Pediatric Diabetic Ketoacidosis
Authors:
Katia M. Lugo-Enriquez, MD, FACEP, Faculty, Florida Hospital Emergency Medicine Residency Program, Orlando, FL.
Nick Passafiume, MD, Florida Hospital Emergency Medicine Residency Program, Orlando, FL.
Peer Reviewer:
Richard A. Brodsky, MD, Pediatric Emergency Medicine, St. Christopher's Hospital for Children, Assistant Professor, Drexel University, Philadelphia, PA.
Children with diabetes, especially type 1, remain at risk for developing diabetic ketoacidosis (DKA). This may seem confounding in a modern society with such advanced medical care, but the fact remains that children who are type 1 diabetics have an incidence of DKA of 8 per 100 patient years.1 In fact, Neu and colleagues have noted in a multicenter analysis of 14,664 patients in Europe from 1995 to 2007 that there was no significant change in ketoacidosis presenting at diabetes onset in children.2 In children younger than 19 years old, DKA is the admitting diagnosis in 65% of all hospital admissions of patients with diabetes mellitus.3 This article reviews the presentation, diagnostic evaluation, treatment, and potential complications associated with pediatric DKA.
The Editor
Introduction
The overall mortality rate for children in DKA is not unimpressive: The range is 0.15% to 0.31%.4 Besides death, one of the most feared repercussions of DKA in children is cerebral edema, an entity that occurs approximately 1% of the time.5,6 Cerebral edema, with the exception of a few case reports in some young adults, has largely been a complication of treatment in the pediatric population, and the exact factors have yet to be completely determined. The mortality associated with cerebral edema may approach 20% to 50%, and the incidence of neurologic morbidity is significant and reported in 35% to 40% of survivors.7-9
Pathophysiology
The pathophysiology of pediatric DKA results from an insufficiency or deficiency of insulin. Without insulin, the peripheral tissues are unable to detect the glucose in the circulation, and the body goes into a mode similar to starvation. Insulin is an important component of the metabolism of carbohydrates, fat, and protein. In the healthy patient, there is a balance between the insulin levels and the stress hormones, which include glucagon, cortisol, epinephrine, and growth hormone. When insulin is depleted or absent, this homeostasis is lost and results in excess of the stress hormones causing hyperglycemia, osmotic diuresis, ketosis, and acidosis. Insulin inhibits glycogenolysis and gluconeogenesis by stimulating the liver to absorb the glucose and convert it to glycogen, and also stimulating the uptake of amino acids by the different tissues.
With continued low insulin concentration, hormone-sensitive lipase activated in adipose tissue stimulates the release of free fatty acids (FFA). Ketogenesis then occurs in the liver, with activation of the hepatic beta-oxidative enzyme sequence and an increase in FFA to the liver. It goes without saying that a larger decline in insulin as compared to the counter-regulatory hormones is required to promote lipolysis and ketogenesis, as compared to the development of hyperglycemia. In the normal starved patient, some ketosis may occur, but severe ketosis is prevented as insulin becomes active, preventing FFA release and worsening ketosis. In the pediatric DKA patient, this mechanism is lacking.10
As the acidosis and ketosis of DKA progress, the long-term effect is for the body to release the counter-regulatory hormones cortisol, catecholamines, and growth hormone.11 A vicious cycle develops, resulting in worsening ketosis and acidosis, which leads to more insulin resistance, which then leads to the influx of more stress and counter-regulatory hormones.12
Etiology
In known type 1 diabetes, the most common reason for a patient to present in DKA is error in insulin management at home or inadequate insulin administration. Often, the reason is due to financial difficulties, but at other times the reason is secondary to child or parental noncompliance with recommended medical management. Other causes of DKA include insulin pump malfunction, infections (pneumonia, urinary tract infections, viral illnesses), and, in developing countries, malnutrition.13 As pediatric patients enter the prepubescent and pubescent phase, there is often noncompliance secondary to the emotional and psychological stress that comes along with checking daily sugars, diet, and in general being a diabetic. Furthermore, despite the widespread prevalence of the disease, it is still taboo in many areas for children to check sugars and be confident in being a diabetic. This psychological stress leads to insulin noncompliance, and, thus, presentations of poorly controlled diabetes like DKA.14
Definition and Laboratory Diagnosis
DKA is generally defined by precise biochemical criteria. There are varying degrees of DKA, as outlined in Table 1. The diagnostic criteria include hyperglycemia, acidosis, ketonemia, and ketonuria. In general, the diagnosis of DKA is made when the blood glucose is greater than 200 mg/dL (or greater than 11 mmol/L), the venous pH is less than 7.3 (or serum bicarbonate less than or equal to 15 mmol/L), and when serum ketones (beta-hydroxybutyrate and acetoacetate) are greater than 3 mmol/L.13 Based on the degree of acidosis, DKA can be divided into three categories: mild, moderate, and severe. The generally accepted criteria for mild DKA are a venous pH between 7.2 and 7.3 and a bicarbonate 10-15 mmol/L. In moderate DKA, the venous pH is defined as 7.1 to 7.2 and the bicarbonate is 5-10 mmol/L. In the most severe form of DKA, the pH is less than 7.1 and the bicarbonate is less than 5 mmol/L.13 In general, the worse the biochemical parameters, the worse the clinical picture, but this is not always the case. For example, a patient with a pH of 7.15 and blood glucose of 568 mg/dL may have only mild nausea and polyuria as presenting symptoms.
Table 1. DKA Classification
|
Type |
pH |
Bicarbonate |
|
Mild |
7.2 to 7.3 |
10-15 mmol/L |
|
Moderate |
7.1 to 7.2 |
5-10 mmol/L |
|
Severe |
< 7.1 |
< 5 mmol/L |
Clinical Presentation
Although one of the cardinal emergent medical diagnoses, the clinical diagnosis of pediatric DKA sometimes can be challenging and subtle, requiring a high degree of suspicion. Classically, patients will complain of polyuria, polydipsia, weight loss, abdominal pain, nausea, and vomiting. Polyuria and polydipsia occur secondary to hyperglycemia, as an osmotic diuresis occurs. Tachypnea (or Kussmaul breathing) is the body's natural reaction to severe acidosis and it is an attempt to blow off CO2. Without this mechanism, the patient will become extremely acidotic very quickly. Weight loss is secondary to a loss of total body water, which may be in excess of 6 L, even in the pediatric population.15,16 Altered mental status is seen in young children who have greater than 10% dehydration, and there have been reports of these same children presenting with hypothermia secondary to peripheral vasoconstriction.17
On physical examination, patients may present with dry mucous membranes, tachycardia, signs of delayed capillary refill and hypoperfusion, Kussmaul respirations, a fruity odor on the breath due to the presence of ketones in the patient, and diffuse abdominal tenderness. In fact, the abdominal exam in DKA has been said to mirror an acute abdomen. DKA is in any emergency physician's differential for acute abdominal pain, especially in the pediatric population.18 Theoretically, patients in DKA may also present in various states of shock, but the etiology is more likely to be hypovolemic rather than cardiogenic. Severe acidosis may depress cardiac contractility and depress smooth muscle tone, but these effects do not appear to be at play in the pathogenesis of diabetic ketoacidosis.
Management
Fluids. In pediatric DKA, a carefully regulated treatment plan must be taken into effect to prevent the most lethal complication of pediatric DKA treatment, cerebral edema. The traditional teaching has been that overly aggressive isotonic fluid administration is a causative factor in cerebral edema; however, this has yet to be proven. That said, the general recommendation is to replace the fluid deficit in pediatric DKA patients over 36 to 48 hours, evenly after the initial resuscitation. The earliest studies in the literature estimating fluid losses in DKA patients were mostly in adults in the 1940s and 1950s.19-21 Later studies have corroborated the data from these initial studies and have determined that the average fluid loss for a patient in severe DKA is 70 mL/kg. Based on a consensus statement by the European Society for Pediatric Endocrinology/Lawson Wilkins Pediatric Endocrine Society (ESPE/LWPES) in 2004, it can be assumed that the initial degree of dehydration is 7% to 10%.22,23 Most of the volume loss is from osmotic diuresis secondary to hyperglycemia, and there may also be significant gastrointestinal losses secondary to the profuse nausea, vomiting, and, often, diarrhea that occurs in some patients in DKA. According to one prospective study, clinical judgment was a very unreliable indicator of the degree of dehydration.24 In this particular study of 33 patients who presented to a pediatric emergency department in DKA, it was found that the majority of patients presented with moderate dehydration (4% to 8%). Given this finding, most authors recommend that all children in DKA should be expected to be in this degree of dehydration.5
Based on the most recent data, it is recommended to be judicious with fluid administration to prevent cerebral edema. Unless the patient's cardiovascular system is compromised (and shock is rare in pediatric DKA), it is probably most prudent to begin with a bolus of isotonic fluids, starting with 10 mL/kg over one hour. This amount may be repeated if the cardiovascular status of the patient necessitates it. In a 2008 study by Fagan et al, physicians tended to overestimate the severity of dehydration clinically, and patients were likely too aggressively rehydrated. To further exemplify these data, a study by Smith and Rotta showed that greater than 63% of patients were thought to be clinically severely dehydrated (greater than 10%), whereas only around 18% of patients had that severity of dehydration when calculated according to percent loss of body weight.26
Based on these studies and others, it appears that the emergency clinician should not base volume resuscitation too much on the clinical appearance of the patient. After the initial fluid bolus, the rate of volume infusion should be slowed and given to a maximum of 1.5 to 2 times the maintenance rate. As the serum glucose falls with therapy, the serum sodium level should rise to normal or above normal levels. Provided this is the case, it is often prudent to switch maintenance fluids over to D5 ½ NS with 20-40 mEq of potassium (to replace total body depletion) after the first 6 hours of therapy (or a glucose less than 250-300 mg/dL or between 12-14 mmol/L). Fluid ins and outs should be monitored hourly, and consideration should be given to placing a urinary catheter, especially in a patient with altered mental status or a lower GCS on presentation. Replacement fluids may decrease the blood glucose by up to 23% secondary to glucosuria and increased renal perfusion.27 In general, total fluid replacement should not exceed 4 L/m2/ 24 h to avoid the potential complication of cerebral edema.2,16,17 Although there is some recent evidence to dispute this (Felner and White gave 5.23 L/m2/24 h without a concomitant increase in the incidence of cerebral edema), judicious use of fluid seems prudent. With the increasing wait times and bed holds in the emergency department, it is prudent for the emergency physician to know not only the initial fluid requirements, but also the ongoing therapy of a patient in DKA. It has become the general consensus that fluid rehydration should be slow, occurring over approximately a 48-hour period.28 A recommended fluid replacement regimen is listed in Table 2.
Table 2. A Recommended Fluid Replacement Regimen
|
Fluid Replacement |
Recommendations |
|
Initial bolus |
Isotonic fluid 10 mL/kg over 1 hour |
|
Rate of infusion |
1.5 to 2 times the maintenance rate |
|
After the 6 hours of therapy or glucose < 250-300 mg/dL |
D5 ½ NS with 20-40 mEq of potassium |
|
Maximum fluid replacement |
4 L/m2/24 hour of fluid replaced (maximum) |
Glucose and Insulin. Although there is consensus that blood sugars must be greater than 200 mg/dL for a patient to be in DKA, there are some infrequent reports of euglycemic DKA.29 The variability in the level of initial glucose at presentation can often be explained by the volume status and the diet of the child prior to arrival to the emergency department.30 A patient who has been fasting or who has poor nutrient intake will have lower levels of glucose at presentation than a patient who has severe dehydration, who will have higher glucose concentrations.
Insulin, of course, is crucial in the treatment of pediatric DKA for suppressing both lipolysis and ketogenesis. An initial insulin bolus or loading dose is no longer recommended. The current standard of care is to begin a regular insulin drip at a rate of 0.05 U/kg to 0.1 U/kg as a continuous infusion.31,32 These rates will achieve a steady state level of serum insulin that corrects the critical issue in DKA. In new-onset diabetics in DKA who have an initial lower blood glucose level, there is an increasing tendency to start at a rate of 0.05 U/kg as an intravenous infusion of insulin to lower the glucose levels and close the anion gap at a slower rate. In general, an insulin infusion should be maintained until resolution of the ketoacidosis (pH greater than 7.3 or serum bicarbonate greater than 15 mmol/L). Glucose and electrolytes should be monitored hourly and, if there is no response to the initial insulin infusion rate, it may be increased, as patients may require higher rates to reverse their acidosis. An important pitfall to avoid is not to discontinue the insulin drip unless the ketoacidosis is completely resolved, as previously mentioned. At the same time, care must be taken to avoid a precipitous drop in glucose. Change to glucose levels should not decrease at a rate faster than 100 mg/dL/hr to decrease the risk of cerebral edema.1
Table 3. Signs and Symptoms of Cerebral Edema
- Altered mental status
- Headache
- Vomiting
- Slowing heart rate
- Ophthalmoplegia
- Anisocoria
- Posturing
- Seizures
As previously noted, dextrose should be added to the intravenous fluid solution as the blood glucose falls below 250-300 mg/dL. Insulin therapy should generally be given with regular insulin as an intravenous infusion because the subcutaneous route produces erratic absorption. That said, there is evidence in the adult DKA literature that treatment of select cases of noncomplicated DKA via an IM route may be more cost effective and produce similar results compared with intravenous management in an ICU setting.33
Transition to IM Insulin. Although the transition to other types of insulin is rarely made in the ED, it is prudent for emergency physicians to know the continued management of the DKA patient, especially as more and more EDs have had protracted lengths of stay while awaiting an ICU bed. With regard to subcutaneous insulin, it should be avoided until the acidosis has resolved due to its decreased absorption in dehydrated pediatric patients.34 Because the onset of action of rapidly acting insulin (lispro or aspart) is 15 minutes, whereas that of regular insulin is 30-60 minutes, the patient should be given the first dose of IM/SQ insulin after the acidosis is resolved, volume status has stabilized, euglycemia is achieved, and the patient is still on an insulin drip. At this stage, it would be within reason to try the patient on subcutaneous insulin, then turn off the insulin drip 15-60 minutes after the first subcutaneous insulin dose (with rapid-acting insulin). With regular insulin, the first subcutaneous dose should be given with the first meal 1-2 hours prior to stopping the insulin infusion. The patient may be started on an ADA diet, and then the insulin infusion is stopped after this.
Sodium. Another important aspect of care in treating DKA is the issue of hyponatremia. Clinicians should consider the possibility of pseudohyponatremia that may result from an elevated glucose. To calculate the true plasma sodium level, one should use the following formula: plasma sodium + (1.6/5.5) x (plasma glucose – 5.5) = corrected plasma sodium. If there is true hyponatremia after correction, ongoing therapy should be with isotonic fluids. If the sodium is normal or high, 0.45% normal saline is given (with or without dextrose, depending on the glucose level).
Table 4. Recommended Treatment for Cerebral Edema
- Elevate the head of the bed by 30°
- Mannitol 1 g/kg first dose, and a second one in 15 minutes
- Rapid sequence intubation with lidocaine, midazolam, and rocuronium
- Brief hyperventilation to attain a PaCO2 of 30
* Do not delay treatment for further evaluation or CT of the brain.
Potassium. At initial presentation in DKA, patients normally present with high or normal potassium levels, even though total body potassium stores are depleted. Children in DKA have total body potassium deficits on the order of 3-6 mmol/kg.35,36 There are many reasons for a shift of potassium to the extracellular space. Increased plasma osmolality causes an osmotic shift of water to the ECF, and potassium follows this gradient from the intracellular pool to the ECF, leading to hyperkalemia initially. On an ECG, tall, peaked, symmetrical T waves are signs of hyperkalemia and are an indication for immediate calcium infusion to stabilize cardiac membranes. Insulin deficiency may lead to glycogenolysis and proteolysis, which may further worsen this gradient, along with acidosis to a degree.37
Potassium is lost from the body via three main routes: vomiting, urinary ketoanion excretion, and osmotic diuresis.37 Because of the massive volume depletion that occurs in DKA, there is a secondary hyperaldosteronism, with resultant increased excretion of potassium. This is the mechanism whereby total body potassium stores are decreased, although the initial potassium on presentation to the emergency department may be low, normal, or elevated.38 As insulin is administered and the acidosis is corrected, potassium is driven intracellularly, thereby decreasing potassium levels.39 Care must be taken not to decrease these potassium levels too fast, or there will be resultant cardiac dysrhythmias. Because of the decreased total body potassium stores, potassium replacement should begin to be replaced immediately and concomitantly with insulin infusions.
Phosphate. Hypophosphatemia has been demonstrated in the adult DKA population, but there are relatively sparse data in the pediatric population. During DKA therapy, there is renal excretion of phosphate as well as rapid entry of phosphate intracellularly.1 There is an increasing body of evidence that phosphorus does not need to be replaced.40 Still, severe loss of phosphate may cause phosphate depletion syndrome, and although this is a rare entity, the resulting depleted 2,3 diphosphoglycerate may result in decreased tissue oxygenation. This resulting hypophosphatemia may persist for several days after the clinical and biochemical resolution of DKA.22 Severe hypophosphatemia (less than 1 mg/dL) may manifest as muscle weakness and insult diaphragmatic tissues. Therefore, when phosphorus is less than 1 mg/dL, it should be replaced.41 Always keep in mind that phosphorus administration may cause hypocalcemia, and if this develops, the phosphate infusion should be terminated immediately.
Acidosis and Bicarbonate. As mentioned previously, the pathophysiology of DKA is such that there is a metabolic acidosis. In general, DKA should be treated with fluids and a continuous insulin infusion until this acidosis has resolved, regardless of blood glucose levels.
There is absolutely no role for bicarbonate administration in pediatric DKA patients who are not critical. Many controlled and well-designed trials have indicated this.42-45 In fact, a rapid correction of acidosis can even be deleterious to the pediatric patient, providing the impetus for a paradoxical CNS acidosis and increasing the risk of cerebral edema.46,47 Two compelling indications for bicarbonate administration in the pediatric diabetic ketoacidosis patient are severe acidemia (with an arterial pH less than 6.9), and in patients with severe, life-threatening hyperkalemia with ECG changes. With regard to resuscitation, bicarbonate is generally not necessary unless the degree of acidosis is thought to affect the efficacy of epinephrine. In the event that bicarbonate administration is deemed necessary, it should be replaced at 0.5 to 1 mEq/kg added to the intravenous fluids and given over one hour.
Monitoring
Specific guidelines for pediatric DKA monitoring are indicated quite concisely in the previously mentioned ESPE/LWPES guidelines. Almost all patients in DKA should be admitted to a pediatric intensive care unit with continuous monitoring, hourly blood glucose levels, serial chemistries, and venous pH checks to evaluate for a closing of the anion gap and acidosis. If acidosis does not improve, either there is an insulin treatment failure, the intravenous line was not primed with insulin, there is a severe acidosis requiring higher levels of insulin infusion, or there is sepsis, renal failure, or inadequate volume resuscitation. Likewise, volume status and mental status, along with GCS, should be noted on arrival as well as hourly. Ideally, there should be a seamless flow and charting of data between the ED and ICU.12
In recent years, studies have evaluated tracking the resolving acidosis with DKA therapy beside the traditional venous blood gases and chemistries. Several studies have validated the use of end tidal CO2 monitoring (EtCO2) for pediatric patients in DKA in the ED. In a 2006 study by Agus, the evaluation of EtCO2 was examined in an inpatient setting. Based on the results of that study, it can be inferred that EtCO2 may save time and money over invasive blood draws and may actually provide the same and often real-time data.48 The benefit of continuous EtCO2 monitoring in DKA patients in the ED is clearly recognizing real-time changes in the patient's acid-base status without awaiting the recommended hourly blood draws. This is more beneficial clinically to the practitioner, saves nursing and lab time, and avoids the frequent needle sticks that can be psychosomatically challenging for the pediatric population. Other emerging ways to track the treatment progression in DKA are commercially available bedside blood beta-hydroxybutyrate meters. Certainly more studies are needed, but these and other noninvasive means of tracking treatment progress in pediatric DKA may save time, nursing resources, and money.49
Complications
The two most common complications of DKA are hypoglycemia and hypokalemia, and their management is critical in the ED. Critical complications such as cerebral edema may confront the emergency physician, and early aggressive management may improve outcome. In addition, less common complications will be discussed to assure a comprehensive review of the issue.
Hypoglycemia. Insulin, despite being the main treatment for DKA, may lead to hypoglycemia, and this is one of the main reasons that serial, hourly blood glucose checks are recommended until the patient's acidosis resolves. The other reason for serial checks is to prevent or identify immediately a precipitous fall in the glucose level that could precipitate an osmotic shift or cerebral edema. Depending on the age and mental status of the patient, the hypoglycemic pediatric patient may be treated with varying types of intravenous dextrose.
Hypokalemia. Hypokalemia is inherent to DKA, as previously noted, and insulin therapy actually drives potassium intracellularly, potentially confounding this issue. U waves may or may not appear on the ECG. Often, it is prudent to add some potassium chloride to the intravenous fluids after insulin therapy is instituted. Very low potassium levels probably deserve careful intravenous replacement. Most hospitals have electrolyte protocols in place for this type of replacement, and the preferred solution is actually potassium acetate, since the potassium chloride can cause worsening acidosis.
Cerebral Edema. One of the most feared complications of pediatric DKA is cerebral edema, and according to the latest research, there is good evidence that the risk of this can be mitigated or reduced. Cerebral edema has been the most dangerous complication of severe DKA since it was first described by Fitzgerald et al in 1961.
Clinically, one must suspect cerebral edema in a pediatric DKA patient who develops altered mental status, headache, vomiting, inappropriate slowing of heart rate, and other signs of increased intracranial pressure.5-6 Ophthalmoplegia, anisocoria, posturing, and seizures may also be observed.51,52 The exact cause of cerebral edema is still the subject of much debate. A complex immunocytogenic and vasogenic cascade is likely at play.12 Epidemiologically, children who present with high blood urea nitrogen concentrations and those who present with more severe hypocapnia are at increased risk for cerebral edema.53
Although some of the latest research and data have gone to prevent cerebral edema, it is still quite possibly the most feared complication of pediatric DKA. Occurring in less than 1% of all presentations of DKA, children who present with cerebral edema secondary to DKA have very high morbidity and mortality. Often, the resulting neurologic impairment may be permanent. In fact, subclinical brain injury is often apparent on a neurochemical basis.50 According to Wooton-Gorges et al, brain ratios of N-acetylaspartate (NAA) to creatinine (Cr) will decrease with neuronal dysfunction. In their study, Wooton-Gorges et al used magnetic resonance spectroscopy to prove these data by noting that NAA/Cr ratios decrease in children with DKA and improve after recovery. By extrapolating these data, one may assume that neuronal function is compromised during DKA and improves as therapy with fluids and insulin resolves the acidosis and the resultant DKA.50 These changes in the brain were noted in three areas, namely the basal ganglia, periaqueductal gray matter, and the occipital gray matter. Because of this, poor glycemic control in patients with chronic type 1 diabetes leads to long-term cognitive impairment. The mechanism in this case appears to be hyperglycemic induced micro-ischemic events, which can facilitate cerebral edema. Although the exact pathophysiology of this process is currently unknown, accumulation of intracellular lactate and the resulting acidosis is a leading theory.
Further research has proven that there may be some alteration in the permeability of the blood-brain barrier during treatment for DKA.1 Although the exact pathophysiologic mechanism of cerebral edema in pediatric DKA is still being elaborated, some theories point to both a cytotoxic and vasogenic mechanism.54 It appears from the limited data that we have that the development of cerebral edema is likely a multifactorial process involving cerebral oligemia, cerebral hyperemia, and some elements of inflammation and cytotoxic insult. In a small prospective study, Vavilala et al determined that whole brain and regional blood-brain barrier permeability increased during diabetic ketoacidosis treatment.55 In this prospective study, children underwent two paired contrast-enhanced perfusion (gadolinium) and diffusion magnetic resonance imaging scans to compare permeability ratios before and after treatment. The results of the study were that whole-brain permeability increased 160%. The greatest regional increase was in the frontal cortex (148%), followed by the occipital cortex (128%), and basal ganglia (112%).55 Currently, the best evidence available points to a multifactorial mechanism. Before treatment begins, animal models have indicated in DKA that cerebral blood flow is decreased. At the same time, as previously noted, the latest MR studies done in children receiving IV rehydration have proven that there is an increased perfusion, while at the same time there is an elevation in apparent diffusion coefficients.55
In addition to the vasogenic mechanism, proponents of the cytotoxic mechanism of brain cerebral edema in pediatric DKA have recently uncovered specific inflammatory mediators involved in the fatal cascade that leads to death. Hoffman et al described this fatal cascade in two patients with the specific mediators involved.56 IL-1β was noted to have a strong presence in the choroid plexus epithelium, while TNF-alpha was expressed to a lesser extent. Also involved were C5b-9 iNOS and ICAM-1, and Hsp70 and IL-10, expressed in various degrees throughout parts of the brain, but all evident in the choroid plexus.56 It certainly will be interesting to see over the next few years how this research progresses, and perhaps a better, more exact scientific understanding of cerebral edema in pediatric DKA will help us to better prevent it, thus significantly reducing the morbidity and mortality associated with pediatric DKA.
To monitor cerebral edema, serum S-100 β-protein has been identified as a potential marker, with an increase over 0.12 mcg/L identified as a risk factor.57 Because this marker has shown promise but is not yet readily available at many institutions, clinical neurological evaluations are currently the standard of care. The Glasgow Coma Scale can be used, but there is good evidence that it is not sensitive enough in young children, the very ones who are at highest risk from death by cerebral edema. Some of the aforementioned clinical symptoms of cerebral edema, even if subtle, can be keys to the diagnosis. Worsening headache, age-inappropriate incontinence, lethargy, altered mental status, or increasing irritability or fussiness may be early indicators in this disease entity, which has its highest mortality in children younger than 5 years old. For these patients, treatment should begin immediately, as brain imaging like noncontrast CT will only delay diagnosis and may not show immediate diagnostic changes.58
If acute cerebral edema is suspected, the management is to elevate the head of the bed by 30 degrees and to administer 1 g/kg of IV mannitol, followed by a repeat dose in 15 minutes. There are a few case reports of hypertonic saline for cerebral edema, but this has yet to be validated.59 If a patient with cerebral edema requires intubation, rapid sequence intubation is recommended. A recommended regimen is lidocaine, midazolam, and rocuronium, followed by mechanical ventilation and brief hyperventilation to a PaCO2 of approximately 30. For a few minutes, symptomatic cerebral edema patients should be hyperventilated to a PaCO2 level present at the time of intubation. Of note, long-term hyperventilation can actually be quite dangerous and should generally be avoided in all patients.
Prolonged QT. One of the little known and often rarely mentioned effects of pediatric diabetic ketoacidosis is prolongation of the QTc. Some physicians may not routinely order an ECG on a child who presents to the ED with hyperglycemia in whom DKA is suspected. After understanding the evidence, hopefully this practice will change.
QTc is actually calculated as the QT interval divided by the square root of the R-R interval. The formula for QTc is actually known as Bazett's formula, and is said to be one of the only reliable values calculated by the computer interpreting device of most ECG models. Emergency physicians know the danger of a prolonged QTc, but pediatric DKA may not have been on the physician's list of conditions that may prolong it.
In an observational study from a pediatric intensive care unit by Kuppermann et al, 14 out of 30 children being treated for DKA had prolonged QTc. In this study, the mean QTc during DKA therapy was 450, but it decreased to 407 as DKA resolved.60 The anion gap was significantly associated with QTc prolongation, with a correlation coefficient of 0.49 (P = .006). In this study, most of the patients had no electrolyte abnormality to account for this QTc prolongation.60 Based on the limited data from this study, one could extrapolate that there is some correlation between severe DKA and QTc prolongation, and that treating ketosis resolves the QTc.
Since the publishing of this study, there has been some controversy over it. Some people have not bought the direct correlation with ketosis and DKA, but it is also hard to explain how 10 of the 14 children in the Kuppermann study did not have any potassium abnormality.
According to a consensus statement by the American Diabetes Association in 2006 prior to the publication of the Kuppermann study, there were not sufficient data to prove that the QTc is prolonged in DKA.37 According to this widely upheld consensus statement, the ADA stated that any changes in the QTc were likely attributed to hypokalemia (widening) and to hyperkalemia (shortening) in children. Likewise, a largely upheld observational study from 1978 by Harrower et al also found no benefit to ECG monitoring in DKA patients.61 In the Harrower evaluation, it was concluded after continuous 24-hour monitoring of adult DKA patients that it added little value to the clinical and biochemical management of the adult DKA patient.61
More recently, since the publication of the Kuppermann study, a rebuttal article by Szabo et al questioned the link between ketosis and prolonged QTc. Based upon rather weak data, Szabo et al attributed prolonged QTc in Kuppermann's study to "psychological stress" altering cardiac biochemical pathways.62 Suffice it to say, there is limited evidence for this and, certainly, a better designed, more well-powered study is needed to test the Kuppermann results. That said, the data from the Harrower study in 1978 appear to be a bit antiquated at present and, based upon the best available evidence, it is this author's recommendation to obtain a routine ECG in all children presenting to the emergency department in DKA. Granted, the impetus for this recommendation is based largely on the poorly powered Kupperman study. The reasons for this recommendation are threefold and have some credence. First of all, the ECG is a cheap, easy, reliable test available in all EDs. Second, while interpretation of the pediatric ECG can be cumbersome for the adult-trained emergency physician, calculation of the QTc is easy, reliable, and can be cross-checked by the machine. Third, obtaining an ECG could potentially allow one to diagnose life-threatening electrolyte abnormalities and treat them before laboratory results are back. This may be especially true in the few rural or community EDs that currently lack point-of-care electrolyte testing. Peaked T waves on an ECG would allow a physician to treat potentially life-threatening hyperkalemia before laboratory results are in hand, thus preventing a potentially fatal arrhythmia. Only further, better designed studies will be able to ascertain whether or not prolonged QTc is a cause of mortality in pediatric DKA patients.
Prothrombotic Tendency and CNS Thrombosis/Hemorrhage. Among the myriad of complications of pediatric DKA that still need further elucidation and research is the prothrombotic tendency of this state. Basic pathology and physiology tell us that the incidence of thrombosis increases in acutely ill patients because of a complex interplay of clotting cascades. In a well-designed study from Turkey, Bicili et al determined that "after hematological parameters at 0th hour were evaluated, increased platelet count, decreased PTT, low protein C, and high factor VIII levels were determined at diagnosis, indicating prothrombotic tendency."63 The study followed up on patients in the 96th hour after therapy was instituted and noted that platelet levels decreased, PTT increased, and protein C and factor VIII levels returned to normal when compared to the initial values.63
It has been noted that this prothrombotic state may predispose children to CNS thrombosis and hemorrhage as well. There are recent data in rat studies demonstrating beta-OHB or AcAc results in edema and hemorrhage.64 Other recent data have shown that in DKA there are increased levels of von Willebrand factor and decreased free, unbound protein S and protein C activity.65-67 In addition, there is associated increased platelet aggregation. There are case series reporting the incidence of DVT in patients with DKA and central venous catheters (especially femoral) to be as high as 50%.68,69 It goes without saying that there can be other large vessel thrombosis or strokes, even in the pediatric population, and there are well-documented case reports of both stroke and myocardial infarction in pediatric DKA patients.
Other Complications
Other potentially life-threatening complications of DKA have been reported in the literature and should be considered in the child with DKA. Among these rare conditions not previously mentioned are pulmonary edema,70-72 pancreatitis,73 renal failure,74 and intestinal necrosis. Sometimes, the therapy itself can lead to life-threatening consequences. Rarely, the metabolic derangements can lead a patient to susceptible infections such as mucormycosis, a rapidly progressive and potentially fatal fungal infection. If this infection is diagnosed, antifungals must be rapidly instituted and surgery is often required in consultation with a pediatric otolaryngologist and an infectious disease specialist.75
Hyperosmolar Hyperglycemia. Hyperosmolar hyperglycemic state (HHS), previously known as hyperosmolar hyperglycemic nonketotic coma (HHNC), is a distinct entity that should be distinguished from DKA. The name was changed because only a minority of patients present in coma. To make a diagnosis of HHS, the ADA agreed on diagnostic criteria in their 2006 consensus statement.37 Among the agreed upon diagnostic criteria are: plasma glucose level of 600 mg/dL or greater, effective serum osmolality of 320 mOsm/kg or greater, profound dehydration up to an average of 9 L, serum pH greater than 7.30, bicarbonate concentration greater than 15 mEq/L, small ketonuria and absent-to-low ketonemia, and some alteration in consciousness.37 While the diagnostic and therapeutic work-up for HHS is beyond the scope of this paper, it is important to note the key distinguishing features of these two clinical entities, which have overlapping features. Namely, in HHS, one will find bicarbonate levels greater than 15 mEq/L, while in DKA, the levels will be lower. Additionally, a patient in HHS will have higher levels of serum osmoles, and, in general, absent to low ketonemia. On the contrary, ketonemia in DKA is often marked.
Limitations
When perusing the pediatric DKA literature, one of the inherent limitations in comparing data is that the definition of DKA used in different studies often varies. For example, Ellis et al76 define DKA using a higher limit of sugar with a blood glucose greater than 16.65 mmol/L. This level of hyperglycemia is different from consensus statements released by ESPE/LWPES in 2004, the ADA in 2006, and the ISPAD in 2007, as noted in the introduction of this paper. According to these consensus guidelines, hyperglycemia is defined as a blood glucose greater than 200 mg/dL (11 mmol/L).22,77 One factor that may improve future studies is to develop a universal consensus on the definition of DKA, which was previously attempted, as noted, but not always followed clinically.
Prevention
It is common knowledge that one of the most frequent presentations of new-onset type 1 diabetes is DKA. Most North American studies appear to reveal that about 40% of type 1 diabetics make their initial presentation to a medical professional in DKA.78 Young children are more likely to present as newly diagnosed type 1 diabetics in DKA, along with children who live in countries with a low prevalence of type 1 diabetes.78 It has been hypothesized that public education about diabetes can decrease the number of children who present as new-onset diabetics in DKA. In a well-designed study from Europe, educating parents and pediatricians improved the rate of new-onset type 1 diabetics who presented in DKA from 80% to 12.5%.79
There have been many attempts and ideas to help especially noncompliant young adolescents comply with their insulin therapy. Many novel ideas have included embracing more modern technology. One such idea has been studied using smart-phone applications for diabetic management. Because a large percentage of the population has access to smart phones, it seems reasonable to surmise that a smart-phone application may reduce the incidence of admissions and, thus, reduce the morbidity and mortality associated with ketosis and acidosis. In one such observational study from England, Farrel et al determined that mobile phone use in young people 15-25 years old is associated with reduced ketoacidosis.80 The future of mobile phones to help people manage their health, especially in the younger pediatric population, is yet to be determined. This seems to be an area where more research would prove rather intriguing.
Discharge and Follow-Up
All patients who present in DKA should be fully resuscitated according to the guidelines outlined in this paper prior to hospital discharge. In many hospitals, patients are downgraded to a pediatric floor once their acidosis has resolved and they are tolerating oral fluids. Patients should be educated about diabetes care whether they are new-onset diabetics or not, and the parents or caregivers must be given appropriate education and motivation as well, as this has been shown to be critical to whether or not the patient may require readmittance.81
Summary
As in the adult population, pediatric DKA has significant risks, morbidity, and mortality. Emergency physicians and general practitioners are typically the first clinicians to encounter patients with DKA and to make the subtle, challenging diagnosis of new-onset type 1 diabetes. DKA may be an elusive diagnosis in pediatrics, especially in children without a history of DKA, and a high degree of suspicion is necessary. The goals in the treatment of pediatric DKA are to reinstitute the volume loss, correct the acidosis, reverse hyperglycemia, and to eliminate the ketosis. At the same time, the provider must avoid the myriad complications of DKA, the most feared of which is cerebral edema. As the literature concludes, the best way to decrease the percentage of cases that present initially as DKA is by educating the general population to recognize the signs and symptoms of diabetes.
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Children with diabetes, especially type 1, remain at risk for developing diabetic ketoacidosis (DKA). This may seem confounding in a modern society with such advanced medical care, but the fact remains that children who are type 1 diabetics have an incidence of DKA of 8 per 100 patient years.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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