History and exam
Other diagnostic factors
common
polyuria
Symptom of hyperglycemia.[1]
polyphagia
Symptom of hyperglycemia.[1]
polydipsia
Symptom of hyperglycemia.[1]
weight loss
Symptom of hyperglycemia.[1]
weakness
Symptom of hyperglycemia.
nausea or vomiting
abdominal pain
dry mucous membranes
Sign of volume depletion.
poor skin turgor
Sign of volume depletion.
sunken eyes
Sign of volume depletion.
tachycardia
Sign of volume depletion.[1]
hypotension
Sign of volume depletion.[1]
Kussmaul respiration
Rapid and deep respiration due to acidosis. Common in DKA.[1]
acetone breath
Sign of ketosis. Common in DKA.[1]
altered mental status
Mental status may be altered, and varies from alert in mild DKA to stupor/coma in severe DKA.[1] Studies have shown that acidosis is independently associated with altered sensorium in patients with DKA, but hyperosmolarity and serum ketone levels are not. Combination of hyperosmolarity and acidosis predicts altered sensorium with good sensitivity (61%) and specificity (87%).[74]
Risk factors
strong
type 1 diabetes
Diabetic ketoacidosis can occur in people with both type 1 and type 2 diabetes, but is much more common in those with type 1 diabetes. One US nationwide cohort study found that adjusted rates of hyperglycemic crises were 53 events per 1000 person-years among adults with type 1 diabetes, compared with 4 events per 1000 person-years among people with type 2 diabetes.[27]
inadequate or inappropriate insulin therapy
Reduction in the net effective concentration of insulin leads to impaired carbohydrate, lipid, and ketone metabolism in diabetic ketoacidosis (DKA). Decreased insulin results in increased gluconeogenesis, accelerated glycogenolysis, and impaired glucose utilization by peripheral tissues.[1]
In one US study conducted in a large urban hospital, poor adherence to insulin treatment accounted for >50% of DKA admissions, particularly affecting African-Caribbean populations and underinsured people.[28] Psychological and social factors may impact on glycemic control, and low socioeconomic status is correlated with a higher risk for DKA.[29][30] Additionally, insulin pump failure (e.g., due to dislodgement, occlusion) can result in rapid DKA development.[4]
infection
The most common precipitating factor for diabetic ketoacidosis (DKA) worldwide is infection, particularly urinary tract infection or pneumonia.[1][13] Increased counter-regulatory hormones, particularly epinephrine, as a systemic response to infection lead to insulin resistance, increased lipolysis, ketogenesis, and volume depletion, which may contribute to the development of hyperglycemic crises in patients with diabetes.[1] Coronavirus disease 2019 (COVID-19) infection has been associated with greater risk of DKA in both type 1 and type 2 ԁiabеtеs.[1] Several studies have reported DKA as the presentation of newly diagnosed type 1 diabetes during or after a COVID-19 infection.[4] The precise mechanisms for new onset diabetes in people with COVID-19 are not known.[4]
myocardial infarction
previous episode of hyperglycemic or hypoglycemic crisis
A substantial proportion of individuals hospitalized with diabetic ketoacidosis (DKA) experience recurrent episodes.[4] In US nationwide studies, up to 22% of people admitted with DKA had at least one readmission within 30 days or the same calendar year.[32] Among those readmitted within 30 days, 40.8% represented recurrent DKA episodes, with approximately 50% being readmitted within 2 weeks.[32][33] Among those readmitted within the same calendar year, 86% had 1-3 DKA readmissions and 14% had ≥4.[33] Assessment of precipitating and contributing causes of DKA admission and close follow-up within 2-4 weeks after discharge may reduce recurrent DKA.[1]
Prior history of hypoglycemic crises, suggestive of greater glycemic variability, is also a risk factor for DKA.[1] One study found severe hypoglycemia to be associated with a three- to fourfold increase in the risk of experiencing a hyperglycemic crisis.[27]
high hemoglobin A1c (HbA1c)
Poorly controlled diabetes is associated with an increased risk of hyperglycemic crises.[4] One study found that for patients with type 1 diabetes, risk of experiencing a hyperglycemic crisis increased when the HbA1c level exceeded 7% (53 mmol/mol).[27] The incidence risk ratio was 7.81 (95% CI 5.78 to 10.54) for HbA1c levels of ≥10% (≥86 mmol/mol) compared with HbA1c levels of 6.5% to 6.9% (48-52 mmol/mol).[27] For patients with type 2 diabetes, the risk increased continuously for all HbA1c levels above 5.6% (38 mmol/mol), and the incidence risk ratio was 7.06 (95% CI 6.26 to 7.96) for HbA1c levels of ≥10% (≥86 mmol/mol).[27]
adverse social determinants of health
Adverse social determinants of health are among the strongest factors associated with recurrent diabetic ketoacidosis (DKA).[1] Multiple studies have suggested that low income, area-level deprivation, housing insecurity, and lack of insurance or presence of underinsurance (in health systems where this is applicable) lead to increased risk of DKA and hyperosmolar hyperglycemic state, with approximately 40% of hyperglycemic crises occurring in lower-income and underserved populations.[1]
age <45 years
One nationwide US cohort study found that rates of hyperglycemic crises were significantly higher among younger adults in patients with type 1 and type 2 diabetes.[27] In 2014, rates of hospitalization for diabetic ketoacidosis in the US were highest among people ages <45 years (44.3 in 1000 persons with diabetes) and decreased with age (5.2 in 1000 persons with diabetes ages 45-64 years; 1.6 in 1000 65-74 years; and 1.4 in 1000 ≥75 years).[11]
weak
presence of other diabetes-related complications
The presence of diabetic neuropathy, nephropathy, and retinopathy has been associated with a higher risk of diabetic ketoacidosis (DKA).[27] One large prospective cohort study found that reduced estimated glomerular filtration rate (eGFR <60 mL/min/1.73 m²), even when excluding patients with end-stage renal disease, was associated with a higher risk of hospitalization for DKA (HR 1.71, 95% CI 1.26 to 2.67) compared to an eGFR >60 mL/min/1.73 m². This association was independent of markers of glycemic control.[34]
presence of other chronic health conditions
The presence of comorbidities including cerebrovascular disease, heart failure, dementia, chronic obstructive pulmonary disease, cirrhosis, or cancer has been associated with an increased risk of diabetic ketoacidosis in patients with type 2 diabetes.[27]
pancreatitis
stroke
Acute medical events such as stroke, with increased levels of counter-regulatory hormones and compromised access to water and insulin, may contribute to the development of hyperglycemic crises.[1]
acromegaly
Hormonal derangements in some endocrine glands lead to increased counter-regulatory hormones and development of diabetic ketoacidosis in patients with concomitant diabetes.[36]
hyperthyroidism
use of certain drugs
Drugs that affect carbohydrate metabolism may precipitate hyperglycemic crises.[1] This may include corticosteroids, thiazide diuretics, pentamidine, sympathomimetics, and atypical antipsychotics.[15]
Cocaine use may be an independent risk factor associated with recurrent diabetic ketoacidosis (DKA).[39] Cannabis use (and associated hyperemesis syndrome) has also been associated with an increased risk of DKA in adults with type 1 diabetes.[4]
Sodium-glucose cotransporter-2 (SGLT2) inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin, ertugliflozin), used for glycemic control of type 2 diabetes (or more recently, cardiovascular event risk reduction), have been the subject of a Food and Drug Administration (FDA) warning about a risk for DKA.[40] The risk is heightened with use of an SGLT2 inhibitor in certain situations, such as during severe illness or a period of prolonged fasting, or perioperatively, and their use should be avoided in such cases.[4] The American Diabetes Association warns that the risk of DKA in people with type 1 diabetes using SGLT2 inhibitors can be 5-17 times higher than in nonusers.[4] In contrast, observational studies and randomized controlled trials have shown that DKA is uncommon in people with type 2 diabetes treated with SGLT2 inhibitors (0.6 to 4.9 events per 1000 patient-years).[41]
The dual SGLT1/SGLT2 inhibitor sotagliflozin, which has been approved to reduce the risk of hospitalization for heart failure in patients with type 2 diabetes with chronic kidney disease or high risk of/established cardiovascular disease, as well as in people with heart failure (both with and without diabetes), has also been been associated with increased rates of DKA. In clinical trials of sotagliflozin in people with type 1 diabetes, results showed improvements in hemoglobin A1c and body weight, but use was associated with an eightfold increase in DKA compared with placebo.[4][42]
Immune checkpoint inhibitor therapy for cancer (PD-1 and PD-L1 blocking antibodies such as nivolumab, pembrolizumab, and avelumab) appears to be associated with a risk for DKA and type 1 diabetes mellitus.[16][43][44][45] It has been estimated that up to 75% of people who develop immune checkpoint inhibitor-induced hyperglycemia/diabetes present with DKA.[46]
Cushing syndrome
Hypercortisolism leads to insulin resistance and may occasionally precipitate diabetic ketoacidosis in patients with concomitant diabetes; it more commonly precipitates hyperosmolar hyperglycemic state.[47]
Hispanic, Asian or black ancestry
One US nationwide cohort study found that black patients with type 1 or type 2 diabetes had higher risks of hyperglycemic crises than individuals in other racial/ethnic groups.[27] This disparity persisted after adjustment for key socioeconomic, clinical, and treatment-related factors, suggesting that additional intrinsic and extrinsic factors are associated with hyperglycemic crises among black patients.[27]
Diabetic ketoacidosis (DKA) has also been increasingly documented as a presenting feature of newly diagnosed type 2 diabetes, referred to as ketosis-prone diabetes.[9][10] Epidemiologic data suggest that people of African or Hispanic origin are at greater risk.[9] Individuals with ketosis-prone type 2 diabetes often have obesity and a strong family history of type 2 diabetes, as well as evidence of insulin resistance.[9] Approximately 80% of obese black patients with DKA have type 2 diabetes, characterized by higher insulin secretion, the absence of autoimmune markers, and a lack of human leukocyte antigen (HLA) genetic association compared with lean patients with type 1 diabetes.[6]
bariatric surgery
prolonged fasting or carbohydrate restriction
Fasting increases the risk of dehydration, hyperglycemia, and ketoacidosis in people with diabetes to a varying degree (depending on type of diabetes and therapy used, among other things).[4] Following a very low carbohydrate or ketogenic diet in conjunction with sodium-glucose cotransporter-2 (SGLT2) inhibitor and dual SGLT1/2 inhibitor use can increase diabetic ketoacidosis risk.[4][19]
pregnancy
Pregnancy is a ketogenic state and there is a risk of diabetic ketoacidosis (DKA) in pregnant individuals with pre-existing diabetes (more so for those with type 1, rather than type 2, diabetes) at lower glucose levels (e.g., may present as euglycemic DKA).[4] Up to 2% of pregnancies with pregestational diabetes are complicated by DKA.[4] However, the incidence of DKA in gestational diabetes is low (<0.1%).[4]
dementia
People with type 2 diabetes and dementia are at increased risk for diabetic ketoacidosis than those without dementia.[4]
mental health disorders
The presence of mental health conditions, such as depression, bipolar disorder, and eating disorders, has been associated with increased risk for hyperglycemic crises.[4]
alcohol and/or substance use
Alcohol and/or substance use are risk factors for diabetic ketoacidosis (DKA).[4] Excessive alcohol intake and use of illicit drugs also increase the risk of DKA associated with the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors and dual SGLT1/2 inhibitors.[4][19]
Cocaine use may be an independent risk factor associated with recurrent DKA.[39] Cannabis use (and associated hyperemesis syndrome) has also been associated with an increased risk of DKA in adults with type 1 diabetes.[4]
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