In the SEARCH study increased prevalence of DKA at presentation was detected in children less than 4 years of age, particularly when compared to youth 15—19 years of age [ 7 ].
The causes for this increased prevalence in younger children are likely multiple. Younger children are more prone to misdiagnosis when initially presenting with T1DM [ 21 ]. However, toddlers may actually suffer a more aggressive progression of metabolic decompensation. There is evidence that younger children have a shorter prodromal period [ 22 ] as well as a more rapid decline in beta cell reserve after diabetes diagnosis [ 19 , 23 ].
A lower BMI or weight loss have also been associated with increased risk for DKA at diagnosis in a number of small studies [ 15 , 24 ]. In the UK, children from an Asian background were at increased risk of presenting with DKA, particularly if under 5 years of age[ 11 ]. Another study from the UK demonstrated that children from non-white ethnicity were at higher risk of a delayed T1DM diagnosis and that a delayed diagnosis was associated with increased risk of DKA at presentation [ 25 ].
In the Israeli Negev, the prevalence of DKA at diabetes diagnosis was significantly higher in the Bedouin minority when compared to either the general population or the Jewish population [ 26 ].
In another study from Israel, children from an Ethiopian origin had an increased prevalence of DKA at presentation [ 15 ]. However, this is not supported by all studies, and others did not find a predilection to minority groups [ 7 , 27 ]. Another predictor of DKA is a lower socioeconomic status [ 28 ]. Several components of the socioeconomic status have been identified as significant.
Lower household income was found in US and Canadian studies to be a risk factor [ 2 , 7 , 9 ]; however, European studies did not necessarily support this [ 29 ]. In the United States, lack of private health insurance was also identified [ 7 , 9 , 30 ].
More years of parental education as well as academic education of the parents were found protective [ 7 , 31 , 32 ]. Such factors include delayed diagnosis of diabetes or a missed diagnosis [ 25 , 21 ], delayed presentation to secondary care, or delayed treatment after T1DM diagnosis [ 10 , 17 ]. Another study assessing a large database of children with established T1DM from Germany and Austria evaluated the incidence of DKA in the most recent year of follow-up [ 34 ].
Insulin omission and poor adherence to treatment are major risk factors [ 37 ] Table 1. Poorer diabetes control, higher hemoglobin A1c, higher insulin doses, and previous episodes of DKA are also important risk factors [ 33 , 34 , 38 ]. Recurrent DKA episodes peak in teenage years, particularly in females [ 33 , 34 ]. Moreover, the incidence of DKA was found to increase with age in females, yet remained stable in males. A study evaluating the role of patient and family psychosocial functioning as predictors of recurrent acute diabetic complications [ 35 ] found girls with recurrent DKA to demonstrate lower social competence and higher rates of behavioral problems.
The families exhibited higher levels of family conflict and decreased family cohesion and organization. Major psychiatric disorders have also been implicated in recurrent DKA [ 39 ]. By definition, hyperglycemia and ketoacidosis are the major components of DKA [ 40 ]. The initial impairment leading to DKA is an absolute or relative insulin deficiency. The sequence of events that follows leads to a patient that suffers hyperglycemia, dehydration, acidosis, electrolyte deficiencies, and variable degrees of cerebral dysfunction [ 41 ] Figure 1.
In a patient with new-onset diabetes, the cause for the insulin deficiency is the progressive deterioration in beta cell reserve and function [ 42 ]. In patients with established diabetes, insulin omission intentional, as a result of insulin pump failure or other technical problems, or related to lack of access to medical care is a major cause. Acute stress, commonly induced by an intercurrent illness, might precipitate DKA.
During stress, counterregulatory hormone glucagon, cortisol, growth hormone, and epinephrine levels increase, causing hyperglycemia and an increased requirement for insulin.
If this increased need for insulin is not met, DKA may ensue. Pathophysiology of diabetic ketoacidosis. Insulin deficiency leads to hyperglycemia as a result of decreased utilization of glucose at the same time of increased hepatic and renal glucose production. Hyperglycemia increases serum osmolality, and in response, thirst is induced and osmotic diuresis occurs. The increased fluid loss further promotes polydipsia. Because of the unavailability of glucose to tissues, compensatory mechanisms are activated.
Counterregulatory hormones are secreted, leading to increased glucose production by gluconeogenesis and glycogenolysis [ 43 ]. Insulin resistance increases and lipolysis is promoted, resulting in production of free fatty acids FFAs. The accumulation of ketones leads to metabolic acidosis. Another result of the decreased insulin and elevated counterregulatory hormone levels is proteolysis and reduced production of proteins.
By this mechanism, substrates for gluconeogenesis are added, further contributing to the hyperglycemia. Initially, plasma ketone body levels rise, causing ketonemia and a base deficit; compensating mechanisms are activated and might lead to measurement of a normal pH. As the condition progresses, ketones further accumulate, ketonuria occurs, and eventually the metabolic acidosis becomes evident.
The ketoacidosis causes decreased bowel motility, particularly of the small bowl, accompanied by nausea and vomiting. At this stage, the patient may be unable to compensate for the urinary fluid losses. In a vicious cycle, dehydration impairs the renal ability to clear glucose and ketoacids, thus further worsening the hyperglycemia and acidosis.
The increasing osmolality, dehydration, and acidosis decrease cerebral function. At presentation, the degree of dehydration ranges from mild to severe, with the majority of children presenting with moderate degrees of dehydration [ 44 ].
To compensate for the acidosis, respiratory mechanisms are activated, causing the labored, rapid, deep breathing typically described in patients with DKA i. The acetone released in the breath results in a characteristic fruity odor. Serum hyperglycemia and hyperosmolarity together with the acidosis and osmotic diuresis lead to significant electrolyte deficiencies and imbalances [ 40 , 45 , 46 ].
However, the serum potassium levels may not reflect these losses, and the actual level may be low, normal, or even elevated, particularly if renal function is impaired.
The entry of hydrogen ions, accumulated extracellularly due to the acidosis, into cells drives out the intracellular potassium. The osmotic diuresis together with the high levels of aldosterone secreted as a result of the dehydration cause significant urinary loss of potassium. Emesis might cause further loss of potassium through the gastrointestinal tract. However, an exception is patients with severe volume depletion, in whom renal insufficiency may lead to hyperkalemia.
During treatment of DKA, both the insulin itself and the reversal of acidosis generate a net shift of potassium back into cells. Moreover, there is some evidence suggesting a kaliuretic effect of insulin [ 47 ]. Altogether, these may result in severe hypokalemia. Patients with hypokalemia at presentation likely suffer more severe total body potassium depletion and are at particular risk of severe hypokalemia and cardiac instability as treatment is provided.
The osmotic diuresis in DKA results in urinary loss of sodium, and the hyperosmolar state drives water out of cells into the extracellular space, leading to dilutional hyponatremia. It should be kept in mind that the administration of chloride during the treatment of DKA may lead to hyperchloremic metabolic acidosis, thus interfering with the correction of acidosis.
Phosphate shifted extracellularly by the acidosis is then lost in the urine. Phosphate losses can be substantial and are estimated to be about 0. Significant hypophosphatemia has the potential to impair oxygen delivery to tissues and cause muscle weakness. However, despite very low serum levels of phosphate in some patients, such complications are rare, and studies did not demonstrate a benefit for phosphorous replacement [ 48 , 49 ]. Beyond the electrolyte deficiencies described, in recent years, several studies have pointed out that a deficiency of thiamine vitamin B1 , a water-soluble vitamin of the B complex, may be clinically significant in patients with DKA.
Thiamine deficiency was found to be common in children with DKA and may worsen with treatment [ 50 ]. The role of this deficiency in the clinical presentation of DKA is yet to be revealed. Metabolic decompensation in DKA usually develops over a period of hours to a few days. Progression can be particularly rapid in patients with established diabetes. Misdiagnosis of a patient with new-onset diabetes may lead to deterioration of the metabolic status. Particularly in young children, misdiagnosis may be a result of the nonspecific symptoms and signs often described in DKA.
The earliest clinical manifestations of DKA are related to hyperglycemia and may differ according to age, length of prodromal period, degree of acidosis, and volume depletion [ 51 , 52 ]. Symptoms and signs in DKA are most often related to the hyperglycemia, dehydration, and acidosis [ 4 , 53 - 55 ]. Sign in via OpenAthens. Pay-Per-View Access. Buy This Article. View Your Tokens. View Metrics. Citing articles via Web Of Science 7. Email alerts Article Activity Alert. Newest Articles Alert.
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Federal Government. Read our disclaimer for details. Recruitment status was: Not yet recruiting First Posted : March 5, Last Update Posted : March 5, Study Description. Detailed Description:. Electrocardiogram and echocardiography will be done to all patient with diabetic ketoacidosis. Outcome Measures. Primary Outcome Measures : Echocardiography parameters [ Time Frame: baseline ] Right and left ventricular dimension during diabetic ketoacidosis and after correction.
Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision. Respiratory failure in diabetic ketoacidosis. World J Diabetes. Alcoholic ketoacidosis. Yip L. Powers AC. Diabetes mellitus: management and therapies. Jacoby R, Nesto R. Acute myocardial infarction in the diabetic patient: pathophysiology, clinical course and prognosis.
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Am J Med Sci. Severe hypophosphatemia in a patient with diabetic ketoacidosis and acute respiratory failure. J Chin Med Assoc. Management of adult diabetic ketoacidosis. Diabetes Metab Syndr Obes. Poole-Wilson PA. Acidosis and contractility of heart muscle. Ciba Found Symp. ISMP list of high-alert medications in acute care settings. Institute for Safe Medication Practices. Accessed January 21, Featured Issue Featured Supplements.
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