Practice EssentialsDiabetic ketoacidosis (DKA) is an acute, major, life-threatening complication of diabetes characterized by hyperglycemia, ketoacidosis, and ketonuria. It occurs when absolute or relative insulin deficiency inhibits the ability of glucose to enter cells for utilization as metabolic fuel, the result being that the liver rapidly breaks down fat into ketones to employ as a fuel source. The overproduction of ketones ensues, causing them to accumulate in the blood and urine and turn the blood acidic. DKA occurs mainly in patients with type 1 diabetes, but it is not uncommon in some patients with type 2 diabetes. Laboratory studies for DKA include glucose blood tests, serum electrolyte determinations, blood urea nitrogen (BUN) evaluation, and arterial blood gas (ABG) measurements. Treatment includes correction of fluid loss with intravenous fluids; correction of hyperglycemia with insulin; correction of electrolyte disturbances, particularly potassium loss; correction of acid-base balance; and management of concurrent infection (if present). Show
Signs and symptoms of diabetic ketoacidosisThe most common early symptoms of DKA are the insidious increase in polydipsia and polyuria. The following are other signs and symptoms of DKA:
Signs and symptoms of DKA associated with possible intercurrent infection are as follows:
See Clinical Presentation for more detail. General findings in diabetic ketoacidosisOn examination, general findings of DKA may include the following:
In addition, evaluate patients for signs of possible intercurrent illnesses such as MI, UTI, pneumonia, and perinephric abscess. Search for signs of infection is mandatory in all cases. Laboratory studiesInitial and repeat laboratory studies for patients with DKA include the following:
Note that high serum glucose levels may lead to dilutional hyponatremia; high triglyceride levels may lead to factitious low glucose levels; and high levels of ketone bodies may lead to factitious elevation of creatinine levels. Imaging studiesRadiologic studies that may be helpful in patients with DKA include the following:
Do not delay administration of hypertonic saline or mannitol in those pediatric cases where cerebral edema is suspected, as many changes may be seen late on head imaging. See Workup for more detail. Management goalsTreatment of ketoacidosis should aim for the following:
PharmacotherapyRegular and analog human insulins [2] are used for correction of hyperglycemia, unless bovine or pork insulin is the only available insulin. Medications used in the management of DKA include the following:
See Treatment and Medication for more detail.  BackgroundDiabetic ketoacidosis (DKA) is an acute, major, life-threatening complication of diabetes. DKA mainly occurs in patients with type 1 diabetes, but it is not uncommon in some patients with type 2 diabetes (most likely latent autoimmune diabetes of adults [LADA] or Flatbush diabetes). DKA is a state of absolute or relative insulin deficiency aggravated by ensuing hyperglycemia, dehydration, and acidosis-producing derangements in intermediary metabolism. The most common causes are underlying infection, disruption of insulin treatment, and new onset of diabetes. (See Etiology.) DKA is defined clinically as an acute state of severe uncontrolled diabetes associated with ketoacidosis that requires emergency treatment with insulin and intravenous fluids. (See Treatment and Management and Medications.) Biochemically, DKA is defined as an increase in the serum concentration of ketones greater than 5 mEq/L, a blood sugar level greater than 250 mg/dL (although it is usually much higher), and a blood (usually arterial) pH less than 7.3. Ketonemia and ketonuria are characteristic, as is a serum bicarbonate level of 18 mEq/L or less (less than 5 mEq/L is indicative of severe DKA). These biochemical changes are frequently associated with increased anion gap, increased serum osmolarity and increased serum uric acid. (See Clinical Presentation.) Herrington et al collected simultaneous arterial and venous samples from 206 critically ill patients and analyzed in duplicate. [3] They calculated coefficients of variation and 95% limits of agreement for arterial and venous samples and constructed statistical plots to assess the degree of agreement between samples. They found that coefficients of variation for arterial and venous samples were similar for pH, serum bicarbonate, and potassium, indicating that both are sufficiently reliable for the management of critically ill patients, particularly those with DKA. Mental status changes can be seen with mild-to-moderate DKA; more severe deterioration in mental status is typical with moderate-to-severe DKA. See Diabetes Mellitus, Type 1 and Diabetes Mellitus, Type 2 for more complete information on these topics. PathophysiologyDiabetic ketoacidosis (DKA) is a complex disordered metabolic state characterized by hyperglycemia, ketoacidosis, and ketonuria. DKA usually occurs as a consequence of absolute or relative insulin deficiency that is accompanied by an increase in counter-regulatory hormones (ie, glucagon, cortisol, growth hormone, epinephrine). This type of hormonal imbalance enhances hepatic gluconeogenesis, glycogenolysis, and lipolysis. Hepatic gluconeogenesis, glycogenolysis secondary to insulin deficiency, and counter-regulatory hormone excess result in severe hyperglycemia, while lipolysis increases serum free fatty acids. Hepatic metabolism of free fatty acids as an alternative energy source (ie, ketogenesis) results in accumulation of acidic intermediate and end metabolites (ie, ketones, ketoacids). Ketone bodies have generally included acetone, beta-hydroxybutyrate, and acetoacetate. It should be noted, however, that only acetone is a true ketone, while acetoacetic acid is true ketoacid and beta-hydroxybutyrate is a hydroxy acid. Meanwhile, increased proteolysis and decreased protein synthesis as result of insulin deficiency add more gluconeogenic substrates to the gluconeogenesis process. In addition, the decreased glucose uptake by peripheral tissues due to insulin deficiency and increased counter regulatory hormones increases hyperglycemia. Ketone bodies are produced from acetyl coenzyme A mainly in the mitochondria within hepatocytes when carbohydrate utilization is impaired because of relative or absolute insulin deficiency, such that energy must be obtained from fatty acid metabolism. High levels of acetyl coenzyme A present in the cell inhibit the pyruvate dehydrogenase complex, but pyruvate carboxylase is activated. Thus, the oxaloacetate generated enters gluconeogenesis rather than the citric acid cycle, as the latter is also inhibited by the elevated level of nicotinamide adenine dinucleotide (NADH) resulting from excessive beta-oxidation of fatty acids, another consequence of insulin resistance/insulin deficiency. The excess acetyl coenzyme A is therefore rerouted to ketogenesis. Progressive rise of blood concentration of these acidic organic substances initially leads to a state of ketonemia, although extracellular and intracellular body buffers can limit ketonemia in its early stages, as reflected by a normal arterial pH associated with a base deficit and a mild anion gap. When the accumulated ketones exceed the body's capacity to extract them, they overflow into urine (ie, ketonuria). If the situation is not treated promptly, a greater accumulation of organic acids leads to frank clinical metabolic acidosis (ie, ketoacidosis), with a significant drop in pH and bicarbonate [4] serum levels. Respiratory compensation for this acidotic condition results in Kussmaul respirations, ie, rapid, shallow breathing (sigh breathing) that, as the acidosis grows more severe, becomes slower, deeper, and labored (air hunger). Ketones/ketoacids/hydroxy acids, in particular, beta-hydroxybutyrate, induce nausea and vomiting that consequently aggravate fluid and electrolyte loss already existing in DKA. Moreover, acetone produces the fruity breath odor that is characteristic of ketotic patients. Glucosuria leads to osmotic diuresis, dehydration and hyperosmolarity. Severe dehydration, if not properly compensated, may lead to impaired renal function. Hyperglycemia, osmotic diuresis, serum hyperosmolarity, and metabolic acidosis result in severe electrolyte disturbances. The most characteristic disturbance is total body potassium loss. This loss is not mirrored in serum potassium levels, which may be low, within the reference range, or even high. Potassium loss is caused by a shift of potassium from the intracellular to the extracellular space in an exchange with hydrogen ions that accumulate extracellularly in acidosis. Much of the shifted extracellular potassium is lost in urine because of osmotic diuresis. Patients with initial hypokalemia are considered to have severe and serious total body potassium depletion. High serum osmolarity also drives water from intracellular to extracellular space, causing dilutional hyponatremia. Sodium also is lost in the urine during the osmotic diuresis. Typical overall electrolyte loss includes 200-500 mEq/L of potassium, 300-700 mEq/L of sodium, and 350-500 mEq/L of chloride. The combined effects of serum hyperosmolarity, dehydration, and acidosis result in increased osmolarity in brain cells that clinically manifests as an alteration in the level of consciousness. Many of the underlying pathophysiologic disturbances in DKA are directly measurable by the clinician and need to be monitored throughout the course of treatment. Close attention to clinical laboratory data allows for tracking of the underlying acidosis and hyperglycemia, as well as prevention of common potentially lethal complications such as hypoglycemia, hyponatremia, and hypokalemia. HyperglycemiaThe absence of insulin, the primary anabolic hormone, means that tissues such as muscle, fat, and liver do not uptake glucose. Counterregulatory hormones, such as glucagon, growth hormone, and catecholamines, enhance triglyceride breakdown into free fatty acids and gluconeogenesis, which is the main cause for the elevation in serum glucose level in DKA. Beta-oxidation of these free fatty acids leads to increased formation of ketone bodies. Overall, metabolism in DKA shifts from the normal fed state characterized by carbohydrate metabolism to a starvation state characterized by fat metabolism. Secondary consequences of the primary metabolic derangements in DKA include an ensuing metabolic acidosis as the ketone bodies produced by beta-oxidation of free fatty acids deplete extracellular and cellular acid buffers. The hyperglycemia-induced osmotic diuresis depletes sodium, potassium, phosphates, and water. Hyperglycemia usually exceeds the renal threshold of glucose absorption and results in significant glucosuria. Consequently, water loss in the urine is increased due to osmotic diuresis induced by glucosuria. This incidence of increased water loss results in severe dehydration, thirst, tissue hypoperfusion, and, possibly, lactic acidosis, or renal impairment. See Hyperosmolar Hyperglycemic State for more complete information on this topic. Dehydration and electrolyte lossTypical free water loss in DKA is approximately 6 liters or nearly 100 mL/kg of body weight. The initial half of this amount is derived from intracellular fluid and precedes signs of dehydration, while the other half is from extracellular fluid and is responsible for signs of dehydration. Patients often are profoundly dehydrated and have a significantly depleted potassium level (as high as 5 mEq/kg body weight). A normal or even elevated serum potassium concentration may be seen due to the extracellular shift of potassium in acidotic conditions, and this very poorly reflects the patient's total potassium stores. The serum potassium concentration can drop precipitously once insulin treatment is started, so great care must be taken to repeatedly monitor serum potassium levels. Urinary loss of ketoanions with brisk diuresis and intact renal function also may lead to a component of hyperchloremic metabolic acidosis. EtiologyThe most common scenarios for diabetic ketoacidosis (DKA) are underlying or concomitant infection (40%), missed or disrupted insulin treatments (25%), and newly diagnosed, previously unknown diabetes (15%). Other associated causes make up roughly 20% in the various scenarios. Causes of DKA in type 1 diabetes mellitus include the following: [5]
Causes of DKA in type 2 diabetes mellitus include the following: [6]
DKA has also been reported in people with type 2 diabetes treated with sodium-glucose cotransporter-2 (SGLT2) inhibitors. [7] DKA also occurs in pregnant women, either with preexisting diabetes or with diabetes diagnosed during pregnancy. Physiologic changes unique to pregnancy provide a background for the development of DKA. DKA in pregnancy is a medical emergency, as mother and fetus are at risk for morbidity and mortality. There is evidence that coronavirus disease 2019 (COVID-19) increases the risk of DKA, possibly in association with beta-cell destruction that may result from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19. [8, 9] Moreover, a study by Vitale et al suggested that in persons with type 2 diabetes who are taking SGLT2 inhibitors, the risk of euglycemic DKA may be further increased in the presence of COVID-19 (as based on five cases). [10, 11] EpidemiologyDespite advancements in self-care of patients with diabetes, DKA accounts for 14% of all hospital admissions of patients with diabetes and 16% of all diabetes-related fatalities. Almost 50% of diabetes-related admissions in young persons are related to DKA. DKA frequently is observed during the diagnosis of type 1 diabetes and often indicates this diagnosis. While the exact incidence is not known, it is estimated to be 1 out of 2000. DKA occurs primarily in patients with type 1 diabetes. The incidence is roughly 2 episodes per 100 patient years of diabetes, with about 3% of patients with type 1 diabetes initially presenting with DKA. It can occur in patients with type 2 diabetes as well; this is less common, however. A study by Zhong et al found that in England, for adults with type 1 or type 2 diabetes, there was a growing incidence of hospitalization for DKA between 1998 and 2013. More specifically, the investigators reported that the incidence for patients with type 1 diabetes rose between 1998 and 2007 and then remained at the same level until 2013, while the incidence associated with type 2 diabetes expanded annually by 4.24% between 1998 and 2013. [12] The incidence of diabetic ketoacidosis in developing countries is not known, but it may be higher than in industrialized nations. [13] The incidence of DKA is higher in whites because of the higher incidence of type 1 diabetes in this racial group. The incidence of DKA is slightly greater in females than in males for reasons that are unclear. Recurrent DKA frequently is seen in young women with type 1 diabetes and is caused mostly by the omission of insulin treatment. Among persons with type 1 diabetes, DKA is much more common in young children and adolescents than it is in adults. DKA tends to occur in individuals younger than 19 years, but it may occur in patients with diabetes at any age. Although multiple factors (eg, ethnic minority, lack of health insurance, lower body mass index, preceding infection, delayed treatment) affect the risk of developing DKA among children and young adults, intervention is possible between symptom onset and development of DKA. [14] PrognosisThe overall mortality rate for DKA is 0.2-2%, with persons at the highest end of the range residing in developing countries. The presence of deep coma at the time of diagnosis, hypothermia, and oliguria are signs of poor prognosis. The prognosis of properly treated patients with diabetic ketoacidosis is excellent, especially in younger patients if intercurrent infections are absent. The worst prognosis usually is observed in older patients with severe intercurrent illnesses (eg, myocardial infarction, sepsis, or pneumonia), especially when these patients are treated outside an intensive care unit. A study by Lee et al reported that in adult patients with DKA, a longer time to resolution was associated with lower pH levels and higher serum potassium concentrations at hospital admission (with both factors being independent predictors). [15] When DKA is treated properly, it rarely produces residual effects. Before the discovery of insulin in 1922, the mortality rate was 100%. Over the last 3 decades, mortality rates from DKA have markedly decreased in developed countries, from 7.96% to 0.67%. [16] A fetal mortality rate as high as 30% is associated with DKA. The rate is as high as 60% in diabetic ketoacidosis with coma. Fetal death typically occurs in women with overt diabetes, but it may occur with gestational diabetes. In children younger than 10 years, diabetic ketoacidosis causes 70% of diabetes-related fatalities. The best results are observed in patients treated in intensive care units during the first 1-2 days of hospitalization, although some hospitals are successful in treating mild cases of DKA in the emergency room (ie, Emergency Valuable Approach and Diabetes Education [EVADE] protocol). A high mortality rate among nonhospitalized patients illustrates the necessity of early diagnosis and implementation of effective prevention programs. Cerebral edema remains the most common cause of mortality, particularly in young children and adolescents. [1] Cerebral edema frequently results from rapid intracellular fluid shifts. Other causes of mortality include severe hypokalemia, adult respiratory distress syndrome, and comorbid states (eg, pneumonia, acute myocardial infarction). A heightened understanding of the pathophysiology of DKA along with proper monitoring and correction of electrolytes has resulted in a significant reduction in the overall mortality rate from this life-threatening condition in most developed countries. A study by Hursh et al indicated that acute kidney injury (AKI) is a frequent development in children hospitalized for DKA. Of 165 hospitalized pediatric DKA patients in the study, AKI developed in 106 (64%). Using an adjusted multinomial logistic regression model, the investigators found a 5-fold increase in the chance of severe AKI (stage 2 or 3) when a patient’s serum bicarbonate level was below 10 mEq/L, while the likelihood of severe AKI rose 22% with each increase in the initial heart rate of five beats/min. The odds of mild AKI (stage 1) developing rose by three fold with an initial corrected sodium level of 145 mEq/L or more. [17] A study by Chen et al indicated that among persons with type 2 diabetes, those with DKA have a 1.55 times greater risk of stroke than do those without DKA. The stroke risk was particularly high in DKA patients with hypertension and hyperlipidemia and in the first six months after the diagnosis of DKA. [18] Patient EducationThe introduction of diabetes educational programs in most diabetes clinics has contributed to a reduction in the occurrence of diabetic ketoacidosis (DKA) in patients with known diabetes. Such programs teach patients how to avoid DKA by self-testing for urinary ketones when their blood glucose is high or when they have unexplained nausea or vomiting and adjusting their insulin regimens on sick days. It is essential to educate patients in the prevention of diabetic ketoacidosis (DKA) so that a recurrent episode can be avoided. Central to patient education programs for adults with diabetes is instruction on the self-management process and on how to handle the stress of intercurrent illness. [19, 20] The patient education program needs to ensure that patients understand the importance of close and careful monitoring of blood sugar levels, particularly during infection, trauma, and other periods of stress. For excellent patient education resources, visit eMedicineHealth's Diabetes Center. In addition, see eMedicineHealth's patient education article Diabetic Ketoacidosis.
Author Osama Hamdy, MD, PhD Medical Director, Obesity Clinical Program, Director of Inpatient Diabetes Program, Joslin Diabetes Center; Associate Professor of Medicine, Harvard Medical School Osama Hamdy, MD, PhD is a member of the following medical societies: American Association of Clinical Endocrinologists, American Diabetes Association Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: on advisory panel of Astra-Zeneca Inc<br/>Received research grant from: USDA Dairy Council <br/>Have a 5% or greater equity interest in: HealthyMation Inc<br/>Received consulting fee from Merck Inc for teaching; Received consulting fee from Abbott Nutrition for consulting; for: Receieved consulting fee Sanofi Aventis for teaching. Chief Editor Romesh Khardori, MD, PhD, FACP (Retired) Professor, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Eastern Virginia Medical School Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, Endocrine Society Disclosure: Nothing to disclose. Acknowledgements Howard A Bessen, MD Professor of Medicine, Department of Emergency Medicine, University of California, Los Angeles, David Geffen School of Medicine; Program Director, Harbor-UCLA Medical Center Howard A Bessen, MD is a member of the following medical societies: American College of Emergency Physicians Disclosure: Nothing to disclose. Barry E Brenner, MD, PhD, FACEP Professor of Emergency Medicine, Professor of Internal Medicine, Program Director for Emergency Medicine, Case Medical Center, University Hospitals, Case Western Reserve University School of Medicine Barry E Brenner, MD, PhD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Chest Physicians, American College of Emergency Physicians, American College of Physicians, American Heart Association, American Thoracic Society, Arkansas Medical Society, New York Academy of Medicine, New York Academy of Sciences,and Society for Academic Emergency Medicine Disclosure: Nothing to disclose. Vasudevan A Raghavan, MBBS, MD, MRCP(UK) Director, Cardiometabolic and Lipid (CAMEL) Clinic Services, Division of Endocrinology, Scott and White Hospital, Texas A&M Health Science Center College of Medicine Vasudevan A Raghavan, MBBS, MD, MRCP(UK) is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Heart Association, National Lipid Association, Royal College of Physicians, and The Endocrine Society Disclosure: Nothing to disclose. Donald W Rucker, MD, MBA, MS Clinical Assistant Professor of Emergency Medicine, University of Pennsylvania School of Medicine Donald W Rucker, MD, MBA, MS is a member of the following medical societies: American College of Emergency Physicians, American College of Physicians, American Medical Association, American Medical Informatics Association, and Society for Academic Emergency Medicine Disclosure: Siemens Healthcare Salary Employment David S Schade, MD Chief, Division of Endocrinology and Metabolism, Professor, Department of Internal Medicine, University of New Mexico School of Medicine and Health Sciences Center David S Schade, MD is a member of the following medical societies: American College of Physicians, American Diabetes Association, American Federation for Medical Research, New Mexico Medical Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, and The Endocrine Society Disclosure: Nothing to disclose. Don S Schalch, MD Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, University of Wisconsin Hospitals and Clinics Don S Schalch, MD is a member of the following medical societies: American Diabetes Association, American Federation for Medical Research, Central Society for Clinical Research, and The Endocrine Society Disclosure: Nothing to disclose. Erik D Schraga, MD Staff Physician, Department of Emergency Medicine, Mills-Peninsula Emergency Medical Associates Disclosure: Nothing to disclose. Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Medscape Salary Employment What type of poisoning will cause burns around the mouth of a child EMT?Caustic substances are highly acidic or alkaline chemicals that can cause severe burns to the mouth and digestive tract when swallowed.
Why are injected poisons impossible to dilute?Injected poisons are impossible to dilute or remove because they are usually absorbed quickly into the body or cause intense local tissue destruction.
How do poisons typically act to harm the body?Ingested and absorbed toxins generally cause bodywide symptoms, often because they deprive the body's cells of oxygen or activate or block enzymes and receptors. Symptoms may include changes in consciousness, body temperature, heart rate, and breathing and many others, depending on the organs affected.
How are airborne substances diluted?Airborne substances are diluted with: oxygen.
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A patient who presents with rapid breathing nausea and vomiting
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