European Society for Paediatric Endocrinology/Lawson Wilkins Pediatric Endocrine Society Consensus Statement on Diabetic Ketoacidosis in Children and Adolescents

Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with type 1 diabetes mellitus (TIDM). Mortality is predominantly related to the occurrence of cerebral edema; only a minority of deaths in DKA are attributed to other causes. Cerebral edema occurs in ∼0. 3% to 1% of all episodes of DKA, and its etiology, pathophysiology, and ideal method of treatment are poorly understood. There is debate as to whether physicians treating DKA can prevent or predict the occurrence of cerebral edema and the appropriate site (s) for children with DKA to be managed. There is agreement that prevention of DKA and reduction of its incidence should be a goal in managing children with diabetes. To explore these issues, the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society for Pediatric Endocrinology (ESPE) convened a panel‖ of expert physicians for a consensus conference. The meeting was chaired by Mark A. Sperling, MD, representing LWPES, and David B. Dunger, MD, representing ESPE. The Consensus statement was developed with close partnership between the ESPE and LWPES and the International Society for Pediatric and Adolescent Diabetes, all 3 organizations being represented by members who participated in the writing process. The statement also was endorsed by related organizations; the Juvenile Diabetes Research Foundation International, the World Federation of Pediatric Intensive and Critical Care Societies, the European Society for Pediatric Critical Care, the European Society of Pediatric and Neonatal Intensive Care, and the Australian Pediatric Endocrine Group were represented by invited participants. Each of the major topics had a presenter and recorder, responsible for review of the literature and providing evidence-based recommendations according to criteria used by the American Diabetes Association (see Appendix; levels of evidence are indicated in capital letters, in parentheses). 1 Type 2 diabetes was not considered. All participants contributed significantly to the development of consensus. This document summarizes the final consensus reached and represents the current “state of the art. ”DKA is caused by a decrease in effective circulating insulin associated with elevations in counterregulatory hormones including glucagon, catecholamines, cortisol, and growth hormone. This leads to increased glucose production by the liver and kidney and impaired peripheral glucose utilization, with resultant hyperglycemia and hyperosmolality. Increased lipolysis, with ketone body (β-hydroxybutyrate β-OHB and acetoacetate) production causes ketonemia and metabolic acidosis. Hyperglycemia and acidosis result in osmotic diuresis, dehydration, and obligate loss of electrolytes. The biochemical criteria for the diagnosis of DKA include hyperglycemia (blood glucose: >11 mmol/L ∼200 mg/dL) with a venous pH <7. 3 and/or bicarbonate <15 mmol/L. There is associated glycosuria, ketonuria, and ketonemia. Rarely, young or partially treated children as well as pregnant adolescents may present with near-normal glucose values (“euglycemic ketoacidosis”). 2DKA is generally categorized by the severity of the acidosis, varying from mild (venous pH: <7. 30; bicarbonate concentration: <15 mmol/L) to moderate (pH: <7. 2; bicarbonate: <10) to severe (pH: <7. 1; bicarbonate: <5). 3, 4There is wide geographic variation in the frequency of DKA at diabetes onset, and rates correlate inversely with regional incidence of TIDM. Reported frequencies range between 15% and 67% in Europe and North America and may be more common in developing countries (A). 5, 6 In Canada and Europe, hospitalization rates for DKA in established and new patients with TIDM have remained stable at ∼10 per 100 000 children over the past 20 years, but severity may be decreasing (B). 7, 8DKA at onset of TIDM is more common in younger children (<4 years of age), children without a first-degree relative with TIDM, and those from families of lower socioeconomic status (A). 4, 9 High-dose glucocorticoids, atypical antipsychotics, diazoxide, and some immunosuppressive drugs have been reported to precipitate DKA in individuals not diagnosed previously with TIDM (B). 10, 11The risk of DKA in established TIDM is 1% to 10% per patient per year (A). 12–15 Risk is increased in children with poor metabolic control or previous episodes of DKA, peripubertal and adolescent girls, children with psychiatric disorders (including those with eating disorders), and those with difficult family circumstances (including lower socioeconomic status and lack of appropriate health insurance). 16 Inappropriate interruption of insulin-pump therapy also leads to DKA. 12, 14Children whose insulin is administered by a responsible adult rarely have episodes of DKA (C), 17 and 75% of episodes of DKA beyond diagnosis probably are associated with insulin omission or treatment error. 17, 18 The remainder are due to inadequate insulin therapy during intercurrent illness (B). 18–20Reported mortality rates from DKA in national population-based studies are reasonably constant: 0. 15% (C) (United States), 21 0. 18% (C) (Canada), 7 0. 25% (C) (Canada), 22 to 0. 31% (B) (United Kingdom). 23 In places with less developed medical facilities, the risk of dying from DKA is greater, and children may die before receiving treatment. 23Cerebral edema accounts for between 57% and 87% of all DKA deaths. 24, 25 The incidence of cerebral edema has been fairly consistent between national population-based studies: 0. 46% (C) (Canada), 22 0. 68% (B) (United Kingdom), 24 and 0. 87% (B) (United States). 25 Single-center studies often report higher frequencies because of ascertainment bias arising from secondary referral patterns: 1. 1% (C) (United States) 26 to 4. 6% (United States). 27Reported mortality rates from cerebral edema in population-based studies are 21% (C), 25 25% (C), 22 and 24% (B). 24 Significant morbidity is evident in 10% (C), 22 21% (B), 25 and 26% (B) 24 of survivors. However, some individual centers have reported markedly lower mortality and serious morbidity after DKA and cerebral edema (B United States28, C United States29). Other possible causes of mortality and morbidity include hypokalemia, hyperkalemia, hypoglycemia, other central nervous system (CNS) complications, hematoma (C), 30 thrombosis (C), 31 sepsis, infections (including rhinocerebral mucormycosis) (C), 32 aspiration pneumonia, pulmonary edema (C), 33 adult respiratory distress syndrome (C), 34 pneumomediastinum and subcutaneous emphysema (C), 35 and rhabdomyolysis (C). 36 Late sequelae relate to cerebral edema and other CNS complications including hypothalamopituitary insufficiency, 37, 38 isolated growth hormone deficiency, 39 and combined growth hormone and thyroid-stimulating hormone deficiency. 40Cerebral edema typically occurs 4 to 12 hours after treatment is activated25, 41 but can be present before treatment has begun (B, 23 C, 42, 43, B25) or may develop any time during treatment for DKA. Symptoms and signs of cerebral edema are variable and include onset of headache, gradual decrease or deterioration in level of consciousness, inappropriate slowing of the pulse rate, and an increase in blood pressure (C). 44, 45In vitro experiments and studies in animals and humans presenting with cerebral edema due to other causes (eg, trauma or stroke) suggest that the etiopathological mechanisms may be complex. A number of mechanisms have been proposed, including the role of cerebral ischemia/hypoxia and the generation of various inflammatory mediators, 46, 47 increased cerebral blood flow, 48 and disruption of cell membrane ion transport49, 50 and aquaporin channels. 51 The generation of intracellular organic osmolytes (myoinositol and taurine) and subsequent cellular osmotic imbalance has also been implicated. 52 Preliminary imaging studies in children with DKA using ultrasound, computed tomography, or magnetic resonance imaging indicate that some degree of cerebral edema may be present even in patients without clinical evidence of raised intracranial pressure (ICP). 53–56Various demographic factors have been associated with an increased risk of cerebral edema including: presentation with new-onset TIDM (B, C) 23, 44 younger age (C), 44 and longer duration of symptoms (C). 26 These associations may be a consequence of the greater likelihood of presenting with severe DKA (C). 25Several potential risk factors, at diagnosis or during treatment, have been identified through epidemiologic studies. Most studies show no association between the degree of hyperglycemia at presentation of DKA with risk of cerebral edema after correcting for other covariates (C). 25, 27Children with ketosis and hyperglycemia without vomiting or severe dehydration can be managed at home or in an outpatient health care setting (eg, emergency ward or units with similar facilities), but the level of care needs to be reevaluated frequently and supervised by an experienced diabetes team (C, 3, 63, 64 E). A specialist/consultant pediatrician with training and expertise in the management of DKA should direct inpatient management. The child also should be cared for in a unit that has experienced nursing staff trained in monitoring and management, clear written guidelines, and access to laboratories for frequent evaluation of biochemical variables. Children with signs of severe DKA (long duration of symptoms, compromised circulation, or depressed level of consciousness) or those who are at increased risk for cerebral edema (including <5 years of age and new onset) should be considered immediately for treatment in an intensive care unit (pediatric, if available) or a children’s ward specializing in diabetes care with equivalent resources and supervision (C, 65 E). If transfer by ambulance to another unit is required, caution should be exercised in the use of sedatives and antiemetics. There should be documentation of hour-by-hour clinical observations, IV and oral medication, fluids, and laboratory results during the entire treatment period (E). Monitoring should include: Those monitoring should be instructed to alert the physician of any of these manifestations, because it may be difficult to clinically discriminate cerebral edema from other causes of altered mental status. The high effective osmolality of the extracellular fluid (ECF) compartment results in a shift of water from the intracellular fluid (ICF) compartment to the ECF. Studies performed in adults with TIDM in whom insulin therapy was withheld have shown fluid deficits of ∼5 L66 together with ∼20% loss of total body sodium and potassium. 67 At the time of presentation, patients are ECF contracted, and clinical estimates of the deficit are usually in the range of 7% to 10%, although these estimates can be subjective and may overestimate the problem. 68 Shock with hemodynamic compromise is a rare event in DKA. The serum sodium measurement is an unreliable measure of the degree of ECF contraction due to the dilutional effect of fluid shift. The effective osmolality (2 Na + K + glucose) at the time of presentation is frequently in the range of 300 to 350 mOsm/L. Elevated serum urea nitrogen and hematocrit may be useful markers of severe ECF contraction. 28, 64The onset of dehydration is associated with a reduction in glomerular filtration rate (GFR), which results in decreased glucose and ketone clearance from the blood. Studies in humans have shown that IV fluid administration alone results in substantial falls in blood glucose levels because of an increase in GFR. 69, 70 The objectives of fluid and sodium replacement therapy in DKA are 1) restoration of circulating volume, 2) replacement of sodium and the ECF and ICF deficit of water, 3) restoration of GFR with enhanced clearance of glucose and ketones from the blood, and 4) avoidance of cerebral edema. Both animal and human studies have shown that ICP rises as IV fluids are administered. 71, 72 There are also animal models of DKA that show that the use of hypotonic fluids, compared with isotonic, is associated with greater rises in ICP. 71 Although there are no category A studies that demonstrate superiority of any fluid regimen over another, there are category C data that suggest that rapid fluid replacement with hypotonic fluid is associated with an increased risk of cerebral edema (see “Risk Factors” above). There are both adult (category A) and pediatric (level B) studies that show that a less-rapid fluid-deficit correction with isotonic or near-isotonic solutions results in earlier reversal of acidosis. 29, 73 However, the use of large amounts of 0. 9% saline has also been associated with the development of hyperchloremic metabolic acidosis. 74, 75There are no data to support the use of colloids in preference to crystalloids in the treatment of DKA. There also are no data to support the use of solutions more dilute than 0. 45% NaCl; the use of these solutions, which contain a large amount of electrolyte-free water, is likely to lead to a rapid osmolar change and movement of fluid into the ICF compartment. Although rehydration alone causes some decrease in blood glucose concentration, insulin therapy is essential to normalize the blood glucose concentration and suppress lipolysis and ketogenesis. Although different routes (subcutaneous, intramuscular, and IV) and doses have been used, extensive evidence indicates that “low-dose” IV insulin administration should be the standard of care. 76Physiologic studies indicate that IV insulin at a dose of 0. 1 unit/kg per hour, which achieves steady-state plasma insulin levels of ∼100 to 200 μU/mL within 60 minutes, is effective. 77 Such plasma insulin levels are able to offset insulin resistance and, in most circumstances, inhibit lipolysis and ketogenesis, exerting maximal or near-maximal effects on suppression of glucose production and stimulated peripheral glucose uptake. 78 The resolution of acidemia invariably takes longer than normalization of blood glucose concentrations. 79Adults with DKA have total body potassium deficits on the order of 3 to 6 mmol/kg; data in children are sparse. 66, 67, 82–85 The major loss of potassium is from the intracellular pool as a result of hypertonicity, insulin deficiency, and buffering of hydrogen ions within the cell. Serum potassium levels at the time of presentation may be normal, increased or decreased: Hypokalemia at presentation may be related to prolonged duration of disease, whereas hyperkalemia primarily results from reduced renal function. 86 Administration of insulin and the correction of acidosis will drive potassium back into the cells, decreasing serum levels. Depletion of intracellular phosphate occurs and phosphate is lost as a result of osmotic diuresis. In adults, deficits are in the range of 0. 5 to 2. 5 mmol/kg, 66, 67, 84 but comparable data in children are unavailable. The fall in plasma phosphate levels after starting treatment is exacerbated by insulin administration as phosphate reenters cells. 87 Low plasma phosphate levels, when indicative of total body depletion in other conditions, have been associated with a wide array of metabolic disturbances; however, particular interest has focused on erythrocyte 2, 3-diphosphoglycerate concentrations and effects on tissue oxygenation. 88 Phosphate depletion persists for several days after resolution of DKA. 66, 82, 84 However, prospective studies have failed to show significant clinical benefit from phosphate replacement. 89–94 Nevertheless, provided that careful monitoring is performed to avoid hypocalcemia, 95, 96 potassium phosphate may be used safely in combination with potassium chloride or acetate to avoid hyperchloremia. Even severe acidosis is reversible by fluid and insulin replacement. Administration of insulin stops further ketoacid synthesis and allows excess ketoacids to be metabolized. The metabolism of keto-anion results in the regeneration of bicarbonate (HCO3−) and spontaneous correction of acidemia. Also, treatment of hypovolemia will improve decreased tissue perfusion and renal function, thus increasing the excretion of organic acids (see “Fluids and Salt”) and reversing any lactic acidosis, which may account for 25% of the acidemia. In DKA, there is an increased anion gap. The major retained anions are β-OHB and acetoacetate. , 10pt, legalpaperarticle amssymb amsfonts amsmath empty document \ gap=[Na^{+}- (Cl^{-}+HCO₃^{-}): \ normally\ 12\ \ 2\ mmol/L\] documentThe indications for bicarbonate therapy in DKA are unclear. Several controlled trials of sodium bicarbonate in small numbers of children and adults (B, C) have been unable to demonstrate clinical benefit or any important difference in the rate of rise in the plasma bicarbonate concentration (C). 25, 97–100There are potential arguments against the use of bicarbonate. 25, 97, 101, 102 Of concern is that bicarbonate therapy may cause paradoxical CNS acidosis and that rapid correction of acidosis caused by bicarbonate will result in hypokalemia and may accentuate sodium load and contribute to serum hypertonicity. In addition, alkali therapy may increase hepatic ketone production, thus slowing the rate of recovery from the ketosis. These findings, however, do not address the issue that there may be select patients who may benefit from cautious alkali therapy, including those with severe acidemia (arterial pH: <6. 9) in whom decreased cardiac contractility and peripheral vasodilatation can further impair tissue perfusion and patients with potentially life-threatening hyperkalemia. Treatment should be initiated as soon as the condition is suspected. The rate of fluid administration should be reduced. Although mannitol has been shown to have possible beneficial effects in case reports, 103–105 there has been no definite beneficial or detrimental effect in retrospective epidemiologic studies. 106 The response may be altered by timing of administration, delayed administration being less effective. IV mannitol should be given (0. 25–1. 0 g/kg over 20 minutes) in patients with signs of cerebral edema before impending respiratory failure (C, E). Repeat in 2 hours if there is no saline to over minutes, may be an to mannitol and may be However, has been associated with poor in retrospective of cerebral detrimental effects have been reported in other as trauma and There are no data use in cerebral diagnosis through and of children as in the decrease DKA incidence at diabetes onset levels of related to the of other members of families with TIDM also the risk of DKA. A and physician at to reduced rates of DKA from to over a period Increased of signs and symptoms of diabetes should lead to earlier in children <5 or blood for glucose may prevent Although are to decrease DKA at onset to be and in and age of the effects of diabetes and report a reduction in the rates of DKA from to In patients on subcutaneous insulin episodes of DKA can be reduced with the of it is likely that episodes of DKA after diagnosis be reduced if all children with diabetes diabetes health care and and have access to a diabetes The of home measurement of β-OHB as a for earlier diagnosis and thus prevention of hospitalization needs to be episodes of DKA are more In a of patients for of all episodes over a omission has been identified as the major in most of these and may be by levels on There is no evidence that mental health alone can on the frequency of DKA in these children but insulin omission can be by providing and treatment combined with adult supervision of insulin administration responsible adults a reduction in episodes of DKA has been reported LWPES and ESPE and the Society for Endocrinology for support of the consensus of for the and and for with the consensus