cause diuresis, and hyperosmolarity can also increase intravascular volume via osmosis.^16,64-68

Multiple prospective studies suggest dehydration cannot be predicted clinically.^{16,64,65,67,68} These studies are based on the percent loss of body weight as a surrogate for dehydration, finding a median degree of dehydration of 5%-8%.^64,65,67,68   Close to 70% of patients were clinically assessed incorrectly, either overestimated or underestimated.  In one study, 60% of patients were in severe DKA based on laboratory and clinical criteria, though the median dehydration was 5.4%. The measured degree of dehydration was not significantly altered between different severity groups. ^64,65,67,68

What should the emergency physician do for treatment?

A major component of resuscitation in DKA is rehydration, which also improves blood glucose levels. You have a number of options for resuscitation, including 10 ml/kg bolus or 20 ml/kg bolus, as well as calculation of the fluid requirement over the following 48 hours.^{15,16,57-59,69-72}

As we’ve discussed, optimal volume amounts are controversial, and dehydration is difficult to assess. Few randomized trials have evaluated IV rate or bolus amount.^69,70

– Felner and White evaluated different protocols for rehydration, both providing an initial bolus.⁵⁷ No difference in cerebral edema was found based on the initial bolus. Following bolus, one group received 1.5 times maintenance fluids plus fluids based on patient weight with 0.5 normal saline, while the other group received 2.5 times maintenance with 0.75 normal saline. This second group demonstrated faster correction of acidosis and was more cost effective.⁵⁷

– The two-bag systems consists of two bags of fluids with similar electrolytes, but with different glucose amounts. Degree of dehydration affects the rate of fluids, while serum glucose and rate of glucose decline affect dextrose infusion (0% versus 10%).

– A study in 2013 used a 3-bag system with 2 bags of rehydration fluids (one containing glucose), and the third bag with insulin.⁷¹ Fluids were administered at 2-2.5 times maintenance. The separate bag with glucose provides the ability to quickly respond to changing serum glucose levels.⁷¹

– A recent study evaluated low volume (10 mL/kg bolus with 1.25 x maintenance rate) versus high volume (20 mL/kg bolus with 1.5 x maintenance rate). The study suggests higher volume infusion rates improved normalization of pH, but no difference in length of stay or time to discharge. No signs or symptoms associated with CE were found in either arm.⁵⁹

– The PECARN network is conducting a trial evaluating four different fluid protocols, with all patients receiving 10 ml/kg bolus with 0.9% NS. The primary outcome is abnormal GCS < 14.⁷²

The Bottom Line: With the current literature, 10-20 ml/kg is safe in clinically dehydrated patients (hemodynamic abnormalities and poor capillary refill, dry mucosal membranes, or sunken eyes), which is supported by the International Diabetes Foundation.⁷³ Signs of hemodynamic instability warrant IV fluid bolus. If no improvement with the first 10 ml/kg bolus, another 10 ml/kg bolus is needed. Frequent reassessment is needed for patients who are hemodynamically unstable or severely dehydrated, as repeat boluses are needed. Maintenance fluids should also be started, with replacement over 48 hrs.⁷³  A patient with normal hydration status should be given maintenance fluids with correction over 48 hours.⁷³ Hypoperfusion in the setting of DKA is likely the most strongly associated factor for CE.

Case: You provide a 10 ml/kg bolus of IV NS, resulting in improvement of the patient’s hemodynamic status. You also begin fluids at 1.5 x maintenance. Once the potassium returns as normal, you begin insulin and call the pediatric intensivist for admission.

Key Points:

– CE is a clinical diagnosis.

– CE may occur subclinically in many patients in DKA. The severe form is rare.

– A variety of mechanisms likely account for CE, including vasogenic and cytotoxic causes.

– The literature evaluating fluid infusion in DKA suffers from low sample sizes, lack of comparator groups, and retrospective nature.

– Several studies with comparator groups suggest IV fluids are not associated with CE, though severity of DKA may be associated including the degree of acidosis and dehydration.

– A fluid bolus of 10 ml/kg is safe and may be repeated if needed.

References/Further Reading:

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