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Emergency Medicine Myths: Cerebral Edema in Pediatric Diabetic Ketoacidosis and Intravenous Fluids
The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–10, 2017 Published by Elsevier Inc. 0736-4679/$ - see front matter
http://dx.doi.org/10.1016/j.jemermed.2017.03.014
Clinical Review EMERGENCY MEDICINE MYTHS: CEREBRAL EDEMA IN PEDIATRIC DIABETIC KETOACIDOSIS AND INTRAVENOUS FLUIDS Brit Long, MD* and Alex Koyfman, MD† *Department of Emergency Medicine, San Antonio Military Medical Center, Fort Sam Houston, Texas and †Department of Emergency Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas Reprint Address: Brit Long, MD, Department of Emergency Medicine, San Antonio Military Medical Center, 3841 Roger Brooke Dr., Fort Sam Houston, TX 78234.
, Abstract—Background: Pediatric diabetic ketoacidosis (DKA) is a disease associated with several complications that can be severe. One complication includes cerebral edema (CE), and patients may experience significant morbidity with this disease. Objective: This review evaluates the myths concerning CE in pediatric DKA including mechanism, presentation of edema, clinical assessment of dehydration, and association with intravenous (i.v.) fluids. Discussion: Multiple complications may occur in pediatric DKA. CE occurs in < 1% of pediatric DKA cases, though morbidity and mortality are severe without treatment. Several myths surround this disease. Subclinical CE is likely present in many patients with pediatric DKA, though severe disease is rare. A multitude of mechanisms likely account for development of CE, including vasogenic and cytotoxic causes. Clinical dehydration is difficult to assess. Literature has evaluated the association of fluid infusion with the development of CE, but most studies are retrospective, with no comparator groups. The few studies with comparisons suggest fluid infusion is not associated with DKA. Rather, the severity of DKA with higher blood urea nitrogen and greater acidosis contribute to CE. Multiple strategies for fluid replacement exist. A bolus of 10 mL/kg of i.v. fluid is likely safe, which can be repeated if hemodynamic status does not improve. Conclusions: Pediatric CE in DKA is rare but severe. Multiple mechanisms result in this disease, and many patients
experience subclinical CE. Intravenous fluids are likely not associated with development of CE, and 10-mL/kg or 20mL/kg i.v. bolus is safe. Published by Elsevier Inc. , Keywords—cerebral edema; dehydration; diabetic ketoacidosis; fluid infusion; pediatric
INTRODUCTION Diabetes mellitus is a common chronic disease among children, with increasing frequency in type 1 and 2 diabetes (1–5). One complication is diabetic ketoacidosis (DKA), which has an incidence of 25% in known type 1 diabetics (3–8). Close to one-third of patients at the time of initial diagnosis of diabetes have DKA, and children younger than 5 years or age are at high risk for DKA (3–7). Other risk factors for DKA at the time of diagnosis include ethnic minority, smaller body mass index, delayed treatment, infectious trigger, and lack of health insurance (1,2,8). Though most commonly occurring in type 1 diabetics, patients with type 2 diabetes can also experience DKA, as 5–25% of patients with type 2 diabetes are in DKA at time of diagnosis (4,8,9). The most common cause is insulin omission, though infection is another common trigger (1,2). Pediatric DKA is demonstrated by hyperglycemia (serum glucose > 200 mg/dL), anion gap metabolic acidosis, and ketonemia (1,10–14). Disease develops
This review does not reflect the views or opinions of the U.S. government, Department of Defense, U.S. Army, U.S. Air Force, or SAUSHEC EM Residency Program.
RECEIVED: 25 February 2017; ACCEPTED: 8 March 2017 1
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absolute or relative deficiency in insulin and excess counterregulatory hormones, resulting in dehydration and electrolyte abnormalities. The mainstay of treatment for these patients includes rehydration with fluids, insulin, and potentially potassium repletion (10– 14). One major complication is cerebral edema.
Google FOAM, and Medline. We sought randomized trials, case controls, case series, and chart reviews that compared groups including patients with DKA and CE and those in DKA with no CE. Much of the literature is relegated to descriptive studies that lack comparator groups. Few randomized studies are available, with the majority including case control and case series (27,28).
Cerebral Edema DISCUSSION Cerebral edema (CE) is clinically apparent and life threatening in 0.5–1% of patients with DKA (2,14–17). Though the mortality of DKA is < 1%, CE accounts for a significant proportion of these deaths due to brain herniation, which can occur prior to initiation of treatment (15,17). Mortality ranges from 20–90%, with one-fourth of survivors suffering permanent neurologic deficits (1,2,14–16,18). However, CE may be asymptomatic or subtle, with minor mental status changes, which can appear in many cases of pediatric DKA (19–22). This severe complication presents most commonly within the first 7 h of treatment (66%), with 33% presenting 10–24 h after initiation of treatment in type 1 and type 2 diabetics (15,16,23–25). The diagnosis is clinical, as approximately 40% of patients with CE display normal neuroimaging (1,2,22,26,27). However, diagnosis can be difficult, depending on the presentation. Muir et al. published several criteria for diagnosing cerebral edema, consisting of diagnostic criteria, major criteria, and minor criteria; this is demonstrated in Table 1 (26). A significant consideration is close evaluation of patient neurologic status, with frequent reassessments during management. If suspected or diagnosed, mannitol is the most common firstline therapy at 1 g/kg i.v., though hypertonic saline (3%) is an option at 5–10 mL/kg i.v. (1,2,10–13). This review will evaluate the literature concerning CE in pediatric DKA, specifically the presentation, underlying mechanism, and potential association with fluid infusion. Authors conducted a search of Google Scholar, PubMed, Table 1. DKA Diagnostic Criteria (26) Pediatric DKA Cerebral Edema Diagnostic Criteria Diagnostic Criteria: abnormal motor or verbal response to pain, decorticate or decerebrate posture, cranial nerve palsy, abnormal neurologic respiratory pattern Major Criteria: altered mentation/fluctuating level of consciousness, heart rate decelerations (more than 20 beats/ min) not improved with hydration or sleep, age-inappropriate incontinence Minor Criteria: vomiting, headache, lethargy or difficulty arousing from sleep, diastolic blood pressure > 90 mm Hg, age < 5 years Diagnosis: 1 diagnostic criterion, 2 major criteria, or 1 major and 2 minor criteria *Sensitivity 92% and Specificity 96% DKA = diabetic ketoacidosis.
A great deal of literature has examined risk factors for the development of CE, with the goal of predicting patients at greater risk for CE. Since the first description of this disease in 1936, a great deal of study has focused on eliciting the cause of CE, means of prevention, and treatment (29). However, CE in pediatric DKA is still a mysterious disease. To evaluate the association of i.v. fluid and CE, first we must evaluate the clinical spectrum of CE and the proposed mechanism, as well as the clinical assessment of dehydration in these patients and management of DKA. Myth: Cerebral Edema in Pediatric DKA is Rare and Always Clinically Apparent CE in pediatric DKA that is clinically overt with marked neurologic change is infrequent (20–23,30). Subtle edema occurs in the majority of patients with DKA, as studies using neuroimaging (computed tomography [CT] or magnetic resonance imaging [MRI]) in children with DKA have demonstrated the presence of edema before treatment is initiated and during therapy (14,15,23,31,32). Patients who have abnormal mental status during treatment are likelier to possess subtle CE, defined by cerebral ventricle narrowing, than those with normal neurologic status during treatment (33). Any abnormal neurologic assessment, including abnormal Glasgow Coma Scale score (GCS), is associated with higher frequency of MRI changes (16,22,26,33). Krane et al. found edema on head CT in 6 patients treated for DKA, though none of these patients experienced clinically evident signs of the disease (22). Cerebral edema is not rare in pediatric DKA, but the severe form likely represents the extreme representation of a disease spectrum. Bottom Line: Cerebral edema occurs along a spectrum in pediatric DKA and is likely more common than originally thought. However, the form of edema that results in herniation is likely rare. Myth: The Mechanism of Cerebral Edema is Predominantly Due to Rapid Osmotic Changes with Treatment Many published treatment recommendations for pediatric DKA attempt to minimize the risk of CE, and providers
A Clinical Review Evaluating Myths Surrounding Cerebral Edema in Pediatric Diabetic Ketoacidosis
may associate rate of fluid infusion or size of bolus to the development of CE (1,2,27,28). Multiple mechanisms for development of CE have been hypothesized, including vasogenic edema from blood-brain barrier destruction, osmotic edema due to fluid therapy, and cytotoxic edema from ischemia. Vasogenic edema refers to damage of the cerebral vascular endothelial layer resulting in increased bloodbrain barrier dysfunction, allowing abnormal diffusion of fluid into the central nervous system (16,19,34,35). This has been suggested from observational data based on MRI showing abnormal diffusion of fluid into the brain (16,19,34,35). Increased cerebral blood flow (CBF) and oxygenation have also been found despite hypocapnia, which suggests a vasogenic component to cerebral edema (34–36). However, these studies are small, with patients without CE. This may contribute, but the data are not definitive. Another mechanism commonly thought to result in edema is serum osmotic changes. This is based on the thought that osmolyte accumulation in the brain is due to the presence of the hyperosmolar state in DKA. Fluids resulting in a rapid decrease in the extracellular osmolar state would cause brain swelling (17,37,38). This is one of the predominant theories behind the recommendation for slow fluid and electrolyte replacement over 48 h, rather than in bolus form (39–42). Although this hypothesis is simple and easy to comprehend, data are lacking to support this (39–42). One study suggests that patients receiving replacement over 12 h vs. 48 h demonstrate no higher risk of edema (43). DKA is a hyperosmolar state, and large osmotic shifts occur in all patients with DKA; however, 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 sole component of edema. The other thought is that the development of CE is due to central nervous system hypoperfusion. During DKA, CBF is decreased prior to treatment (15,19,30,44). This hypoperfusion can result in cytotoxic edema due to ischemia (15,19,30,44). Levels of cerebral lactate increase and brain levels of high-energy phosphate decrease when DKA is left untreated, suggesting poor CBF (45). Thus, it may be that CE is a consequence of hypoperfusion during DKA. This is similar to cytotoxic edema in ischemic stroke. One descriptive study found no evidence of edema on neuroimaging at the initial time of neurologic decline, though patients demonstrated severe symptoms (26). Imaging completed several hours to days later showed evidence of CE including hemorrhage or cerebral infarction in several patients (46–50). Rather than osmotic changes, hypoperfusion during severe DKA results in neurologic decompensation (15,19,46–50). Once ischemic insult has occurred,
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vasogenic edema through hyperglycemia may further increase neurologic damage (1,2,16). 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: Cerebral Edema is Directly Linked to Greater Rates of Intravenous Fluid Infusion or Larger Fluid Boluses Many have sought associations between DKA treatment and CE development. However, a review of the literature demonstrates a paucity of well-constructed, controlled trials. A summary of this literature is demonstrated in Table 2 (14,15,18,24,25,27,28,31,32,39,51–57). The majority of studies are poorly controlled and retrospective, with no control or comparison groups. One of the first descriptions of CE and i.v. fluid infusion was suggested in 1971, which was an observational study with cerebrospinal fluid pressure measured during treatment (58). No cases of CE were diagnosed, but the authors state that treatment raised cerebrospinal fluid pressure (58). Another example is a study in 1988, which is a review of 42 cases of DKA that found increased fluid administration rate to be associated with decreased time to herniation (39). Though this study utilized no controls, this is one of the primary studies used for the argument that increased fluid infusion causes CE and harm (39). One of the first studies evaluating risk factors for cerebral edema with comparator groups was conducted by Glaser et al. in 2001 (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. They randomly selected patients with DKA but no cerebral edema, and matched patients with regard to age, onset of diabetes (new or established diagnosis), initial serum glucose, and initial venous pH. Investigators used logistic regression to compare three groups. Authors evaluated i.v. fluid administration by the volume infused per kilogram of weight per hour. The adjusted relative risk (RR) for i.v. fluid was 1.1 (95% confidence interval [CI] 0.4–3.0). Factors associated with CE include lower initial partial pressures of arterial carbon dioxide (RR 3.4 for each decrease by 7.8 mm Hg, 95% CI 1.9–6.3), higher blood urea nitrogen (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) (15,27,28).
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Table 2. Literature Summary of CE in Pediatric DKA Study
Year
Cases
Design
Results
Rosenbloom et al. (25) Duck, Wyatt (39)
1980
17 cases of CE
Case series
CE not related to treatment
1988
42 cases of CE
Case series
Rosenbloom (24)
1990
69 cases of CE
Case series
Bello & Sotos (54)
1990
11 cases of CE, 20 control cases
Retrospective chart review
Mel & Werther (51)
1995
6 cases of CE in 3134 DKA cases
Hale et al. (52)
1997
4 cases of CE, 10 control cases
Retrospective evaluation of two treatment groups Retrospective case-control
CE may be related to fluids, with edema in severe dehydration CE is not related to treatment of DKA including fluid CE may be related to osmolarity change CE not related to treatment
Mahoney et al. (18)
1999
9 cases of CE, 195 cases of DKA
Retrospective chart review
Glaser et al. (15)
2001
61 cases of CE, 174 cases of DKA
Retrospective case-control
Edge et al. (14)
2001
34 cases of CE, 2940 DKA cases
Descriptive Study
Felner & White (55)
2001
0.3–0.5% CE in 520 DKA cases
Marcin et al. (53) Lawrence et al. (31) Edge et al. (32)
2002 2005 2006
61 cases of CE 17 cases of CE, 28 control cases 43 cases of CE, 169 controls
Retrospective evaluation of two treatment groups Retrospective chart review Retrospective case-control Retrospective case-control
Hsia et al. (56)
2014
2.0-5.2% suspected cases of CE in 163 DKA cases
Bakes et al. (57)
2015
50 cases of DKA randomized to separate infusion strategies
Retrospective cohort study evaluating two treatment groups Randomized control trial (n = 25 in each arm)
CE may be related to decline in serum sodium levels, not fluid CE may be related to fluid over 50 mL/kg; CE related to dehydration CE not related to treatment with fluids or insulin CE can occur with DKA, though fluid choice likely not associated CE risk similar between treatment groups, fluid likely not related CE not related to fluid infusion CE not associated with fluid CE associated with more fluid, but dehydrated patients received more fluid Adverse outcomes not related to fluid infusion or osmolarity change Higher volume infusion related to faster resolution of metabolic normalization; no cases of CE
CE = cerebral edema; DKA = diabetic ketoacidosis.
Lawrence et al. conducted a case-control study, including patients younger than 16 years with DKA and cerebral edema (31). Investigators evaluated 17 cases of CE and 28 controls with DKA, defined by low pH or bicarbonate with ketonuria. Cerebral edema was found on initial presentation of DKA in 19% of patients, though no specific definition was utilized for cerebral edema. Investigators evaluated i.v. fluid through the volume infused per kilogram per hour. Cerebral edema was associated with lower initial bicarbonate, higher serum BUN, and higher initial glucose. Fluid infusion rates were not associated with significant difference in cerebral edema, though adjusted RR or odds ratio (OR) were not reported (27,28,31). Edge et al. 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). 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 i.v. fluid, which was divided into tertiles of total i.v. fluid adminis-
tered. Importantly, unlike the prior two studies by Glaser et al. and Lawrence et al., this study measured infused volume without correcting for patient weight (15,31). The study discarded a significant number of cases and control patients due to misclassification, which created 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. With inclusion of all patients, the results of this study demonstrate an association of higher infusion volumes with CE within the first 3 h of treatment (OR 7.3; 95% CI 1.51–35.12) and within 4 h (OR 6.55; 95% CI 1.38–30.97). When patients with incomplete data were not analyzed, results were similar, with much larger CIs. However, authors did not utilize BUN in matching or adjusting for their analysis. This is important, as higher BUN is associated with greater dehydration, and in this study, patients with severe dehydration were given larger boluses of i.v. fluids (27,28,32). Other studies have suggested fluid infusion is not correlated with cerebral edema. Rosenbloom et al. did not find an association between fluid infusion and edema, and two episodes of CE occurred in patients with oral
A Clinical Review Evaluating Myths Surrounding Cerebral Edema in Pediatric Diabetic Ketoacidosis
rehydration only, and a second study by Rosenbloom found similar results, with no correlation between fluid and edema (24,25). Mel and Werther conducted a 20-year retrospective study evaluating two different fluid rehydration protocols, with one rapidly correcting dehydration within 6 h and the other using rehydration over 24 h (51). No difference in rates of cerebral edema occurred (51). Hale et al. found no difference in volume administered in patients with cerebral edema and those without (52). Marcin et al. retrospectively evaluated 61 patients under the age of 18 years with DKA and cerebral edema (53). Investigators utilized an ordinal logistic regression analysis, finding that 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 (53). Hoffman et al. evaluated serial head CTs in 9 patients with DKA, finding no change in pretreatment CT and CT 6–8 h after treatment (21). One study in 1997 found that 6 of 7 patients undergoing CT demonstrated evidence of edema before treatment was started (59). No evidence of edema was found on head CT in patients treated for DKA (59). A summary of the literature, with discussion of the design and results, is shown in Table 2. This Table includes the majority of studies evaluating DKA; however, case series with no cases of CE and observational studies without comparison groups were excluded from this Table. Bottom Line: Intravenous fluid infusion, either size of bolus or infusion rate, is likely not associated with development of cerebral edema. What is Associated with Development of Cerebral Edema? Several factors have been consistently associated with development of CE in pediatric DKA, unlike fluid
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infusion size or rate, which are discussed in Table 3 (15,17,18,24,31,32,37,53,60,61). Similar to the prior studies discussed, these studies are mostly retrospective and uncontrolled; however, the studies by Glaser et al., Lawrence et al., and Edge et al. are more rigorously designed and include groups for comparison (14,15,18,24,25,31,32,39,51,53,55). Bello and Sotos found declining sodium to be an ominous sign (54). However, fluid rate was not associated (54). Glaser et al. suggest that treatment with bicarbonate, higher serum BUN, and lower partial pressures of arterial CO2 are related to development of edema (15). These imply that patients who were more toxic in the initial stages of DKA demonstrate higher rates of CE. The same studies that suggest that greater infusion rates are associated with CE also include younger age, higher BUN, and new diagnosis of diabetes, though as discussed, these studies did not utilize controls (14,18,24,25,39,51,53,55). A large number of patient factors may be associated with CE, demonstrated in Table 3. Many of these factors are associated with greater dehydration. Another component is patient age, as the brains of younger patients may be more susceptible to metabolic and vascular changes in DKA (1,2,15,16). Ultimately, patients who are sicker with greater dehydration upon initial presentation are at higher risk for CE. Part of the assessment for DKA severity revolves around dehydration, as patients with 5–7% are classified as moderate DKA, whereas those with 10–14% may be classified as severe DKA (1,2,12,13,16). Classically, examination findings such as reduced skin elasticity, dry mucosal membranes, tachycardia, and hyperpnea were thought to be associated with 5% dehydration, whereas 10% dehydration was assumed if capillary refill > 10 s was found with sunken eyes (16,62,63). However, the degree of dehydration is often overestimated (64–68). Physical examination findings such as reduced skin turgor, capillary refill, dry membranes, and sunken eyes are not reliable predictors of hydration status in patients with DKA, as they may not be due to
Table 3. Potential Risk Factors of CE in Pediatric DKA DKA-Induced Cerebral Edema Risk Factors
Studies
New onset Younger age (<5 years) Severe acidemia (pH < 7.1) Severe hypocapnia (PCO2 < 20 mm Hg) Insulin administration during first hour of resuscitation High blood urea nitrogen Lower initial bicarbonate Treatment with bicarbonate Slow increase in serum sodium concentration during treatment
Rosenbloom (24) & Duck, Wyatt (39) Rosenbloom (24) & Duck, Wyatt (39) Edge et al. (32), Lawrence et al. (31), Durr et al. (37), Mahoney et al. (18) Glaser et al. (15), Mahoney et al. (18) Edge et al. (32) Glaser et al. (15), Lawrence et al. (31), Marcin et al. (53) Lawrence et al. (31) Glaser et al. (15), Chua et al. (60), Bureau et al. (61) Glaser et al. (15), Harris et al. (17), Duck & Wyatt (39), Bello & Sotos (54)
CE = cerebral edema; DKA = diabetic ketoacidosis.
0.45% saline
10 mL/kg 0.9% NS None 5% of body weight Replace deficit + maintenance fluids over 48 h evenly
PECARN = Pediatric Emergency Care Applied Research Network.
10 mL/kg 0.9% NS 10 mL/kg 0.9% NS 10% of body weight Replace half of fluid deficit + maintenance fluids over 12 h, then remaining deficit + maintenance fluids over following 24 h 0.45% saline Standard initial fluid bolus Additional fluid Assumed fluid deficit Deficit replacement
Replacement fluid
A1 Protocol
Table 4. PECARN Study Groups (72)
Fluids are vital in the initial stages of resuscitation for rehydration, while also improving blood glucose levels. Inadequate resuscitation may worsen cerebral hypoperfusion. A number of regimens are advocated for resuscitation, including 10-mL/kg bolus or 20-mL/kg bolus over 1–2 h, as well as calculation of the fluid requirement over the following 48 h (15,16,55–57,69–72). However, as discussed, the optimal volume and resuscitation rate are controversial, and dehydration is difficult to assess. To date, few randomized trials have evaluated infusion rate or i.v. bolus amount, though studies have evaluated bag systems for treatment (69,70). Felner and White evaluated different protocols for rehydration, both utilizing an initial bolus (55). No difference in cerebral edema was found based on the initial bolus. After bolus, one group received 1.5 times maintenance fluids plus fluids based on patient weight with 0.5 normal saline, whereas 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 (55). A two-bag system consists of two bags of fluids with similar electrolyte contents, but with different glucose amounts that are provided into the same i.v. line. Dehydration and patient needs affect the rate of fluids, whereas serum glucose and rate of glucose decline affect dextrose infusion (0% vs. 10%). At first, no glucose is provided, but as hyperglycemia improves, dextrose is titrated to allow for control of glucose decrease. Another study released in 2013 utilized a three-bag system, with two bags of rehydration fluids (one containing glucose),
A2
What Should the Emergency Physician Do for Treatment?
10 mL/kg 0.9% NS 10 mL/kg 0.9% NS 10% of body weight Replace half of fluid deficit + maintenance fluids over 12 h, then remaining deficit + maintenance fluids over following 24 h 0.9% saline
B1
B2
only fluid loss (64–67). Confounding factors include tachypnea, resulting in dry mucous membranes, and vasoconstriction, leading to cool extremities. Acidosis can cause tachypnea, vasoconstriction, and dry mucous membranes from Kussmaul respirations (65,68). The hyperosmolarity can drastically affect intravascular volume, as diuresis can result in hypovolemia, whereas hyperosmolarity increases intravascular volume through osmosis (16,64–68). Multiple prospective studies demonstrate that dehydration cannot be adequately 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).
0.9% saline
B. Long and A. Koyfman 10 mL/kg 0.9% NS None 5% of body weight Replace deficit + maintenance fluids over 48 h evenly
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A Clinical Review Evaluating Myths Surrounding Cerebral Edema in Pediatric Diabetic Ketoacidosis
and the third bag with insulin (71). Fluids were administered at 2–2.5 times maintenance. This system demonstrates improved flexibility and timeliness when compared with a single-bag system. The separate bag with glucose provides the ability to quickly respond to changing serum glucose levels (71). A recent study evaluated the volume infusion on metabolic normalization, length of stay, and adverse outcomes, including patients 0 to 18 years of age with type 1 diabetes mellitus and DKA (57). Investigators randomized patients to low volume (10-mL/kg bolus with 1.25 times maintenance rate) vs. high volume (20-mL/kg bolus with 1.5 maintenance rate). The study suggests that higher volume infusion rates improved normalization of pH, but made no difference in length of stay or time to discharge. No adverse events, including signs/symptoms of cerebral edema, occurred in either group (57). The Pediatric Emergency Care Applied Research Network (PECARN) network is currently completing a trial evaluating fluid infusion in pediatric DKA, including patients under the age of 18 years (Table 4) (72). This trial is a prospective study utilizing four different fluid protocols, shown in Table 2. Of note, all patients receive an initial 10-mL/kg bolus of 0.9% saline. The primary study outcome is abnormal GCS (< 14) during treatment. Those with initial GCS < 14 are excluded from evaluating the primary outcome, but not secondary outcomes including clinically overt edema, forward and backward digit span recall tests, and memory tests 3 months after recovery from DKA (72). Results of this trial are pending. At this time, 10 mL/kg is safe in clinically dehydrated patients with poor capillary refill, dry mucosal membranes, or sunken eyes, and this is recommended by the International Diabetes Foundation (73). Hemodynamic status must be carefully assessed, and any signs of hemodynamic instability warrant i.v. fluid bolus. If the patient is severely dehydrated and hemodynamic status does not improve after the first i.v. bolus, a second bolus may be provided. Maintenance fluid with further replacement can then be calculated for replacement over 48 h (73). If the patient is not severely dehydrated, maintenance fluids can be provided with correction over 48 h (73). Dehydration and hypoperfusion in the setting of DKA are likely the factors most strongly associated with CE. CONCLUSIONS Pediatric DKA and CE are diseases that can cause significant morbidity and mortality. CE is a clinical diagnosis and is rare in its severe form. A variety of myths concerning CE in pediatric DKA are present. CE may occur subclinically in many patients in DKA. A variety of mechanisms likely account for CE, including vasogenic and cytotoxic causes. Patients with DKA are often dehy-
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drated, but dehydration can be difficult to assess clinically. The literature evaluating fluid infusion in DKA suffers from low sample sizes, lack of comparator groups, and retrospective nature. However, several studies with comparator groups suggest that i.v. fluids are not associated with CE, though severity of DKA may be associated, including the degree of acidosis and dehydration. A fluid bolus of 10–20 mL/kg is likely safe and may be repeated if needed.
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8 19. Glaser N, Gorges S, Marcin J, et al. Mechanism of cerebral edema in children with diabetic ketoacidosis. J Pediatr 2004;145:164–71. 20. Glaser N, Wooton-Gorges S, Buonocore M, et al. Frequency of subclinical cerebral edema in children with diabetic ketoacidosis. Pediatr Diabetes 2006;7:75–80. 21. Hoffman W, Steinhart C, El Gammal T, Steele S, Cuadrado A, Morse P. Cranial CT in children and adolescents with diabetic ketoacidosis. AJNR Am J Neuroradiol 1988;9:733–9. 22. Krane E, Rockoff M, Wallman J, Wolfsdorf J. Subclinical brain swelling in children during treatment of diabetic ketoacidosis. N Engl J Med 1985;312:1147–51. 23. Edge JA. Cerebral oedema during treatment of diabetic ketoacidosis: are we any nearer finding a cause? Diabetes Metab Res Rev 2000;16:316–24. 24. Rosenbloom AL. Intracerebral crises during treatment of diabetic ketoacidosis. Diabetes Care 1990;13:22–33. 25. Rosenbloom AL, Riley WJ, Weber FT, et al. Cerebral edema complicating diabetic ketoacidosis in childhood. J Pediatr 1980; 96:357–61. 26. Muir AB, Quisling RG, Yang MCK, Rosenbloom AL. Cerebral edema in childhood diabetic ketoacidosis. Natural history, radiographic findings, and early identification. Diabetes Care 2004;27: 1541–6. 27. Brown TB. Cerebral oedema in childhood diabetic ketoacidosis: is treatment a factor? Emerg Med J 2004;21:141–4. 28. Hom J, Sinert R. Is fluid therapy associated with cerebral edema in children with diabetic ketoacidosis? Ann Emerg Med 2008;52:69–751. 29. Dillon ES, Riggs HE, Dyer WW. Cerebral lesions in uncomplicated fatal diabetic ketoacidosis. Am J Med Sci 1936;192:360–5. 30. Lam T, Anderson S, Glaser N, O’Donnell M. Bumetanide reduces cerebral edema formation in rats with diabetic ketoacidosis. Diabetes 2005;54:510–6. 31. Lawrence SE, Cummings EA, Gaboury I, Daneman D. Populationbased study of incidence and risk factors for cerebral edema in pediatric diabetic ketoacidosis. J Pediatr 2005;146:688–92. 32. Edge JA, Jakes RW, Roy Y, et al. The UK case-control study of cerebral oedema complicating diabetic ketoacidosis in children. Diabetologia 2006;49:2002–9. 33. Glaser N, Marcin J, Wooton-Gorges S, et al. Correlation of clinical and biochemical findings with DKA-related cerebral edema in children using magnetic resonance diffusion weighted imaging. J Pediatr 2008;153:541–6. 34. Figueroa RE, Hoffman WH, Momin Z, Pancholy A, Passmore GG, Allison J. Study of subclinical cerebral edema in diabetic ketoacidosis by magnetic resonance imaging T2 relaxometry and apparent diffusion coefficient maps. Endocr Res 2005;31: 345–55. 35. Vavilala MS, Richards TL, Roberts JS, et al. Change in blood-brain barrier permeability during pediatric diabetic ketoacidosis treatment. Pediatr Crit Care Med 2010;11:332–8. 36. Roberts JS, Vavilala MS, Schenkman KA, Shaw D, Martin LD, Lam AM. Cerebral hyperemia and impaired cerebral autoregulation associated with diabetic ketoacidosis in critically ill children. Crit Care Med 2006;34:2217–23. 37. Durr JA, Hoffman WH, Sklar AH, el Gammal T, Steinhart CM. Correlates of brain edema in uncontrolled IDDM. Diabetes 1992;41: 627–32. 38. Silver SM, Clark EC, Schroeder BM, Sterns RH. Pathogenesis of cerebral edema after treatment of diabetic ketoacidosis. Kidney Int 1997;51:1237–44. 39. Duck S, Wyatt D. Factors associated with brain herniation in the treatment of diabetic ketoacidosis. J Pediatr 1988;113:10–4. 40. Harris G, Fiordalisi I, Finberg L. Safe management of diabetic ketoacidemia. J Pediatr 1988;113:65–7. 41. Arieff A, Kleeman C. Cerebral edema in diabetic comas. II. Effects of hyperosmolality, hyperglycemia and insulin in diabetic rabbits. J Clin Endocrinol Metab 1974;38:1057–67. 42. Prockop L. Hyperglycemia, polyol accumulation, and increased intracranial pressure. Arch Neurol 1971;25:126–40. 43. Fiordalisi I, Novotny WE, Holbert D, Finberg L, Harris GD, Critical Care Management Group. 18 yr prospective study of paediatric dia-
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betic ketoacidosis: an approach to minimizing the risk of brain herniation during treatment. Pediatr Diabetes 2007;8:142–9. Yuen N, Anderson S, Glaser N, O’Donnell M. Cerebral blood flow and cerebral edema in rats with diabetic ketoacidosis. Diabetes 2008;57:2588–94. Glaser N, Yuen N, Anderson S, Tancredi D, O’Donnell M. Cerebral metabolic alterations in rats with diabetic ketoacidosis: effects of treatment with insulin and intravenous fluids and effects of bumetanide. Diabetes 2010;59:702–9. Wootton-Gorges SL, Buonocore MH, Kuppermann N, et al. Cerebral proton magnetic resonance spectroscopy in children with diabetic ketoacidosis. AJNR Am J Neuroradiol 2007;28:895–9. Wootton-Gorges SL, Buonocore MH, Kuppermann N, et al. Detection of cerebral {beta}-hydroxybutyrate, acetoacetate, and lactate on proton MR spectroscopy in children with diabetic ketoacidosis. AJNR Am J Neuroradiol 2005;26:1286–91. Hoffman WH, Andjelkovic AV, Zhang W, Passmore GG, Sima AA. Insulin and IGF-1 receptors, nitrotyrosin and cerebral neuronal deficits in two young patients with diabetic ketoacidosis and fatal brain edema. Brain Res 2010;1343:168–77. Hoffman WH, Artlett CM, Zhang W, et al. Receptor for advanced glycation end products and neuronal deficit in the fatal brain edema of diabetic ketoacidosis. Brain Res 2008;1238:154–62. Hoffman WH, Stamatovic SM, Andjelkovic AV. Inflammatory mediators and blood brain barrier disruption in fatal brain edema of diabetic ketoacidosis. Brain Res 2009;1254:138–48. Mel JM, Werther GA. Incidence and outcome of diabetic cerebral oedema in childhood: are there predictors? J Pediatr Child Health 1995;31:17–20. Hale PM, Rezvani I, Braunstein AW, et al. Factors predicting cerebral edema in young children with diabetic ketoacidosis and new onset type I diabetes. Acta Paediatr 1997;86:626–31. Marcin JP, Glaser N, Barnett P, et al. Factors associated with adverse outcomes in children with diabetic ketoacidosis-related cerebral edema. J Pediatr 2002;141:793–7. Bello FA, Sotos JF. Cerebral oedema in diabetic ketoacidosis in children. Lancet 1990;336:64. Felner EI, White PC. Improving management of diabetic ketoacidosis in children. Pediatrics 2001;108:735–40. Hsia DS, Tarai SG, Alimi A, et al. Fluid management in pediatric patients with DKA and rates of suspected clinical cerebral edema. Pediatr Diabetes 2015;16:338–44. Bakes K, Haukoos JS, Deakyne SJ, et al. Effect of volume of fluid resuscitation on metabolic normalization in children presenting in diabetic ketoacidosis: a randomized controlled trial. J Emerg Med 2016;50:551–9. Clements RS Jr, Blumenthal SA, Morrison AD, Winegrad AI. Increased cerebrospinal- fluid pressure during treatment of diabetic ketoacidosis. Lancet 1971;2:671–5. Smedman L, Escobar R, Hesser U, et al. Subclinical cerebral oedema does not occur regularly during treatment for diabetic ketoacidosis. Acta Pediatr 1997;86:1172–6. Chua HR, Schneider A, Bellomo R. Bicarbonate in diabetic ketoacidosis – a systematic review. Ann Intensive Care 2011;1:23. Bureau MA, Be´gin R, Berthiaume Y, Shapcott D, Khoury K, Gagnon N. Cerebral hypoxia from bicarbonate infusion in diabetic acidosis. J Pediatr 1980;96:968–73. Rosenbloom AL. Diabetic ketoacidosis: treatment guidelines. Clin Pediatr (Phila) 1996;35:261–6. Finberg L. Appropriate therapy can prevent cerebral swelling in diabetic ketoacidosis. J Clin Endocrinol Metab 2000;85: 507–8. Koves I, Neutze J, Donath S, et al. The accuracy of clinical assessment of dehydration during diabetic ketoacidosis in childhood. Diabetes Care 2004;27:2485–7. Ugale J, Mata A, Meert K, Samaik A. Measured degree of dehydration in children and adolescents with type 1 diabetic ketoacidosis. Pediatr Crit Care Med 2012;13:e103–7. Smith L, Rotta A. Accuracy of clinical estimates of dehydration in pediatric patients with diabetic ketoacidosis. Pediatr Emerg Care 2002;18:395–6.
A Clinical Review Evaluating Myths Surrounding Cerebral Edema in Pediatric Diabetic Ketoacidosis 67. Sottosanti M, Morrison G, Singh R, et al. Dehydration in children with diabetic ketoacidosis: a prospective study. Arch Dis Child 2012;97:96–100. 68. Fagan MJ, Avner J, Khine H. Initial fluid resuscitation for patients with diabetic ketoacidosis: how dry are they? Clin Pediatr 2008; 47:851–5. 69. Grimberg A, Cerri RW, Satin-Smith M, et al. The ‘‘two bag system’’ for variable intravenous dextrose and fluid management: benefits in diabetic ketoacidosis management. J Pediatr 1999;134:376–8. 70. Poirier MP, Greer D, Satin-Smith M. A prospective study of the ‘‘two-bag system’’ in diabetic ketoacidosis management. Clin Pediatr (Phila) 2004;43:809–13.
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71. White PC, Dickson BA. Low morbidity and mortality in children with diabetic ketoacidosis treated with isotonic fluids. J Pediatr 2013;163:761–6. 72. Glaser NS, Ghetti S, Casper TC, Dean JM, Kuppermann N, Pediatric Emergency Care Applied Research Network (PECARN) DKA FLUID Study Group. Pediatric diabetic ketoacidosis, fluid therapy, and cerebral injury: the design of a factorial randomized controlled trial. Pediatr Diabetes 2013;14:435–46. 73. International Diabetes Federation. ISPAD guideline for diabetes in childhood and adolescence. Available at: http://www.idf.org/sites/ default/files/Diabetes-in-Childhood-and-Adolescence-Guidelines. pdf. Accessed February 20, 2017.
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ARTICLE SUMMARY 1. Why is this topic important? Cerebral edema is a severe complication of pediatric diabetic ketoacidosis (DKA), though it is rare. Many studies have evaluated risk factors associated with the development of cerebral edema. 2. What does this review attempt to show? This review evaluates the literature concerning cerebral edema (CE) in pediatric DKA including mechanism, presentation of edema, clinical assessment of dehydration, and association with intravenous (i.v.) fluids. 3. What are the key findings? CE occurs in <1% of DKA cases. The literature evaluating CE consists of mainly retrospective observational studies. A multitude of mechanisms account for the development of CE, including vasogenic and cytotoxic edema. Signs commonly used to evaluate for dehydration are not reliable, but hemodynamic status should be carefully assessed. Subclinical CE is likely common in DKA. Much of the literature suggesting an association with i.v. fluids and CE are retrospective, with no comparator groups. Several well-constructed case-control studies suggest i.v. fluid infusion may not be associated with CE. A bolus of 10 mL/kg of fluids is safe in patients with severe dehydration or hemodynamic concerns. 4. How is patient care impacted? CE in pediatric DKA is rare, and hemodynamic status should be carefully assessed. If hypotensive or hemodynamically stable, i.v. fluid bolus should be given and the patient reassessed. If no evidence of instability is present, fluids may still be provided.
http://dx.doi.org/10.1016/j.jemermed.2017.03.014
Clinical Review EMERGENCY MEDICINE MYTHS: CEREBRAL EDEMA IN PEDIATRIC DIABETIC KETOACIDOSIS AND INTRAVENOUS FLUIDS Brit Long, MD* and Alex Koyfman, MD† *Department of Emergency Medicine, San Antonio Military Medical Center, Fort Sam Houston, Texas and †Department of Emergency Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas Reprint Address: Brit Long, MD, Department of Emergency Medicine, San Antonio Military Medical Center, 3841 Roger Brooke Dr., Fort Sam Houston, TX 78234.
, Abstract—Background: Pediatric diabetic ketoacidosis (DKA) is a disease associated with several complications that can be severe. One complication includes cerebral edema (CE), and patients may experience significant morbidity with this disease. Objective: This review evaluates the myths concerning CE in pediatric DKA including mechanism, presentation of edema, clinical assessment of dehydration, and association with intravenous (i.v.) fluids. Discussion: Multiple complications may occur in pediatric DKA. CE occurs in < 1% of pediatric DKA cases, though morbidity and mortality are severe without treatment. Several myths surround this disease. Subclinical CE is likely present in many patients with pediatric DKA, though severe disease is rare. A multitude of mechanisms likely account for development of CE, including vasogenic and cytotoxic causes. Clinical dehydration is difficult to assess. Literature has evaluated the association of fluid infusion with the development of CE, but most studies are retrospective, with no comparator groups. The few studies with comparisons suggest fluid infusion is not associated with DKA. Rather, the severity of DKA with higher blood urea nitrogen and greater acidosis contribute to CE. Multiple strategies for fluid replacement exist. A bolus of 10 mL/kg of i.v. fluid is likely safe, which can be repeated if hemodynamic status does not improve. Conclusions: Pediatric CE in DKA is rare but severe. Multiple mechanisms result in this disease, and many patients
experience subclinical CE. Intravenous fluids are likely not associated with development of CE, and 10-mL/kg or 20mL/kg i.v. bolus is safe. Published by Elsevier Inc. , Keywords—cerebral edema; dehydration; diabetic ketoacidosis; fluid infusion; pediatric
INTRODUCTION Diabetes mellitus is a common chronic disease among children, with increasing frequency in type 1 and 2 diabetes (1–5). One complication is diabetic ketoacidosis (DKA), which has an incidence of 25% in known type 1 diabetics (3–8). Close to one-third of patients at the time of initial diagnosis of diabetes have DKA, and children younger than 5 years or age are at high risk for DKA (3–7). Other risk factors for DKA at the time of diagnosis include ethnic minority, smaller body mass index, delayed treatment, infectious trigger, and lack of health insurance (1,2,8). Though most commonly occurring in type 1 diabetics, patients with type 2 diabetes can also experience DKA, as 5–25% of patients with type 2 diabetes are in DKA at time of diagnosis (4,8,9). The most common cause is insulin omission, though infection is another common trigger (1,2). Pediatric DKA is demonstrated by hyperglycemia (serum glucose > 200 mg/dL), anion gap metabolic acidosis, and ketonemia (1,10–14). Disease develops
This review does not reflect the views or opinions of the U.S. government, Department of Defense, U.S. Army, U.S. Air Force, or SAUSHEC EM Residency Program.
RECEIVED: 25 February 2017; ACCEPTED: 8 March 2017 1
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absolute or relative deficiency in insulin and excess counterregulatory hormones, resulting in dehydration and electrolyte abnormalities. The mainstay of treatment for these patients includes rehydration with fluids, insulin, and potentially potassium repletion (10– 14). One major complication is cerebral edema.
Google FOAM, and Medline. We sought randomized trials, case controls, case series, and chart reviews that compared groups including patients with DKA and CE and those in DKA with no CE. Much of the literature is relegated to descriptive studies that lack comparator groups. Few randomized studies are available, with the majority including case control and case series (27,28).
Cerebral Edema DISCUSSION Cerebral edema (CE) is clinically apparent and life threatening in 0.5–1% of patients with DKA (2,14–17). Though the mortality of DKA is < 1%, CE accounts for a significant proportion of these deaths due to brain herniation, which can occur prior to initiation of treatment (15,17). Mortality ranges from 20–90%, with one-fourth of survivors suffering permanent neurologic deficits (1,2,14–16,18). However, CE may be asymptomatic or subtle, with minor mental status changes, which can appear in many cases of pediatric DKA (19–22). This severe complication presents most commonly within the first 7 h of treatment (66%), with 33% presenting 10–24 h after initiation of treatment in type 1 and type 2 diabetics (15,16,23–25). The diagnosis is clinical, as approximately 40% of patients with CE display normal neuroimaging (1,2,22,26,27). However, diagnosis can be difficult, depending on the presentation. Muir et al. published several criteria for diagnosing cerebral edema, consisting of diagnostic criteria, major criteria, and minor criteria; this is demonstrated in Table 1 (26). A significant consideration is close evaluation of patient neurologic status, with frequent reassessments during management. If suspected or diagnosed, mannitol is the most common firstline therapy at 1 g/kg i.v., though hypertonic saline (3%) is an option at 5–10 mL/kg i.v. (1,2,10–13). This review will evaluate the literature concerning CE in pediatric DKA, specifically the presentation, underlying mechanism, and potential association with fluid infusion. Authors conducted a search of Google Scholar, PubMed, Table 1. DKA Diagnostic Criteria (26) Pediatric DKA Cerebral Edema Diagnostic Criteria Diagnostic Criteria: abnormal motor or verbal response to pain, decorticate or decerebrate posture, cranial nerve palsy, abnormal neurologic respiratory pattern Major Criteria: altered mentation/fluctuating level of consciousness, heart rate decelerations (more than 20 beats/ min) not improved with hydration or sleep, age-inappropriate incontinence Minor Criteria: vomiting, headache, lethargy or difficulty arousing from sleep, diastolic blood pressure > 90 mm Hg, age < 5 years Diagnosis: 1 diagnostic criterion, 2 major criteria, or 1 major and 2 minor criteria *Sensitivity 92% and Specificity 96% DKA = diabetic ketoacidosis.
A great deal of literature has examined risk factors for the development of CE, with the goal of predicting patients at greater risk for CE. Since the first description of this disease in 1936, a great deal of study has focused on eliciting the cause of CE, means of prevention, and treatment (29). However, CE in pediatric DKA is still a mysterious disease. To evaluate the association of i.v. fluid and CE, first we must evaluate the clinical spectrum of CE and the proposed mechanism, as well as the clinical assessment of dehydration in these patients and management of DKA. Myth: Cerebral Edema in Pediatric DKA is Rare and Always Clinically Apparent CE in pediatric DKA that is clinically overt with marked neurologic change is infrequent (20–23,30). Subtle edema occurs in the majority of patients with DKA, as studies using neuroimaging (computed tomography [CT] or magnetic resonance imaging [MRI]) in children with DKA have demonstrated the presence of edema before treatment is initiated and during therapy (14,15,23,31,32). Patients who have abnormal mental status during treatment are likelier to possess subtle CE, defined by cerebral ventricle narrowing, than those with normal neurologic status during treatment (33). Any abnormal neurologic assessment, including abnormal Glasgow Coma Scale score (GCS), is associated with higher frequency of MRI changes (16,22,26,33). Krane et al. found edema on head CT in 6 patients treated for DKA, though none of these patients experienced clinically evident signs of the disease (22). Cerebral edema is not rare in pediatric DKA, but the severe form likely represents the extreme representation of a disease spectrum. Bottom Line: Cerebral edema occurs along a spectrum in pediatric DKA and is likely more common than originally thought. However, the form of edema that results in herniation is likely rare. Myth: The Mechanism of Cerebral Edema is Predominantly Due to Rapid Osmotic Changes with Treatment Many published treatment recommendations for pediatric DKA attempt to minimize the risk of CE, and providers
A Clinical Review Evaluating Myths Surrounding Cerebral Edema in Pediatric Diabetic Ketoacidosis
may associate rate of fluid infusion or size of bolus to the development of CE (1,2,27,28). Multiple mechanisms for development of CE have been hypothesized, including vasogenic edema from blood-brain barrier destruction, osmotic edema due to fluid therapy, and cytotoxic edema from ischemia. Vasogenic edema refers to damage of the cerebral vascular endothelial layer resulting in increased bloodbrain barrier dysfunction, allowing abnormal diffusion of fluid into the central nervous system (16,19,34,35). This has been suggested from observational data based on MRI showing abnormal diffusion of fluid into the brain (16,19,34,35). Increased cerebral blood flow (CBF) and oxygenation have also been found despite hypocapnia, which suggests a vasogenic component to cerebral edema (34–36). However, these studies are small, with patients without CE. This may contribute, but the data are not definitive. Another mechanism commonly thought to result in edema is serum osmotic changes. This is based on the thought that osmolyte accumulation in the brain is due to the presence of the hyperosmolar state in DKA. Fluids resulting in a rapid decrease in the extracellular osmolar state would cause brain swelling (17,37,38). This is one of the predominant theories behind the recommendation for slow fluid and electrolyte replacement over 48 h, rather than in bolus form (39–42). Although this hypothesis is simple and easy to comprehend, data are lacking to support this (39–42). One study suggests that patients receiving replacement over 12 h vs. 48 h demonstrate no higher risk of edema (43). DKA is a hyperosmolar state, and large osmotic shifts occur in all patients with DKA; however, 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 sole component of edema. The other thought is that the development of CE is due to central nervous system hypoperfusion. During DKA, CBF is decreased prior to treatment (15,19,30,44). This hypoperfusion can result in cytotoxic edema due to ischemia (15,19,30,44). Levels of cerebral lactate increase and brain levels of high-energy phosphate decrease when DKA is left untreated, suggesting poor CBF (45). Thus, it may be that CE is a consequence of hypoperfusion during DKA. This is similar to cytotoxic edema in ischemic stroke. One descriptive study found no evidence of edema on neuroimaging at the initial time of neurologic decline, though patients demonstrated severe symptoms (26). Imaging completed several hours to days later showed evidence of CE including hemorrhage or cerebral infarction in several patients (46–50). Rather than osmotic changes, hypoperfusion during severe DKA results in neurologic decompensation (15,19,46–50). Once ischemic insult has occurred,
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vasogenic edema through hyperglycemia may further increase neurologic damage (1,2,16). 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: Cerebral Edema is Directly Linked to Greater Rates of Intravenous Fluid Infusion or Larger Fluid Boluses Many have sought associations between DKA treatment and CE development. However, a review of the literature demonstrates a paucity of well-constructed, controlled trials. A summary of this literature is demonstrated in Table 2 (14,15,18,24,25,27,28,31,32,39,51–57). The majority of studies are poorly controlled and retrospective, with no control or comparison groups. One of the first descriptions of CE and i.v. fluid infusion was suggested in 1971, which was an observational study with cerebrospinal fluid pressure measured during treatment (58). No cases of CE were diagnosed, but the authors state that treatment raised cerebrospinal fluid pressure (58). Another example is a study in 1988, which is a review of 42 cases of DKA that found increased fluid administration rate to be associated with decreased time to herniation (39). Though this study utilized no controls, this is one of the primary studies used for the argument that increased fluid infusion causes CE and harm (39). One of the first studies evaluating risk factors for cerebral edema with comparator groups was conducted by Glaser et al. in 2001 (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. They randomly selected patients with DKA but no cerebral edema, and matched patients with regard to age, onset of diabetes (new or established diagnosis), initial serum glucose, and initial venous pH. Investigators used logistic regression to compare three groups. Authors evaluated i.v. fluid administration by the volume infused per kilogram of weight per hour. The adjusted relative risk (RR) for i.v. fluid was 1.1 (95% confidence interval [CI] 0.4–3.0). Factors associated with CE include lower initial partial pressures of arterial carbon dioxide (RR 3.4 for each decrease by 7.8 mm Hg, 95% CI 1.9–6.3), higher blood urea nitrogen (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) (15,27,28).
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Table 2. Literature Summary of CE in Pediatric DKA Study
Year
Cases
Design
Results
Rosenbloom et al. (25) Duck, Wyatt (39)
1980
17 cases of CE
Case series
CE not related to treatment
1988
42 cases of CE
Case series
Rosenbloom (24)
1990
69 cases of CE
Case series
Bello & Sotos (54)
1990
11 cases of CE, 20 control cases
Retrospective chart review
Mel & Werther (51)
1995
6 cases of CE in 3134 DKA cases
Hale et al. (52)
1997
4 cases of CE, 10 control cases
Retrospective evaluation of two treatment groups Retrospective case-control
CE may be related to fluids, with edema in severe dehydration CE is not related to treatment of DKA including fluid CE may be related to osmolarity change CE not related to treatment
Mahoney et al. (18)
1999
9 cases of CE, 195 cases of DKA
Retrospective chart review
Glaser et al. (15)
2001
61 cases of CE, 174 cases of DKA
Retrospective case-control
Edge et al. (14)
2001
34 cases of CE, 2940 DKA cases
Descriptive Study
Felner & White (55)
2001
0.3–0.5% CE in 520 DKA cases
Marcin et al. (53) Lawrence et al. (31) Edge et al. (32)
2002 2005 2006
61 cases of CE 17 cases of CE, 28 control cases 43 cases of CE, 169 controls
Retrospective evaluation of two treatment groups Retrospective chart review Retrospective case-control Retrospective case-control
Hsia et al. (56)
2014
2.0-5.2% suspected cases of CE in 163 DKA cases
Bakes et al. (57)
2015
50 cases of DKA randomized to separate infusion strategies
Retrospective cohort study evaluating two treatment groups Randomized control trial (n = 25 in each arm)
CE may be related to decline in serum sodium levels, not fluid CE may be related to fluid over 50 mL/kg; CE related to dehydration CE not related to treatment with fluids or insulin CE can occur with DKA, though fluid choice likely not associated CE risk similar between treatment groups, fluid likely not related CE not related to fluid infusion CE not associated with fluid CE associated with more fluid, but dehydrated patients received more fluid Adverse outcomes not related to fluid infusion or osmolarity change Higher volume infusion related to faster resolution of metabolic normalization; no cases of CE
CE = cerebral edema; DKA = diabetic ketoacidosis.
Lawrence et al. conducted a case-control study, including patients younger than 16 years with DKA and cerebral edema (31). Investigators evaluated 17 cases of CE and 28 controls with DKA, defined by low pH or bicarbonate with ketonuria. Cerebral edema was found on initial presentation of DKA in 19% of patients, though no specific definition was utilized for cerebral edema. Investigators evaluated i.v. fluid through the volume infused per kilogram per hour. Cerebral edema was associated with lower initial bicarbonate, higher serum BUN, and higher initial glucose. Fluid infusion rates were not associated with significant difference in cerebral edema, though adjusted RR or odds ratio (OR) were not reported (27,28,31). Edge et al. 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). 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 i.v. fluid, which was divided into tertiles of total i.v. fluid adminis-
tered. Importantly, unlike the prior two studies by Glaser et al. and Lawrence et al., this study measured infused volume without correcting for patient weight (15,31). The study discarded a significant number of cases and control patients due to misclassification, which created 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. With inclusion of all patients, the results of this study demonstrate an association of higher infusion volumes with CE within the first 3 h of treatment (OR 7.3; 95% CI 1.51–35.12) and within 4 h (OR 6.55; 95% CI 1.38–30.97). When patients with incomplete data were not analyzed, results were similar, with much larger CIs. However, authors did not utilize BUN in matching or adjusting for their analysis. This is important, as higher BUN is associated with greater dehydration, and in this study, patients with severe dehydration were given larger boluses of i.v. fluids (27,28,32). Other studies have suggested fluid infusion is not correlated with cerebral edema. Rosenbloom et al. did not find an association between fluid infusion and edema, and two episodes of CE occurred in patients with oral
A Clinical Review Evaluating Myths Surrounding Cerebral Edema in Pediatric Diabetic Ketoacidosis
rehydration only, and a second study by Rosenbloom found similar results, with no correlation between fluid and edema (24,25). Mel and Werther conducted a 20-year retrospective study evaluating two different fluid rehydration protocols, with one rapidly correcting dehydration within 6 h and the other using rehydration over 24 h (51). No difference in rates of cerebral edema occurred (51). Hale et al. found no difference in volume administered in patients with cerebral edema and those without (52). Marcin et al. retrospectively evaluated 61 patients under the age of 18 years with DKA and cerebral edema (53). Investigators utilized an ordinal logistic regression analysis, finding that 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 (53). Hoffman et al. evaluated serial head CTs in 9 patients with DKA, finding no change in pretreatment CT and CT 6–8 h after treatment (21). One study in 1997 found that 6 of 7 patients undergoing CT demonstrated evidence of edema before treatment was started (59). No evidence of edema was found on head CT in patients treated for DKA (59). A summary of the literature, with discussion of the design and results, is shown in Table 2. This Table includes the majority of studies evaluating DKA; however, case series with no cases of CE and observational studies without comparison groups were excluded from this Table. Bottom Line: Intravenous fluid infusion, either size of bolus or infusion rate, is likely not associated with development of cerebral edema. What is Associated with Development of Cerebral Edema? Several factors have been consistently associated with development of CE in pediatric DKA, unlike fluid
5
infusion size or rate, which are discussed in Table 3 (15,17,18,24,31,32,37,53,60,61). Similar to the prior studies discussed, these studies are mostly retrospective and uncontrolled; however, the studies by Glaser et al., Lawrence et al., and Edge et al. are more rigorously designed and include groups for comparison (14,15,18,24,25,31,32,39,51,53,55). Bello and Sotos found declining sodium to be an ominous sign (54). However, fluid rate was not associated (54). Glaser et al. suggest that treatment with bicarbonate, higher serum BUN, and lower partial pressures of arterial CO2 are related to development of edema (15). These imply that patients who were more toxic in the initial stages of DKA demonstrate higher rates of CE. The same studies that suggest that greater infusion rates are associated with CE also include younger age, higher BUN, and new diagnosis of diabetes, though as discussed, these studies did not utilize controls (14,18,24,25,39,51,53,55). A large number of patient factors may be associated with CE, demonstrated in Table 3. Many of these factors are associated with greater dehydration. Another component is patient age, as the brains of younger patients may be more susceptible to metabolic and vascular changes in DKA (1,2,15,16). Ultimately, patients who are sicker with greater dehydration upon initial presentation are at higher risk for CE. Part of the assessment for DKA severity revolves around dehydration, as patients with 5–7% are classified as moderate DKA, whereas those with 10–14% may be classified as severe DKA (1,2,12,13,16). Classically, examination findings such as reduced skin elasticity, dry mucosal membranes, tachycardia, and hyperpnea were thought to be associated with 5% dehydration, whereas 10% dehydration was assumed if capillary refill > 10 s was found with sunken eyes (16,62,63). However, the degree of dehydration is often overestimated (64–68). Physical examination findings such as reduced skin turgor, capillary refill, dry membranes, and sunken eyes are not reliable predictors of hydration status in patients with DKA, as they may not be due to
Table 3. Potential Risk Factors of CE in Pediatric DKA DKA-Induced Cerebral Edema Risk Factors
Studies
New onset Younger age (<5 years) Severe acidemia (pH < 7.1) Severe hypocapnia (PCO2 < 20 mm Hg) Insulin administration during first hour of resuscitation High blood urea nitrogen Lower initial bicarbonate Treatment with bicarbonate Slow increase in serum sodium concentration during treatment
Rosenbloom (24) & Duck, Wyatt (39) Rosenbloom (24) & Duck, Wyatt (39) Edge et al. (32), Lawrence et al. (31), Durr et al. (37), Mahoney et al. (18) Glaser et al. (15), Mahoney et al. (18) Edge et al. (32) Glaser et al. (15), Lawrence et al. (31), Marcin et al. (53) Lawrence et al. (31) Glaser et al. (15), Chua et al. (60), Bureau et al. (61) Glaser et al. (15), Harris et al. (17), Duck & Wyatt (39), Bello & Sotos (54)
CE = cerebral edema; DKA = diabetic ketoacidosis.
0.45% saline
10 mL/kg 0.9% NS None 5% of body weight Replace deficit + maintenance fluids over 48 h evenly
PECARN = Pediatric Emergency Care Applied Research Network.
10 mL/kg 0.9% NS 10 mL/kg 0.9% NS 10% of body weight Replace half of fluid deficit + maintenance fluids over 12 h, then remaining deficit + maintenance fluids over following 24 h 0.45% saline Standard initial fluid bolus Additional fluid Assumed fluid deficit Deficit replacement
Replacement fluid
A1 Protocol
Table 4. PECARN Study Groups (72)
Fluids are vital in the initial stages of resuscitation for rehydration, while also improving blood glucose levels. Inadequate resuscitation may worsen cerebral hypoperfusion. A number of regimens are advocated for resuscitation, including 10-mL/kg bolus or 20-mL/kg bolus over 1–2 h, as well as calculation of the fluid requirement over the following 48 h (15,16,55–57,69–72). However, as discussed, the optimal volume and resuscitation rate are controversial, and dehydration is difficult to assess. To date, few randomized trials have evaluated infusion rate or i.v. bolus amount, though studies have evaluated bag systems for treatment (69,70). Felner and White evaluated different protocols for rehydration, both utilizing an initial bolus (55). No difference in cerebral edema was found based on the initial bolus. After bolus, one group received 1.5 times maintenance fluids plus fluids based on patient weight with 0.5 normal saline, whereas 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 (55). A two-bag system consists of two bags of fluids with similar electrolyte contents, but with different glucose amounts that are provided into the same i.v. line. Dehydration and patient needs affect the rate of fluids, whereas serum glucose and rate of glucose decline affect dextrose infusion (0% vs. 10%). At first, no glucose is provided, but as hyperglycemia improves, dextrose is titrated to allow for control of glucose decrease. Another study released in 2013 utilized a three-bag system, with two bags of rehydration fluids (one containing glucose),
A2
What Should the Emergency Physician Do for Treatment?
10 mL/kg 0.9% NS 10 mL/kg 0.9% NS 10% of body weight Replace half of fluid deficit + maintenance fluids over 12 h, then remaining deficit + maintenance fluids over following 24 h 0.9% saline
B1
B2
only fluid loss (64–67). Confounding factors include tachypnea, resulting in dry mucous membranes, and vasoconstriction, leading to cool extremities. Acidosis can cause tachypnea, vasoconstriction, and dry mucous membranes from Kussmaul respirations (65,68). The hyperosmolarity can drastically affect intravascular volume, as diuresis can result in hypovolemia, whereas hyperosmolarity increases intravascular volume through osmosis (16,64–68). Multiple prospective studies demonstrate that dehydration cannot be adequately 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).
0.9% saline
B. Long and A. Koyfman 10 mL/kg 0.9% NS None 5% of body weight Replace deficit + maintenance fluids over 48 h evenly
6
A Clinical Review Evaluating Myths Surrounding Cerebral Edema in Pediatric Diabetic Ketoacidosis
and the third bag with insulin (71). Fluids were administered at 2–2.5 times maintenance. This system demonstrates improved flexibility and timeliness when compared with a single-bag system. The separate bag with glucose provides the ability to quickly respond to changing serum glucose levels (71). A recent study evaluated the volume infusion on metabolic normalization, length of stay, and adverse outcomes, including patients 0 to 18 years of age with type 1 diabetes mellitus and DKA (57). Investigators randomized patients to low volume (10-mL/kg bolus with 1.25 times maintenance rate) vs. high volume (20-mL/kg bolus with 1.5 maintenance rate). The study suggests that higher volume infusion rates improved normalization of pH, but made no difference in length of stay or time to discharge. No adverse events, including signs/symptoms of cerebral edema, occurred in either group (57). The Pediatric Emergency Care Applied Research Network (PECARN) network is currently completing a trial evaluating fluid infusion in pediatric DKA, including patients under the age of 18 years (Table 4) (72). This trial is a prospective study utilizing four different fluid protocols, shown in Table 2. Of note, all patients receive an initial 10-mL/kg bolus of 0.9% saline. The primary study outcome is abnormal GCS (< 14) during treatment. Those with initial GCS < 14 are excluded from evaluating the primary outcome, but not secondary outcomes including clinically overt edema, forward and backward digit span recall tests, and memory tests 3 months after recovery from DKA (72). Results of this trial are pending. At this time, 10 mL/kg is safe in clinically dehydrated patients with poor capillary refill, dry mucosal membranes, or sunken eyes, and this is recommended by the International Diabetes Foundation (73). Hemodynamic status must be carefully assessed, and any signs of hemodynamic instability warrant i.v. fluid bolus. If the patient is severely dehydrated and hemodynamic status does not improve after the first i.v. bolus, a second bolus may be provided. Maintenance fluid with further replacement can then be calculated for replacement over 48 h (73). If the patient is not severely dehydrated, maintenance fluids can be provided with correction over 48 h (73). Dehydration and hypoperfusion in the setting of DKA are likely the factors most strongly associated with CE. CONCLUSIONS Pediatric DKA and CE are diseases that can cause significant morbidity and mortality. CE is a clinical diagnosis and is rare in its severe form. A variety of myths concerning CE in pediatric DKA are present. CE may occur subclinically in many patients in DKA. A variety of mechanisms likely account for CE, including vasogenic and cytotoxic causes. Patients with DKA are often dehy-
7
drated, but dehydration can be difficult to assess clinically. The literature evaluating fluid infusion in DKA suffers from low sample sizes, lack of comparator groups, and retrospective nature. However, several studies with comparator groups suggest that i.v. fluids are not associated with CE, though severity of DKA may be associated, including the degree of acidosis and dehydration. A fluid bolus of 10–20 mL/kg is likely safe and may be repeated if needed.
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71. White PC, Dickson BA. Low morbidity and mortality in children with diabetic ketoacidosis treated with isotonic fluids. J Pediatr 2013;163:761–6. 72. Glaser NS, Ghetti S, Casper TC, Dean JM, Kuppermann N, Pediatric Emergency Care Applied Research Network (PECARN) DKA FLUID Study Group. Pediatric diabetic ketoacidosis, fluid therapy, and cerebral injury: the design of a factorial randomized controlled trial. Pediatr Diabetes 2013;14:435–46. 73. International Diabetes Federation. ISPAD guideline for diabetes in childhood and adolescence. Available at: http://www.idf.org/sites/ default/files/Diabetes-in-Childhood-and-Adolescence-Guidelines. pdf. Accessed February 20, 2017.
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ARTICLE SUMMARY 1. Why is this topic important? Cerebral edema is a severe complication of pediatric diabetic ketoacidosis (DKA), though it is rare. Many studies have evaluated risk factors associated with the development of cerebral edema. 2. What does this review attempt to show? This review evaluates the literature concerning cerebral edema (CE) in pediatric DKA including mechanism, presentation of edema, clinical assessment of dehydration, and association with intravenous (i.v.) fluids. 3. What are the key findings? CE occurs in <1% of DKA cases. The literature evaluating CE consists of mainly retrospective observational studies. A multitude of mechanisms account for the development of CE, including vasogenic and cytotoxic edema. Signs commonly used to evaluate for dehydration are not reliable, but hemodynamic status should be carefully assessed. Subclinical CE is likely common in DKA. Much of the literature suggesting an association with i.v. fluids and CE are retrospective, with no comparator groups. Several well-constructed case-control studies suggest i.v. fluid infusion may not be associated with CE. A bolus of 10 mL/kg of fluids is safe in patients with severe dehydration or hemodynamic concerns. 4. How is patient care impacted? CE in pediatric DKA is rare, and hemodynamic status should be carefully assessed. If hypotensive or hemodynamically stable, i.v. fluid bolus should be given and the patient reassessed. If no evidence of instability is present, fluids may still be provided.