literature review diabetic ketoacidosis

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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

StatPearls [Internet].

Adult diabetic ketoacidosis.

Jenna M. Lizzo ; Amandeep Goyal ; Vikas Gupta .

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Last Update: July 10, 2023 .

• Continuing Education Activity

Diabetic ketoacidosis (DKA) is characterized by uncontrolled hyperglycemia, metabolic acidosis, and increased body ketone concentration. It is a life-threatening complication of diabetes and is usually seen in patients with type-1 diabetes mellitus. Rarely it may also occur in patients with type-2 diabetes mellitus. DKA is a state of a relative or absolute insulin deficiency that is worsened by hyperglycemia, dehydration, and acidosis. In most cases, the trigger is an infection, new-onset diabetes, or lack of compliance with treatment. This activity highlights the role of the interprofessional team in evaluating and managing patients suffering from this disorder in order to achieve the best outcomes.

• Review the etiology of diabetic ketoacidosis.
• Describe the management of a patient with diabetic ketoacidosis.
• Summarize the abnormal laboratory parameters in a patient with diabetic ketoacidosis.
• Explain the importance of improving care coordination among an interprofessional team to improve outcomes for patients affected by diabetic ketoacidosis.
• Introduction

Diabetic ketoacidosis (DKA) is characterized by hyperglycemia, acidosis, and ketonemia. It is a life-threatening complication of diabetes and typically seen in patients with type-1 diabetes mellitus, though it may also occur in patients with type-2 diabetes mellitus. In most cases, the trigger is new-onset diabetes, an infection, or a lack of compliance with treatment.

Diabetic ketoacidosis more commonly occurs in patients with type 1 diabetes, though it can also occur in patients with type 2 diabetes. Patients with type 2 diabetes are also at risk. In both populations, catabolic stress of acute illness or injuries such as trauma, surgery, or infections may be a trigger. Common precipitating factors for DKA are non-compliance, new-onset diabetes, and other acute medical illness. The most common types of infections are pneumonia and urinary tract infections. Other conditions like alcohol abuse, trauma, pulmonary embolism, and myocardial infarction can also precipitate DKA. Drugs that affect carbohydrate metabolisms, such as corticosteroids, thiazides, sympathomimetic agents, and pentamidine, may precipitate DKA. Conventional, as well as atypical antipsychotic drugs, may also cause hyperglycemia and rarely DKA. [1]

SGLT2 inhibitors can predispose to diabetic ketoacidosis via multiple mechanisms. When SGLT2 inhibitors are used together with insulin, insulin doses are often decreased to avoid hypoglycemia. A lower dose of insulin may not be sufficient to suppress lipolysis and ketogenesis. SGLT2 is also expressed in pancreatic α-cells. SGLT2 inhibitors promote glucagon secretion and may decrease urinary excretion of ketone bodies, leading to an increase in plasma ketone body levels as well as hyperglycemia and DKA. [2]  While hyperglycemia is typically the hallmark of DKA, a small subset of patients may experience euglycemic DKA. Euglycemic DKA results in a high anion gap metabolic acidosis with positive serum and urine ketones when serum glycemic levels are less than 250 mg/dL. SGLT-2 inhibitors may precipitate euglycemic DKA. [3]

One of the major causes of recurrent DKA in the inner-city population in the United States is non-compliance with insulin. Socioeconomic and educational factors play a significant role in poor adhesion to medications, including insulin. A recent report suggests that cocaine abuse is an independent risk factor associated with DKA recurrence. [4]

• Epidemiology

Diabetic ketoacidosis incidence ranges from 0 to 56 per 1000 person-years, shown in different studies from different geographic areas. DKA has a higher prevalence rate among women and non-Whites. Incidence is higher among patients using injectable insulin compared to the subcutaneous insulin infusion pumps. [5]

Rates of DKA among children varies widely from country to country. The lowest incidence was found in Nigeria (2.9 cases per 100,000). The highest incidence rate was found in Sweden and Finland, with 41.0 and 37.4 per 100,000. [6]  In the United States, one study reported nursing home residents accounted for 0.7% of DKA. Increased mortality was associated with nursing home residence among patients with DKA. [7]  Mortality rate greater than 5% has been reported in the elderly and patients with concomitant life-threatening illnesses. Death in these conditions is rarely because of the metabolic complications of hyperglycemia or ketoacidosis alone.

The prognosis substantially worsens at the extremes of age in the presence of coma, hypotension, and severe comorbidities. [1]  In urban Black patients, poor compliance with insulin was the leading precipitating cause of DKA. Substance abuse is a major contributing factor for non-adherence to therapies. Obesity is common in Blacks with DKA; it is found in more than half of those with newly diagnosed diabetes mellitus. Enhanced patient education and better access to medical care help in reducing the development of these hyperglycemic emergencies. [8]   

Diabetic ketoacidosis (DKA) is one of the life-threatening but preventable complications of diabetes. CDC's United States Diabetes Surveillance System (USDSS) indicated an increase in hospitalization rates for DKA from 2009 to 2014, most notably in persons aged less than 45 years. [9]  However, overall mortality due to hyperglycemic crisis among adults with diabetes has declined in the U.S. Scope for further improvement remains, especially to further reduce death rates among Black men and to prevent deaths occurring at home. [10]  

The geriatric population is at particular risk for developing hyperglycemic crises with the development of diabetes. Some of the causes are increased insulin resistance and a decrease in the thirst mechanism. The elderly are particularly vulnerable to hyperglycemia and dehydration, the critical components of hyperglycemic emergencies. With increased diabetes surveillance and aggressive early treatment of hyperglycemia and its complications, morbidity, and mortality from acute diabetic crises in the geriatric population can be significantly reduced. [11]

• Pathophysiology

Diabetes mellitus is characterized by insulin deficiency and increased plasma glucagon levels, which can be normalized by insulin replacement. [12]  Normally, once serum glucose concentration increases, it enters pancreatic beta cells and leads to insulin production. Insulin decreases hepatic glucose production by inhibiting glycogenolysis and gluconeogenesis. Glucose uptake by skeletal muscle and adipose tissue is increased by insulin. Both of these mechanisms result in the reduction of blood sugar. In diabetic ketoacidosis, insulin deficiency and increased counter-regulatory hormones can lead to increased gluconeogenesis, accelerated glycogenolysis, and impaired glucose utilization. This will ultimately cause worsening hyperglycemia.

Insulin deficiency and increased counterregulatory hormones also lead to the release of free fatty acids into circulation from adipose tissue (lipolysis), which undergo hepatic fatty acid oxidation to ketone bodies (beta-hydroxybutyrate and acetoacetate), resulting in ketonemia and metabolic acidosis. [1]  Glucagon is not crucial for the development of ketoacidosis in diabetes mellitus, as has previously been mentioned; however, it may accelerate the onset of ketonemia and hyperglycemia in situations of insulin deficiency. [13]  Patients treated with SGLT2 are at increased risk of developing euglycemic DKA.

Diuresis induced by hyperglycemia, dehydration, hyperosmolarity, and electrolyte imbalance results in a decrease of glomerular filtration. Due to worsening renal function, hyperglycemia/hyperosmolality worsens. Potassium utilization by skeletal muscle is also impaired by hyperosmolality and impaired insulin function. This results in intracellular potassium depletion. Osmotic diuresis also leads to loss of potassium resulting in low total body potassium. The potassium level in patients with DKA varies, and a patient's normal plasma potassium level might indicate low total body potassium. [4]  Hyperosmolarity appears to be the main factor responsible for the lowering of consciousness in patients with diabetic ketoacidosis. [14]  

New data suggests that hyperglycemia leads to a severe inflammatory state and an increase in proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-beta, -6, and -8), C-reactive protein, lipid peroxidation, and reactive oxygen species, as well as cardiovascular risk factors, plasminogen activator inhibitor-1 and free fatty acids in the absence of apparent infection or cardiovascular pathology. After insulin therapy and IV fluid hydration, the pro-inflammatory cytokines return to normal values within 24 hours. [1]

• History and Physical

The patient with diabetic ketoacidosis may present with a myriad of symptoms and physical exam findings. Patients may have symptoms of hyperglycemia like polyphagia, polyuria, or polydipsia. As patients become more volume-depleted, they may experience decreased urine output, dry mouth, or decreased sweating indicative of dehydration. They may complain of many other symptoms, including anorexia, nausea, vomiting, abdominal pain, and weight loss.

If there is a superimposed infection that triggered the episode of DKA, the patient may have other infectious symptoms like fever, cough, or other urinary symptoms. In patients who may be developing cerebral edema, headache, or confusion may be present. Medication history should also be elicited, including what medications the patient is prescribed and how the patient has been using them. Substance use (drug and alcohol) should be ascertained. [15]  

On examination, vital signs typically reveal tachycardia and tachypnea. Due to the possibility of an infectious trigger for DKA, the patient may be febrile or hypothermic. Blood pressure may also vary, though hypotension is possible and indicative of a more severe disease process. Patients are often ill-appearing. Kussmaul breathing, which is labored, deep, and tachypneic, may occur. Some providers may appreciate a fruity scent to the patient's breath, indicative of the presence of acetone. Patients may have signs of dehydration, including poor capillary refill, skin turgor, and dry mucous membranes. Abdominal tenderness is possible. In the most severe cases, altered mental status, general drowsiness, and focal neurologic deficits can be appreciated and are signs of cerebral edema. If found, this needs to be treated immediately. [16]

Commonly accepted criteria for diabetic ketoacidosis are blood glucose greater than 250 mg/dl, arterial pH less than 7.3, serum bicarbonate less than 15 mEq/l, and the presence of ketonemia or ketonuria. The normal anion gap is 12 mEq/l. Anion gap greater than 14-15 mEq/l indicates the presence of an increased anion gap metabolic acidosis. [17]  Arterial pH may be normal or even raised if other types of metabolic or respiratory alkalosis coexist. Typical examples are vomiting or diuretic use. [18]  Blood glucose may be normal or minimally elevated in patients with DKA (<300 mg/dl), where the underlying risk of hypoglycemia preexists, such as in patients with alcohol use disorder or patients receiving insulin or SGLT2 inhibitors. 

The majority of patients with DKA who present to the hospital are found to have leukocytosis. Serum sodium in the lab report is falsely low in DKA and can be corrected by adding 1.6 mEq to the measured serum sodium for each 100 mg/dl of glucose above 100 mg/dl. Serum potassium is usually elevated because of a shift of potassium from the intracellular to the extracellular space caused by acidosis and insulin deficiency. However, total body potassium may be depleted or may quickly become depleted with insulin administration. Magnesium is often low and requires repletion as well. The serum phosphate level in DKA may be elevated despite total-body phosphate depletion. [19]  

Other tests like cultures of urine, sputum, and blood, serum lipase, and chest radiograph may need to be performed depending upon the case. Pneumonia and urinary tract infections are the most common infections precipitating DKA. Measurement of glycated hemoglobin (A1C) provides information about glucose trends over months.

In acute DKA, the ketone body ratio (3-beta-hydroxybutyrate:acetoacetate) rises from normal (1:1) to as high as 10:1. In response to insulin therapy, 3-beta-hydroxybutyrate (3-HB) levels commonly decrease long before acetoacetate (AcAc) levels. The frequently employed nitroprusside test only detects acetoacetate in blood and urine. This test provides only a semiquantitative assessment of ketone levels and is associated with false-positive results. Recently, inexpensive quantitative tests of 3-HB levels have become available for common use, and these tests offer options for monitoring and treating diabetes and other states characterized by the abnormal metabolism of ketone bodies. [20]

The serum level of pancreatic enzymes is elevated in DKA due to disorder in carbohydrate metabolism. [21]  In DKA, patients presenting with abdominal pain and elevated pancreatic enzymes should not be diagnosed with acute pancreatitis promptly. [22] In the case of a dilemma, imaging like a CT scan would help in distinguishing mild to moderate elevation of enzymes due to DKA from acute pancreatitis. Lipid derangement is commonly seen in patients with DKA. In one study, before insulin treatment, mean plasma triglyceride and cholesterol levels were 574 mg/dl (range 53 to 2355) and 212 mg/dl (range 118 to 416), respectively. Insulin therapy resulted in rapid decreases in plasma triglyceride levels below 150 mg/dl at 24 hours. Plasma apoprotein (apo) B levels were in the normal upper range (101 mg/dl) before treatment and decreased with therapy due to significant decreases in VLDL, but not IDL or LDL apoB. [23]

An ECG will help detect ischemic changes or signs of hypokalemia or hyperkalemia. Peaked T waves can signal hyperkalemia, and low T waves with U wave indicating hypokalemia.

Imaging: A chest X-ray may be done to rule out consolidation. MRI, and to some degree, CT imaging of the head can detect cerebral edema, but imaging should not delay treatment if cerebral edema is suspected.

• Treatment / Management

Fluid resuscitation and maintenance, insulin therapy, electrolyte replacement, and supportive care are the mainstays of management in diabetic ketoacidosis. 

In patients with DKA, the fluid deficit could be up to 10-15% of the body weight. [1] Immediate fluid resuscitation is vital to correct hypovolemia, restore tissue perfusion, and to clear ketones. Hydration improves glycemic control independent of insulin. 

Choice of Fluids 

Isotonic fluids have been well established for more than 50 years as preferred fluids. Colloids vs. crystalloids were compared for critically ill patients, in a 2013 meta-analysis, and crystalloid was found to be non-inferior. [24] Traditionally, 0.9% normal saline has been used. There has been a concern that normal saline may contribute to hyperchloremia and hyperchloremic metabolic acidosis; however, this typically occurs when it is used for large volumes. There have been small studies comparing normal saline with other solutions like Ringer lactate. These studies did not show differences in clinical outcomes. [25] [26] [27]  Normal saline continues to be used for initial hydration. 

Infusion Rate

Infusion of 15-20 ml per Kg body weight in the first 1 hour is typically appropriate. Aggressive hydration with 1 liter/hour for 4 hours has been compared in a study to a slower rate of hydration at half the rate. Slower hydration was found to be equally effective. [28]  However, in critically ill patients, including those with hypotension, aggressive fluid therapy is preferred. There has been extensive debate regarding the risk of cerebral edema in patients with aggressive early volume resuscitation. There are studies that have demonstrated rates of increased cerebral edema with aggressive volume, particularly in the pediatric population. Yet other studies show no difference in outcome and theorize that patients at greatest risk from cerebral edema present at a later stage and are the most severe volume depleted. [29]

Maintainance:

The subsequent choice for fluid replacement depends on hemodynamics, the state of hydration, serum electrolyte levels, and urinary output. [1]  In patients who have high serum sodium level, 0.45% NaCl infused at 4–14 ml/kg/hour or 250–500 mL/hr is appropriate, and for patients with hyponatremia, 0.9% NaCl at a similar rate is preferred. [30]  Maintenance fluids may need to be adjusted if hyperchloremic metabolic acidosis becomes a concern, then you can switch to the Ringer lactate solution.

Insulin Therapy

The discovery of insulin, along with the antibiotics, has led to a drastic decrease in mortality with DKA, down to 1%. Intravenous insulin by continuous infusion is the standard of care. Previous treatment protocols have recommended the administration of an initial bolus of 0.1 U/kg, followed by the infusion of 0.1 U/kg/h. A more recent prospective randomized trial demonstrated that a bolus is not necessary if patients are given hourly insulin infusion at 0.14 U/kg/hr. [31]  When the plasma glucose reaches 200-250 mg/dl, and if the patient still has an anion gap, then dextrose containing fluids should be initiated, and the insulin infusion rate may need to be reduced. 

Treatment of adult patients who have uncomplicated, mild diabetic ketoacidosis can be treated with subcutaneous insulin lispro hourly in a non-intensive care setting may be safe and cost-effective as opposed to treatment with intravenous regular insulin in the intensive care setting as shown in many studies. [32]  In one of these studies, the patients received subcutaneous insulin lispro at a dose of 0.3 U/kg initially, followed by 0.1 U/kg every hour until blood glucose was less than 250 mg/dl. Then insulin dose was decreased to 0.05 or 0.1 U/kg given every hour until the resolution of DKA. [32]  Similarly, insulin aspart has been used and found to be similar in efficacy. [33]

Patients with DKA should be treated with insulin until resolution. Criteria for resolution of ketoacidosis include blood glucose less than 200 mg/dl and two of the following criteria: a serum bicarbonate level >=more than 15 mEq/l, a venous pH more than 7.3, or a calculated anion gap equal or less than 12 mEq/l. Patients can be transitioned to subcutaneously administered insulin when DKA has resolved, and they are able to eat. Those previously treated with insulin might be recommended on their home dose if they had been well controlled.

Insulin-naive patients should receive a multi-dose insulin regimen beginning at a dose of 0.5 to 0.8 U/kg/day. To prevent the recurrence of ketoacidosis in the transition period, insulin infusion should be continued for 2 hrs after the starting of subcutaneous insulin and check blood sugar and complete metabolic profile again before stopping the insulin drip. If the patient cannot tolerate oral intake, intravenous insulin, and fluids may be continued. The use of long-acting insulin analogs during the initial management of DKA may facilitate the transition from intravenous to subcutaneous insulin therapy. [34]  

Electrolyte Replacement

Patients with DKA are often found to initially have mild to moderate hyperkalemia, despite a total body deficit of potassium. The initiation of insulin causes an intracellular shift of potassium and lowers the potassium concentration, potentially resulting in severe hypokalemia. [35] [36] Hence patients with serum potassium levels of less than 3.3 mmol/L need initial management with fluid resuscitation and potassium replacement while delaying commencement of insulin until after potassium levels are above 3.3 mmol/L, to avoid cardiac arrhythmias, arrest, and respiratory muscle weakness. [34]  In other patients, potassium replacement should be started when the serum concentration is less than 5.2 mEq/L to maintain a level of 4 to 5 mEq/L. The administration of 20 to 30 mEq of potassium per liter of fluids is sufficient for most patients; however, lower doses are required for patients with acute or chronic renal failure. [37]  

Hypokalemia is commonly associated with hypomagnesemia. Repletion of both potassium and magnesium may need to be done, and it may be difficult to improve potassium levels until magnesium levels are repleted.

Bicarbonate

Bicarbonate replacement does not appear to be beneficial. In one study, the difference in time to resolution of acidosis (8 hours vs. 8 hours; p = 0.7) and time to hospital discharge (68 hours vs. 61 hours; p = 0.3) was found to be statistically insignificant between patients who received intravenous bicarbonate (n = 44) compared with those who did not (n = 42). [38]  In another pediatric study, children with diabetic ketoacidosis who have low PaCO2 and high BUN concentrations at presentation and those treated with bicarbonate were at increased risk for cerebral edema. [39]  Proposed pitfalls of the use of sodium bicarbonate therapy in DKA may include paradoxical CSF acidosis, hypokalemia, large sodium bolus, and cerebral edema. However, it may be used in patients with severe acidemia. The most recent ADA guidelines do recommend the use of sodium bicarbonate therapy in patients with pH less than 7.1. [38]

The role of phosphate replacement in DKA has been looked at in different studies. In one randomized study with 44 patients, phosphate therapy did not alter the duration of DKA, insulin dosage required to correct the acidosis, abnormal muscle enzyme levels, glucose disappearance, or morbidity and mortality. Although theoretically appealing, phosphate therapy is not an essential part of the treatment for DKA in most patients, an unusual case of severe hypophosphatemia (1.0 mg/dl) related seizure in a child with diabetic ketoacidosis (DKA) has been described in the literature. [40]

Laboratory Monitoring

• Hourly point-of-care testing (POCT) glucose should be performed
• Serum glucose and electrolyte levels may need to be done every 2 hours until the patient is stable, then every 4 hours
• Initial blood urea nitrogen (BUN)
• Initial VBG or ABG monitoring, followed by as-needed precipitating events

There are multiple risks associated with intubation in patients with DKA. Intubation should be avoided if at all possible. Treating as above with a focus on administering fluids and insulin will almost always lead to an improvement in acidosis and overall clinical presentation. Patients attempt to compensate for severe acidosis by creating a compensatory respiratory alkalosis that manifests via tachypnea and Kussmaul breathing. If patients are no longer able to generate respiratory alkalosis due to comatose state or severe fatigue, intubation should be considered. However, the risks of intubation in DKA include a rise in PaCO2 during sedation and/or paralysis, which can decrease pH further, increasing the risk of aspiration due to gastroparesis, and difficulty matching the degree of respiratory compensation once the patient is on a ventilator. If a patient is intubated and placed on a ventilator, it is essential to attempt to match the patient's minute ventilation such that respiratory alkalosis is created to compensate for the metabolic acidosis of DKA. If not, there will be worsening acidosis, which can ultimately lead to cardiac arrest. It is reasonable to start with a tidal volume of 8 ml/kg based on ideal body weight and respiratory rate, similar to the patient's compensating respiratory rate. However, care should be taken that auto-PEEP is not occurring due to the rapid respiratory rate. [41]

Cerebral Edema

Mental status and neurologic exam should be monitored in all patients with DKA. In any patient who is severely obtunded or comatose or who has declining mental status despite treatment or focal neurologic deficits, there should be a very low threshold to treat for cerebral edema. Mannitol is typically the first-line agent, though there are also studies in both TBI literature and DKA literature regarding the use of 3% saline. 

Precipitating Events

Infection is a very common trigger for DKA in patients who have new-onset diabetes and previously established diabetes. If there is any suspicion of infection, antibiotics should be administered promptly. As discussed, there can be other events that trigger DKA as well. Treating both DKA and any other underlying etiologies should be done.

• Differential Diagnosis

Diabetic ketoacidosis has a diverse presentation, and this is why several other common pathologies may mimic this diagnosis. It is imperative for the providers to consider the following differential diagnoses when the diagnosis of DKA is suspected:

• Hyperosmolar hyperglycemic nonketotic syndrome
• Starvation ketosis
• Myocardial infarction
• Pancreatitis
• Alcoholic ketoacidosis
• Lactic acidosis
• Sepsis 
• Toxicologic exposure (ethylene glycol, methanol, paraldehyde, salicylate)
• Diabetic medication overdose

Diabetic ketoacidosis still carries a mortality rate of 0.2 to 2.5% in developing countries. Patients who present in a comatose state, hypothermia, and oliguria tend to have the worst outcomes. For most patients treated promptly, the outcomes are good, especially if the trigger is not an infection. Elderly patients with concurrent illnesses such as myocardial infarction, pneumonia, or sepsis tend to have long hospital stays and high mortality.

The most important cause of mortality is cerebral edema, usually seen in younger patients. The cerebral edema is primarily due to the intracellular shifts. Another important cause of morbidity is renal dysfunction. A recent study has noted that among patients with type-2 diabetes mellitus who develop DKA, there is a high risk of stroke within the first six months after the event.

• Complications

Hypoglycemia is the most common complication of diabetic ketoacidosis while being treated, occurring in an estimated 5–25% of patients with DKA. [37]  Acute adverse outcomes of hypoglycemia include seizures, arrhythmias, and cardiovascular events. Hourly blood sugar monitoring is needed in the acute phase of treatment. 

Hypokalemia is common. Severe hypokalemia can cause muscle weakness, cardiac arrhythmias, and cardiac arrest. [8]  Monitoring and management are described in this article under the DKA management section in detail. Other possible electrolyte disturbances are hyperchloremia, which can occur in up to 1/3rd of patients, and hypomagnesemia, and hyponatremia. [42]

Cerebral edema is less common in adults than in children. Risk factors include younger age, new-onset diabetes, longer duration of symptoms, the lower partial pressure of carbon dioxide, severe acidosis, low initial bicarbonate level, low sodium level, high glucose level at presentation, rapid hydration, and retained fluid in the stomach. [39]

Rhabdomyolysis may occur in patients with DKA though it occurs more commonly with HHS. It may result in acute kidney failure. Severe hypophosphatemia in relation to DKA can also cause rhabdomyolysis. [43]

Acute respiratory failure could be associated with DKA. Causes could be pneumonia, ARDS, or pulmonary edema. Two varieties of pulmonary edema in DKA have been recognized, secondary to elevated pulmonary venous pressure, and because of increased pulmonary capillary permeability. [44]

TTP and myocarditis have also been described with DKA.

• Deterrence and Patient Education

Education on the disease process of diabetes, including short and long term complications, should be given to all patients. Patients should be taught how and when to check their glucose. Patients should receive education about how to use oral hypoglycemic meds and/or insulin, their side effects, and the importance of compliance. Dietitians, nurses, and multi-disciplinary home health can be important members of the team in assisting with this education.

• Enhancing Healthcare Team Outcomes

Diabetic ketoacidosis is a life-threatening complication of diabetes, and any delay in treatment can lead to death. The disorder can present with varied signs and symptoms and affects many organs; thus, it is best managed by an interprofessional team dedicated to the management of patients with diabetes mellitus. The majority of patients first present to the emergency department, and it is here that the treatment usually starts.

The triage nurse has to be familiar with the signs and symptoms of DKA and immediately admit the patient and notify the emergency department physician. While the patient is being resuscitated, placed on a monitor, and having blood drawn, the intensivist and an endocrinologist should be consulted.

Immediate blood work is necessary to determine the state of ketoacidosis, and imaging may be necessary to rule out pneumonia. If the mental status is altered, a CT scan may be required, and thus the radiologist must be notified about the patient's hemodynamic status. No patient with DKA should go unmonitored to a radiology suite.

The infectious disease expert and cardiologist should be consulted if there is suspicion of infection or MI as the trigger.

The pharmacist and nurses should determine if the patient was compliant with insulin treatment. Following discharge, the social workers should be involved in the care since recurrent DKA admissions are common, especially in inner-city hospitals. Socioeconomic status, education status, access to insulin, the presence of health care coverage, and the presence of mental illness, etc. play a big role in these patients.

An interprofessional team, including social workers, are often needed to address these particular situations. Meticulous discharge planning, involving social workers for patients with socioeconomic needs, and hospital initiated follow up clinics for discharged patients are some of the factors important to reduce the recurrences of DKA in the same individual. Finally, patient education is highly recommended, as in many cases, the cause of DKA is failing to comply with treatment.

In developed countries, the morbidity and mortality rates are low chiefly because of a streamlined interprofessional approach to the management of these patients. However, in developing countries, mortality rates of 0.3 to 2.5% are still reported. The major cause of death in most young patients is cerebral edema.

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Disclosure: Jenna Lizzo declares no relevant financial relationships with ineligible companies.

Disclosure: Amandeep Goyal declares no relevant financial relationships with ineligible companies.

Disclosure: Vikas Gupta declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Lizzo JM, Goyal A, Gupta V. Adult Diabetic Ketoacidosis. [Updated 2023 Jul 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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• Published: 14 May 2020

Diabetic ketoacidosis

• Ketan K. Dhatariya 1 , 2 ,
• Nicole S. Glaser 3 ,
• Ethel Codner 4 &
• Guillermo E. Umpierrez 5  

Nature Reviews Disease Primers volume  6 , Article number:  40 ( 2020 ) Cite this article

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• Diabetes complications
• Endocrine system and metabolic diseases
• Glycobiology

Diabetic ketoacidosis (DKA) is the most common acute hyperglycaemic emergency in people with diabetes mellitus. A diagnosis of DKA is confirmed when all of the three criteria are present — ‘D’, either elevated blood glucose levels or a family history of diabetes mellitus; ‘K’, the presence of high urinary or blood ketoacids; and ‘A’, a high anion gap metabolic acidosis. Early diagnosis and management are paramount to improve patient outcomes. The mainstays of treatment include restoration of circulating volume, insulin therapy, electrolyte replacement and treatment of any underlying precipitating event. Without optimal treatment, DKA remains a condition with appreciable, although largely preventable, morbidity and mortality. In this Primer, we discuss the epidemiology, pathogenesis, risk factors and diagnosis of DKA and provide practical recommendations for the management of DKA in adults and children.

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Elsie Bertram Diabetes Centre, Norfolk and Norwich University Hospitals NHS Foundation Trust, Colney Lane, Norwich, Norfolk, UK

Ketan K. Dhatariya

Norwich Medical School, University of East Anglia, Norfolk, UK

Department of Pediatrics, University of California Davis, School of Medicine, Sacramento, CA, USA

Nicole S. Glaser

Institute of Maternal and Child Research, School of Medicine, University of Chile, Santiago, Chile

Ethel Codner

Diabetes & Endocrinology, Emory University School of Medicine, Atlanta, GA, USA

Guillermo E. Umpierrez

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Contributions

Introduction (G.E.U., N.S.G., K.K.D., E.C.); Epidemiology (G.E.U., N.S.G., K.K.D., E.C.); Mechanisms/pathophysiology (G.E.U., N.S.G., K.K.D., E.C.); Diagnosis, screening and prevention (G.E.U., N.S.G., K.K.D., E.C.); Management (G.E.U., N.S.G., K.K.D., E.C.); Quality of life (N.S.G.); Outlook (N.S.G, E.C.); Overview of Primer (G.E.U.). All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole and have given their approval for this version to be published.

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K.K.D. is an employee of the UK National Health Service. N.S.G. has grants from American Diabetes Association (ADA, 1-17-IBS-186) and from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, U34DK123894). E.C. is partly funded by Fondo Nacional de Ciencia y Tecnología (FONDECYT) grant no. 1170895 from the Government of Chile. G.E.U. is partly supported by research grants from the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) under Award Number UL1TR002378 from the Clinical and Translational Science Award program and an NIH grant U30, P30DK11102, and has received research grant support to Emory University for investigator-initiated studies from Dexcom, Novo Nordisk and Sanofi.

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A reduction in intravascular and/or extracellular fluid volume, such that there may be an inability to adequately perfuse tissue.

Also known as the BMI standard deviation score. The z-score is a measure of a child’s relative weight adjusted for age and gender.

The negative base-10 logarithm of the acid dissociation constant (Ka) of a solution. The lower the pKa, the stronger the acid.

The ability of molecules in the circulation to stabilize the acid–base balance in an attempt to maintain the pH.

An estimate of how much blood passes through the renal glomeruli every minute, which is often calculated from serum creatinine levels, age, sex and body weight.

The loss of kidney function as a result of poor renal or glomerular perfusion, for example, due to haemorrhage, cardiac failure or hypovolaemia.

A state in which the circulating extracellular fluid has a higher osmotic pressure than the pressure that would be observed in a healthy individual.

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Dhatariya, K.K., Glaser, N.S., Codner, E. et al. Diabetic ketoacidosis. Nat Rev Dis Primers 6 , 40 (2020). https://doi.org/10.1038/s41572-020-0165-1

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This article has a correction. Please see:

• Diabetic ketoacidosis in adults - November 02, 2015
• Shivani Misra , clinical research fellow and specialist trainee year 6 in metabolic medicine 1 2 ,
• Nick S Oliver , consulant diabetologist and reader in diabetes 1 3
• 1 Department of Diabetes, Endocrinology & Metabolism, Imperial College, London W2 1PG, UK
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What you should know

Diabetic ketoacidosis (DKA) is a common, serious, and preventable complication of type 1 diabetes, with a mortality of 3-5%. It can also occur in patients with other types of diabetes

It can be the first presentation of diabetes. This accounts for about 6% of cases

The diagnosis is not always apparent and should be considered in anyone with diabetes who is unwell

Diagnosis is based on biochemical criteria. However, hyperglycaemia may not always be present and low blood ketone levels (<3 mmol/L) do not always exclude DKA

Immediate treatment consists of intravenous fluids, insulin, and potassium, with careful monitoring of blood glucose and potassium levels to avoid hypoglycaemia and hypokalaemia

Knowledge of the type of diabetes at the time of DKA does not affect immediate treatment, and all patients with DKA should be advised to continue with insulin on discharge

Subsequent management should focus on patient education and support to avoid recurrence

Patients should be managed by a specialist multidisciplinary team during and after an episode of DKA

What is DKA?

Diabetic ketoacidosis (DKA) is an extreme metabolic state caused by insulin deficiency. The breakdown of fatty acids (lipolysis) produces ketone bodies (ketogenesis), which are acidic. Acidosis occurs when ketone levels exceed the body’s buffering capacity (figure ⇓ ). 1 2

Diabetic ketoacidosis may follow absolute insulin deficiency or relative insulin deficiency. Relative insulin deficiency may occur in the presence of increased levels of counter-regulatory hormones such as glucagon, cortisol, and catecholamines. Insulin deficiency results in lipolysis and ketogenesis. Ketone bodies are acidic and may initially be buffered, but when levels are high enough, will result in acidosis

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How common is DKA?

Data from the UK National Diabetes audit shows a crude one year incidence of 3.6% among people with type 1 diabetes. 3 In the UK nearly 4% of people with type 1 diabetes experience DKA each year, 3 the number of DKA episodes per 100 patient years is 4.8, 4 about 6% of cases of DKA occur in adults newly presenting with type 1 diabetes, 5 and about 8% of episodes occur in hospital patients who did not primarily present with DKA. 6

How does DKA present?

DKA usually develops quickly, within 24 hours. Typically, patients develop polyuria and polydipsia along with vomiting, dehydration, and, if severe, an altered mental state, including coma (box 1). Signs of the underlying cause may also be present—for example, infection. 7 Abdominal pain is a common feature of DKA and may be part of the acute episode or, less often, represent an underlying cause. DKA should be considered in any unwell patient with diabetes (type 1 or type 2).

Box 1 Signs and symptoms of diabetic ketoacidosis 7

Weight loss

Nausea and vomiting

Weakness and lethargy

Altered mental state

Kussmaul respiration (a characteristic deep hyperventilation)

Acetone on breath (smell of pear drops)

Box 2 What precipitates DKA? 5 7 8

There may be no obvious precipitant, 8 for example, in ketosis-prone diabetes (an atypical form of type 2 diabetes), in which DKA is the presenting condition but insulin can later be discontinued.

Discontinuation of insulin, whether unintentional or deliberate. A variety of factors may contribute to deliberate insulin omission: fear of weight gain or hypoglycaemia, financial barriers, and psychological factors, such as a needle phobia and stress

Inadequate insulin

Cardiovascular disease: for example, stroke or myocardial infarction

Drug treatments: steroids, thiazides, sodium-glucose cotransporter-2 inhibitors

Consider the diagnosis in any unwell patient with diabetes

How is DKA diagnosed?

DKA is usually diagnosed in the presence of hyperglycaemia, acidosis, and ketosis. However, hyperglycaemia may not be present (euglycaemic ketoacidosis), and low levels of blood ketones (<3 mmol/L) may not always exclude a diagnosis. Clinical judgment therefore remains crucial.

Guidelines differ on the exact biochemical thresholds for diagnosis (table 1 ⇓ ).

Guidelines for diagnosis of diabetic ketoacidosis (DKA) in adults

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The Joint British Diabetes Societies 9 10 recommend a glucose cut-off of >11 mmol/L. The higher cut-off recommended by the American Diabetes Association (>13.9 mmol/L) 7 may fail to identify euglycaemic ketoacidosis.

Internationally there is little consensus on how ketones should be assessed, the cut-off used, or whether ketones have a role in monitoring for resolution of DKA 11 (table 2 ⇓ ). 12 13

Characteristics of different methods for ketone testing 12

The evidence in favour of a specific DKA diagnostic threshold using 3-hydroxybutyrate is also difficult to evaluate. The more recent observational studies 14 15 16 show a variation in 3-hydroxybutyrate levels that mean using a cut-off of 3 mmol/L risks missing patients with lower levels. 12 Taken together these data mean that a ketone value of less than 3 mmol/L may not always exclude the diagnosis of DKA. Other variables and clinical judgment should be taken into consideration.

What is the main approach to management?

The mainstay of treatment is carefully monitored delivery of intravenous fluids and insulin. Fluids correct hyperglycaemia, dehydration, and electrolyte imbalances such as hypokalaemia. Insulin reduces glucose levels and suppresses ketogenesis. This approach coupled with the treatment of the precipitating cause and appropriate patient education before discharge should in most cases result in good outcomes.

Intravenous fluids

The initial fluid of choice in most guidance is 0.9% saline, despite hypotonic fluid losses, as it restores intravascular volume while preventing a rapid change in extracellular osmolality. 1 Subsequent fluid administration depends on the patient’s haemodynamic status and which guideline is being followed, with the American Diabetes Association recommending 0.45% saline if the sodium level is normal or high 7 and the Joint British Diabetes Societies 9 recommending continued use of 0.9% saline. The randomised trial evidence to guide fluid choice is limited. 17 18 The risk of hyperchloraemic metabolic acidosis from continued use of 0.9% saline 19 has prompted the use of isotonic electrolyte solutions in some studies. 18 20

Potassium supplementation

Hypokalaemia is a major and potentially fatal complication of DKA. All guidelines recommend potassium replacement after the first litre of fluid (or in the first litre if hypokalaemia is present). The Joint British Diabetes Societies recommend potassium monitoring at one hour and two hours after admission and every two hours thereafter.

Bicarbonate

Bicarbonate is not routinely recommended. 21 22 It should be considered only under specialist supervision in patients with severe acidosis (pH <7) in whom the effects of acidaemia on myocardial contractility and cardiac output may be life threatening. 7 9 Even in these patients the benefits are unclear. 23 Harmful effects may include exacerbation of existing hypokalaemia. They may also include a late metabolic alkalosis, with a shift of the oxygen dissociation curve towards the left, making tissue anoxia more likely. 1 23

What dose of insulin?

Both the Joint British Diabetes Societies and American Diabetes Association recommend a weight based rate of delivery of 0.1 units/kg/h. An initial bolus dose of insulin is not advised, based on a randomised controlled trial that found no benefit. 24

A steady delivery of low dose insulin adequately suppresses lipolysis (and thus ketogenesis). With concomitant intravenous fluids, glucose levels may normalise rapidly. However, ketoacidosis corrects more slowly: on average it takes six hours of treatment before glucose decreases to less than 14 mmol/L, compared with 12 hours before ketoacidosis is corrected. 7 25 Adequate insulin should therefore continue beyond the resolution of hyperglycaemia to ensure the eradication of ketones. This has led to the shift away from a “sliding scale” that titrates insulin against glucose levels, to fixed rate intravenous insulin infusion.

How should patients be monitored?

Some of the major complications of DKA are related to its treatment (box 3). Blood glucose and potassium levels must be closely monitored and patients must have regular review, as too much insulin results in hypoglycaemia and hypokalaemia whereas not enough may fail to adequately suppress ketogenesis.

The Joint British Diabetes Societies recommend high levels of care and central venous access for those with severe DKA: people with severe metabolic derangement (pH <7.1, bicarbonate <5 mmol/L, blood ketones >6 mmol/L or hypokalaemia on admission (K+ <3.5 mmol/L)), a reduced Glasgow coma score, or haemodynamic instability. However, the guidelines are not prescriptive and people at extremes of age or with comorbidities may also require higher levels of care.

There is no substitute for careful monitoring and responding to the patient as treatment progresses.

Box 3 Complications of diabetic ketoacidosis in adults 7

Thromboembolism (DKA is a prothrombotic state)

Arrhthymias and cardiac arrest (secondary to hyperkalaemia at presentation)

Iatrogenic: hypokalaemia, hypoglycaemia, 5 26 cerebral oedema (rare in adults) 27

Mortality from DKA has improved considerably, but still persists at between 3% and 5%. 27 28 Death is most often associated with the precipitating illness (for example, cardiovascular disease or infection) and rates are worse with increasing age. 27

When should patients transition from intravenous to subcutaneous insulin?

Patients should move to subcutaneous insulin once DKA has resolved. There is no consensus on what marks the biochemical endpoint of DKA (table 1), so transition to subcutaneous insulin is advised when patients are eating and drinking. If patients are not eating and drinking but ketones are suppressed, a variable rate intravenous insulin infusion can be considered until oral intake is resumed. Crucially in such cases, there should be overlap between intravenous and subcutaneous insulin in order to prevent any period of insulin deficiency that risks recurrent ketogenesis. UK guidance recommends continuation of intravenous insulin for at least 30-60 minutes after the initiation of subcutaneous long acting insulin. In people with established type 1 diabetes, there is some evidence that continuing subcutaneous long acting insulin throughout the admission prevents rebound hyperglycaemia, 29 and local practice may vary. Transition to subcutaneous insulin is best supported by members of the specialist diabetes team in line with national guidance.

How can DKA be prevented?

Patients with established type 1 diabetes should be given as much information as possible about risk factors for DKA and how to monitor their own glucose and ketone levels. Discussions from the accompanying TweetChat (box 4) show the need for better education, as many participants were unaware of the importance of ketone testing or the difference between ketosis and ketoacidosis.

Structured educational programmes provide advice on how to avoid omitting insulin; sick day rules, including increasing insulin doses if unwell; and when to test ketones. 30 They have been shown to reduce rates of DKA. 31 However, such programmes are not universally offered, and uptake can be poor. 32

Patients should be advised to measure their ketone levels if they are unwell as this may identify incipient ketosis, which can be dealt with by increasing insulin doses. They should be encouraged to seek medical attention if levels are increased.

Testing ketones in capillary blood has not been shown to be better for preventing DKA than urine testing. 33 People with recurrent DKA may have underlying precipitants, and psychological support may be helpful.

Drugs such as sodium-glucose cotransporter-2 inhibitors should be used with caution in people at high risk of DKA, although these associations are still being elucidated.

Box 4 Patients perspectives on DKA, from TweetChat

“No one has ever explained it. I’ve educated myself but no idea when to go into hosp . . .”

“Considering it’s such a major diabetic issue, it’s shocking and scary how many people don’t know what DKA actually is . . .”

“When I was diagnosed, I was in what is termed a semi-coma for three days. It was totally missed by my GP that I had T1 . . .”

“It’s horrible and still fills me with panic that I was so very close to death, GP misdiagnosed three times!”

“When I was diagnosed, impact on mental health was never considered”

“Yep was drifting in and out of a coma. Now I panic when I get high sugars, would rather hypo any day”

Issues for healthcare professionals to consider, from structured and unstructured discussions between patient contributors:

DKA is a frightening experience. Consider the need to address patients’ fears and concerns during recovery

Take care in your initial interactions with patients with DKA. Focusing on an intravenous infusion rather than the person may impact on that person’s future self management

Consider your behaviour and language when talking to someone with a new diagnosis of type 1 diabetes. Ensuring the patient gets positive messages about type 1 diabetes is critical, as is ensuring access to support

Provide advice about how to access further educational resources, including the importance of structured educational programmes

Ensure that the episode of DKA is not viewed as a failure of self care, and that a personalised care plan is in place to prevent further episodes.

How patients were involved in the creation of this article

We obtained patient perspectives on DKA through a live TweetChat on 15 July 2015. This was arranged and advertised by the Great Britain Diabetes Online Community (#GBDOC, www.gbdoc.co.uk ), which undertakes a weekly TweetChat on issues relevant to people with diabetes (box 4). We also incorporated opinions from selected patient contributors who had experienced DKA. These discussions led to the inclusion of a new section on issues for health professionals to consider.

Questions for future research

Could a lower dose of insulin result in an adequate outcome without risking hypoglycaemia and hypokalaemia?

Are there different metabolic outcomes between fixed rate and variable rate infusions of insulin?

Should there be a composite endpoint for diabetic ketoacidosis (DKA) that takes into account resolution of acidosis without hypoglycaemia and hypokalaemia?

How can education about DKA be optimised in accessible structured educational programmes?

What is the best level of care for people admitted with DKA?

Is fear of DKA a barrier to optimal self management of type 1 diabetes?

Additional educational resources

Information for healthcare professionals.

Joint British Diabetes Societies Inpatient Care Group. The management of diabetic ketoacidosis in adults ( www.diabetes.org.uk/Documents/About%20Us/What%20we%20say/Management-of-DKA-241013.pdf )—UK guidelines on how to manage and treat diabetic ketoacidosis (DKA)

American Diabetes Association. Hyperglycemic crises in adult patients with diabetes ( http://care.diabetesjournals.org/content/32/7/1335.short ) —American guidelines on how to manage and treat diabetic ketoacidosis (DKA)

Information for patients

Diabetes Research & Wellness Foundation ( www.drwf.org.uk/ ) —peer support and educational resources for people with diabetes

Diabetes.co.uk the global diabetes community ( www.diabetes.co.uk )—peer support and educational resources for people with diabetes

Diabetes UK ( www.diabetes.org.uk/ )—peer support and educational resources for people with diabetes

Dose adjustment for normal eating ( www.dafne.uk.com/ )—advice on structured education about type 1 diabetes and prevention of DKA

GBDOC. TweetChat this week! ( http://gbdoc.co.uk/ )—forum for people to chat and discuss diabetes with other people who have diabetes

Cite this as: BMJ 2015;351:h5660

Related links

Read more diabetes articles online at bmj.co/diabetes

Contributors: SM and NSO contributed to this article through conception, research, writing, development, and editing. NSO is the guarantor.

Funding: SM is a clinical research fellow funded by the Diabetes Research & Wellness Foundation Sutherland-Earl Clinical Research Fellowship.

Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following: SM has received educational funding to support attendance at diabetes conferences during her training, from Lilly Diabetes, Abbott Diabetes Care, and Animas, applied for through the Young Diabetologists and Endocrinologists forum and structured educational support streams. NSO has received honorariums from Abbott Diabetes and Roche for participation in advisory boards to discuss future insulin pump, continuous glucose monitoring, and artificial pancreas technologies. These technologies are not included in the scope of this manuscript.

Provenance and peer review: Commissioned; externally peer reviewed.

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Diabetic Ketoacidosis: A Review and Update

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Diabetic ketoacidosis (DKA) remains a significant complication of diabetes in both the United States and around the world. Diabetic ketoacidosis remains a significant complication of diabetes in both the United States and worldwide with its associated high rates of hospital admissions. Therefore, it becomes vital that the healthcare professional be able to manage the hyperglycemic crises associated with diabetes. Moreover, with increasing healthcare costs and a changing healthcare system, prevention of diabetic ketoacidosis remains essential. Though management of diabetic ketoacidosis has followed a set algorithm for many years, there are exciting management alternatives on the horizon such as subcutaneous insulin administration for uncomplicated DKA patients. By understanding DKA, including its pathogenesis, presentation, treatment, and prevention, admissions may be decreased and length of stay shortened.

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Introduction

There are two major hyperglycemic crises associated with diabetes: diabetic ketoacidosis and the hyperosmotic hyperglycemic state. There are ~120,000 admissions for diabetic ketoacidosis and hyperglycemic hyperosmolar state per year in the United States alone [ 1 ]. Diabetic ketoacidosis primarily results from insulin deficiency and hyperglycemic hyperosmolar state (HHS) from severe insulin resistance. Both of the crises result in subsequent glucagon and counter-regulatory hormone excess from lack of suppression from insulin [ 2 •]. Normally, with elevated blood glucose, as occurs after a digested meal, there is production and release of insulin by the beta cells in the islets of Langerhans. With this surge of insulin, the production of new glucose is suppressed appropriately. Conversely, in a state of starvation, there is an increase in counter regulatory hormones such as glucagon in which stores are appropriately mobilized and glucose production increased. This is a catabolic state, which allows for sustenance in times when nutrition is not available [ 3 , 4 ].

• Pathogenesis

In diabetic ketoacidosis (DKA), the balance between catabolism and anabolism is, in a sense, broken. With the lack of insulin, there is decreased storage of glucose, increased breakdown of glycogen stores, and increased synthesis of glucose in both the liver and kidney. To add to the overall hyperglycemic state, there is also a concomitant decreased utilization of glucose in peripheral tissues [ 2 •, 3 ]. The situation is complicated by the fact that in this more catabolic state there is breakdown of proteins to form new amino acids that in turn are used to build glucose [ 2 •, 3 ]. Moreover, the risk of DKA increases with any increased stress state. In a so-called “stressed state,” there is a relative abundance of epinephrine and cortisol. Epinephrine acts to block the action of insulin and stimulates the release of glucagon. Growth hormone also has a similar role as epinephrine and cortisol. In a stressed state, such as infection, myocardial infarction, intoxication, pregnancy, or stroke there is an increased demand for insulin, but a diminished supply by the stress put on the pancreas [ 1 , 5 ].

While elevated blood glucose from the increased glycogenolysis and gluconeogenesis is certainly a major problem, the cornerstone of DKA lies in ketogenesis. Insulin is normally the most important regulator in production and utilization of ketones. Insulin will inhibit lipolysis and oxidation of free fatty acids. Insulin also increases oxidation of ketones in the peripheral tissues [ 6 ]. Thus there is both overproduction and underutilization of ketones in an insulin-deficient state [ 6 ]. Also, glucagon itself will stimulate hormone-sensitive lipase, which in turn mobilizes adipose stores and converts triglycerides to free fatty acids [ 2 •]. These free fatty acids are then transported across the mitochondrial membrane, and they are eventually used for synthesis of ketones, namely in the form of acetoacetic acid, which is oxidized to form betahydroxybutyrate or decarboxylated to form acetone. Unfortunately, with ketone overproduction, peripheral tissues cannot utilize these molecules and ketosis predominates [ 7 ]. Conversely, in HHS there is usually enough insulin to suppress ketogenesis, but not control blood sugars [ 8 ]. In HHNK, blood sugars are usually higher as ketoacidosis produces more severe symptoms and presentation is usually earlier.

Symptoms of ketosis include nausea, vomiting, abdominal pain, and respiratory insufficiency. Increased ketone production results in the attempt for the body to buffer with bicarbonate. Because of this buffering, there is an increase in unmeasured anions that cause a gapped metabolic acidosis. Vomiting may induce a hidden alkalosis. Furthermore, with the pre-renal azotemia that ensues, there is retention of other acids besides ketoacids [ 6 ].

Many of the remaining problems with DKA are from the resultant osmotic diuresis. Elevated blood glucose shifts water into the extracellular compartment. However, the expansion of the extra-cellular compartment is short lived as the ability to reabsorb glucose at the level of the renal tubule is limited and osmotic diuresis occurs. Thus, glycosuria and polyuria result. Water losses are typically greater than electrolyte losses, and thus there is an increased serum osmolality [ 6 ]. Polydipsia results from the hyperosmolarity after osmoreceptors are triggered in the brain. Many of the other symptoms may result from the pro-inflammatory state of DKA, and elevated cytokines have been documented during diabetic ketoacidosis [ 9 ]. Sodium tends to be low secondary to the fact that glucose is osmotically active and will draw fluids into the extracellular space. Potassium is variable based on the degree of acidosis and the time of presentation of the DKA.

Management of Adult Patients with Diabetic Ketoacidosis

Initial evaluation.

DKA usually occurs quickly, over hours to days. Patients may have symptoms of hyperglycemia, including polyuria, polydipsia, polyphagia, and weight loss. The more acute symptoms include abdominal pain, vomiting, dehydration, weakness, altered mentation, and coma. Abdominal pain must be worked up carefully, as an abdominal process may have precipitated the ketoacidosis state. Findings on examination include increased skin turgor, Kussmaul respirations, tachycardia, hypotension, altered mentation, and coma [ 10 ]. Hypothermia may also be present. In a hypothermic patient normal body temperatures may signal an infection [ 11 ].

Though the majority of patients presenting with DKA are type 1 diabetics, ketosis-prone type 2 diabetics have been described. These patients may represent 20 % of DKA patients. They are typically middle-aged obese persons of varying ethnic backgrounds. After the acute hospitalization, these patients are usually able to discontinue insulin therapy for months to years, and may be treated with oral diabetic medications [ 12 ]. The most common metabolic abnormalities in DKA are summarized in Table  1 .

Identification of co-morbid inciting events including infection, cerebrovascular accident, alcohol abuse, pancreatitis, myocardial infarction, trauma, new onset diabetes, hyperthyroid state, medications, and insulin noncompliance is paramount to successful management [ 13 , 14 , 15 •]. Initial laboratory evaluation should include serum glucose, electrolytes with calculated anion gap, plasma osmolality, BUN, creatinine, urinalysis (serum ketones if urine ketones positive), CBC with differential, ABG if serum bicarbonate is substantially reduced, and EKG. Supplemental testing including chest X-ray, cultures, and HgA1C is performed as indicated [ 13 ]. Successful management and therapeutic goals include strict monitoring of clinical and laboratory parameters with correction of hyperglycemia, electrolyte imbalances, improving circulatory volume and tissue perfusion; identifying and treating precipitating events irrespective of the type of diabetes is also paramount to successful care [ 16 – 18 ]. The optimal care site (intensive care unit, step-down unit or medical ward) has not been substantiated in randomized prospective studies for the treatment of DKA. Consequently, patients are triaged based on known prognostic indicators, clinical status, availability of resources and institutional policy [ 18 ]. The development of written therapeutic guidelines and interdisciplinary collaboration has standardized care and led to better outcomes [ 19 , 20 ] (Fig.  1 ). With a systematic approach to treatment clinical stability is typically achieved within 12–36 h [ 1 ].

Protocol for the management of adult patients with DKA. Copyright 2006 American Diabetes Association, From Kitabchi et al. [ 20 ], Reprinted by permission of The American Diabetes Association . *DKA diagnostic criteria: serum glucose >250 mg/dl, arterial pH <7.3, serum bicarbonate <18 mEq/l, and moderate ketonuria or ketonemia. Normal laborarory values vary; check local lab normal ranges for all electrolytes. † After history and physical exam, obtain capillary glucose and serum or urine ketones (nitroprusside method). Begin 1 liter of 0.9 % NaCl over 1 h and draw arterial blood gases, complete blood count with differential, urinalysis, serum glucose, blood urea nitrogen (BUN), electrolytes, chemistry profile, and creatinine levels STAT. Obtain electrocardiogram, chest X-ray, and specimens for bacterial cultures, as needed. ‡ Serum Na + should be corrected for hyperglycemia (for each 100 mg/dl glucose >100 mg/dl, add 1.6 mEq to sodium value for corrected serum sodium value). Adapted from Reference [ 1 ]

Other causes of an anion gap acidosis should be kept in mind when reviewing blood work, particularly if ketones are not elevated in a hyperglycemic patient. Lactic acidosis may be present either alone or with diabetic ketoacidosis and signals poor tissue oxygenation. Starvation ketosis results from poor carbohydrate availability. In starvation ketosis, the anion gap will be mildly elevated. Ketones may be present in the urine but rarely in the blood. In long-standing alcoholics, alcoholic ketoacidosis should be considered. Acidosis may also occur from ingested toxins including salicylates, methanol, and ethylene glycol [ 10 ].

Blood monitoring should occur every 2–4 h, including serum electrolytes, renal function, CO2 content and pH [ 1 , 13 , 18 ]. Venous pH monitoring demonstrates a 0.03 unit level of agreement with arterial values and may be an acceptable surrogate for arterial measurements and may reduce the intensity of arterial sampling [ 21 ]. Serum glucose should be monitored more closely on an hourly basis until blood glucose reaches 250 mg/dL and the clinical condition stabilizes wherefrom glucose levels may be checked every 1–2 h [ 18 , 22 ]. The serum bicarbonate trend and anion gap are valuable indices of therapeutic response [ 1 , 13 ]. Ketonemia may persist despite clearing of hyperglycemia [ 16 ] therefore closure of the anion gap is a better monitoring parameter [ 13 ].

Volume Status/Fluid Replacement

Aggressive rehydration and amelioration of the hyperosmolar state may enhance the effect of low-dose insulin therapy. Initial fluid resuscitation goals include expansion of the intravascular, interstitial and intracellular volume and restoration of renal perfusion [ 13 , 15 •, 18 , 23 , 24 ]. To adequately assess the severity of sodium and water deficit, the serum sodium is corrected by adding 1.6 mg/dL to the measured serum sodium for each 100 mg/dL of glucose above 100 mg/dL [ 15 •, 18 ]. The use of normal saline (0.9 %) pervades the existing guidelines for initial resuscitation [ 15 •, 16 ]. This is accomplished over the first hour with isotonic saline (0.9 % sodium chloride) with an infusion rate of 15–20 mL/Kg lean body weight per hour unless contraindicated due to cardiovascular or renal compromise and the risk of iatrogenic volume overload (average adult ~1–1.5 L/h) [ 15 •, 18 ]. Patients in shock may require a more rapid rate of infusion. Initial volume re-expansion should not exceed 50 mL/kg in the first 4 h. Thereafter fluid replacement is guided by clinical exam, hemodynamics, hydration status, serum electrolyte levels, and urine output [ 15 •, 25 ]. The severity of dehydration and volume depletion can be estimated using the following guidelines in close comparison with the clinical examination: (1) steady state blood pressure with an increase in orthostatic pulse indicates a 10 % decrease in extra cellular volume (~2 L deficit), (2) an orthostatic drop in blood pressure (>15/10 mmHg) indicates a 15–20 % decrease in extra cellular volume (~3–4 L deficit) and (3) supine hypotension indicates a decrease of >20 % in extra cellular fluid volume (>4 L deficit) as defined by Kitabchi et al. [ 18 ]. A complication of large volume intravenous saline resuscitation during the initial treatment of DKA is the development of hyperchloremic non-anion gap metabolic acidosis, which is usually transient [ 18 , 26 ] and resolves within 24–48 h with enhanced renal excretion [ 18 ]. A recent randomized controlled trial failed to demonstrate superiority with Ringer’s lactate when used in the acute treatment of DKA [ 27 ].

Ultimately the total volume deficit should be replete within the first 24 h, with half of the estimated total body deficit given over the first 8–12 h [ 22 ]. In patients with normal or elevated corrected serum sodium, 0.45 % sodium chloride is the replacement fluid of choice infused at a rate of 4–14 mL/kg per hour [in the range of 250–500 ml/h]. Isotonic saline at a comparable rate may be continued if the corrected serum sodium is low [ 15 •, 16 , 25 ]. Dextrose should be added to intravenous fluids when blood glucose falls to <200–250 mg/dL [ 1 , 18 ].

Potassium Replacement

Severe insulin deficiency, hyperosmolality, and acidemia may cause spuriously elevated levels of serum potassium despite total-body potassium deficiency [ 13 , 15 •]. During the acute treatment of DKA, serum potassium concentration may precipitously decline as potassium is driven into the intracellular compartment [ 18 ]. Initially the serum potassium should be checked every 1–2 h over the first 5 h of treatment as the most dramatic changes occur during this period [ 16 ]. Potassium replacement is initiated when the serum potassium concentration falls below the upper level of normal for a given laboratory (typically <5.3 mEq/L) in the setting of adequate renal perfusion and urine output with a goal range of serum potassium between 4.0 and 5.0 mEq/L [ 15 •, 28 ]. As a rule, potassium chloride (20–30 mEq/L) is added to each liter of one-half isotonic saline to accomplish this goal [ 13 , 15 •]; however, additional doses may be necessary [ 27 ]. One-third of potassium replacement may be administered as potassium phosphate to offset the chloride load given with intravenous fluids and to prevent hypophosphatemia [ 18 ]. Rarely, severe total-body potassium depletion manifests as low or low-normal serum potassium levels on admission and requires aggressive repletion to avert cardiac dysrhythmia or cardiopulmonary distress, as vigorous treatment potentiates further decline [ 13 , 15 •]. Initiation of insulin therapy is withheld until potassium deficits are corrected when serum potassium is <3.3 mEq/L. If serum potassium is >5.3, potassium chloride supplementation is held and serum potassium levels are monitored closely every 2 h [ 14 ].

Insulin Therapy: Intravenous Insulin and Subcutaneous Transition

Insulin therapy may exacerbate hypokalemia and its consequences; therefore, initiation of insulin should be delayed until serum potassium reaches 3.3 mEq/L and should ensue after intravascular volume expansion. Traditionally, a continuous intravenous infusion of regular insulin is the treatment of choice to inhibit lipolysis with the exception of mild episodes of DKA [ 13 , 14 , 29 , 30 ]. The mainstay of DKA treatment with intravenous regular insulin occurs in the intensive care setting due to technical constraints, concomitant life-threatening illnesses and institutional policy [ 15 •, 31 ]. The standard is an initial intravenous bolus of regular insulin 0.1 units/kg body weight followed by a continuous infusion of regular insulin at a dose of 0.1 unit/kg/h [ 1 , 13 , 18 , 28 , 31 ]. Alternatively, an intravenous infusion alone of regular insulin at a starting rate of 0.14 units/kg/h (~10 units/h in a 70-kg patient) without the priming loading dose has recently been proposed in a prospective randomized study [ 25 ]. The acute intravenous treatment of DKA can also be initiated with insulin glulisine, however selection is guided by institutional preference and cost-containment [ 30 ]. The expected fall in serum glucose concentration within the first hour is 50 mg/dL. If this is not attained, re-address hydration status then titrate insulin infusion by doubling every hour until a steady glucose decline between 50 and 75 mg/h is achieved [ 13 , 15 •, 18 ]. When the serum glucose reaches ~200–250 mg/dL the insulin infusion rate is decreased to 0.02–0.05 units/kg per hour and dextrose (5–10 %) is added to the intravenous fluids to prevent precipitous falls in plasma osmolality, thereby allowing continued insulin administration with the goal serum glucose between 140 and 200 mg/dL and resolution of metabolic acidosis [ 1 , 13 , 14 , 15 •, 18 ].

The ideal route of insulin administration remains debatable in the acute treatment of DKA and includes regular insulin via continuous intravenous infusion or by frequent subcutaneous or intramuscular injections [ 14 , 15 •, 25 , 29 , 31 – 33 ]. Overwhelmingly, experts have recommended intravenous insulin infusion as the treatment of choice in the intensive care setting, as it is a predictable means of administration allowing for maximal peak insulin within the first hour of treatment [ 15 •, 25 , 29 ]. In mild, uncomplicated cases of DKA a subcutaneous regimen of newer rapid-acting insulin analogues (insulin aspart, lispro, glulisine) have been proposed as safe and effective alternatives to the use of intravenous regular insulin in prospective, randomized trials [ 14 , 30 , 31 ]. Subcutaneous analogs may be more cost-effective on the general wards compared to treatment with intravenous regular insulin in the intensive care unit in patients without major co-morbidities [ 31 ]. Barriers include inadequacy of nursing staff on general ward floors to implement the strict monitoring protocol. Regimens include subcutaneous rapid-acting insulin aspart or lispro loading dose of 0.3 units/kg body weight followed by subcutaneous insulin aspart or lispro at 0.1 units/kg/h until blood glucose levels <200–250 mg/dL. At this juncture, intravenous fluids are switched to a dextrose-containing solution and the rapid-acting analog dose is reduced (0.05–0.1 units/kg/h) to maintain serum glucose of 200 mg/dL until resolution of diabetic ketoacidosis [ 14 , 31 , 32 ]. This approach is utilized less frequently in the clinical setting, possibly due to titration difficulties with longer half-life preparations or familiarity with standard insulin infusions [ 1 ].

The following criteria mark the resolution of DKA according to the ADA guidelines: glucose <200 mg/dL, serum bicarbonate ≥18 mEq/L, serum anion gap <12 mEq/L and a venous pH of >7.3 [ 14 ]. Once the acidosis has resolved with normalization of the anion gap and the patient is tolerating PO intake, a subcutaneous insulin regimen can be initiated which includes a combination of short- or rapid-acting and intermediate- or long-acting insulin as needed to maintain blood glucose control [ 13 ] in the range of 90–140 mg/dL. More recently, a regimen of long-acting basal insulin (i.e., glargine) and rapid-acting insulin analogs (i.e., lispro, aspart, glulisine) has been recommended as a more physiological approach for glucose control in in patients with a low incidence of hypoglycemic events [ 30 , 34 ]. Upon this transition, a 1–2 h overlap with the intravenous insulin infusion must occur to prevent a precipitous decrease in serum insulin levels and the re-development of hyperglycemia and ketoacidosis [ 13 , 15 •, 18 , 30 ]. In patients who are NPO at the close of the anion gap, the intravenous insulin infusion should be maintained and supplemented with subcutaneous regular insulin as needed every 4 h in 5-unit increments for every 50 mg/dL increase in blood glucose above 150 mg/dL [ 13 , 18 ]. In a prior diabetic on a home insulin regimen, their home dose of insulin may be resumed with adjustments made for target serum glucose control. In the insulin-naïve patient, the initial basal dose of long-acting insulin should be 0.5–0.8 units/kg per day with a fractionated schedule of short-acting bolus insulin with adjustments to maintain target serum glucose [ 13 , 18 , 30 ]. If appropriate, oral anti-hyperglycemic therapy and nutrition counseling can be implemented at discharge for some type 2 diabetics [ 13 ].

Bicarbonate Therapy

Bicarbonate replacement is a controversial issue and a unified consensus is lacking. Currently, there are no prospective randomized trials to evaluate the utility of bicarbonate therapy in DKA with severe metabolic acidosis (pH <6.9), and to date the use of bicarbonate has been unsubstantiated in small clinical trials. Alkali therapy in DKA has not been routinely recommended, as metabolic derangements tend to correct with insulin therapy and fluids as hypovolemia, tissue perfusion and renal function improve [ 18 , 22 ]. In a small randomized prospective study, the administration of bicarbonate in severe diabetic ketoacidosis (arterial pH 6.9–7.14) did not significantly affect the rate of glucose decline, ketone levels or correction of acidosis [ 32 , 35 ]. Other studies found no significant difference with bicarbonate infusion compared to saline in altering blood glucose concentration and, conversely, bicarbonate may impair ketone and lactate clearance [ 36 ]. Paucity of data on beneficial versus adverse effects of bicarbonate therapy have limited its recommended use to severe acidosis [ 37 , 38 ] and electrocardiographic hyperkalemic changes [ 1 ]. Proponents of alkali therapy argue severe metabolic acidosis is associated with intracellular acidosis and end organ dysfunction, particularly its deleterious cardiopulmonary effects [ 18 , 39 , 40 ]. As a consequence of the increased severity of metabolic acidosis with pH <7.0, bicarbonate may empirically be given as an isotonic solution with an initial dose of 50 mmol intravenous bicarbonate (one ampoule of 7.5 % NaHCO 3 solution in 250 ml sterile water) with 15 mEq of KCL for each ampoule of bicarbonate administered if serum potassium <5.5 mEq/L [ 18 ]. Alternatively, if the pH is <6.9, 100 mmol (100 mEq) administered in 400 mL sterile water may be infused at 200 mL/h with frequent re-dosing every 2 h until pH exceeds 7.0 [ 1 , 15 •, 22 ]. Further research is needed for its use as an adjunctive therapy.

Phosphate Therapy

Whole-body phosphate depletion is a hallmark of poorly controlled diabetes and typically remains asymptomatic [ 13 ]. Hyperglycemia and hyperosmolarity cause an intracellular to extracellular shift of serum phosphate. For this reason, serum phosphate levels may be normal or increased at the onset of DKA [ 15 •, 18 ]. Insulin therapy in the setting of DKA may unveil hypophosphatemia as insulin drives phosphate back into cells. This is typically inconsequential until serum phosphate levels fall to <1.0 mg/dL or, in patients with cardiac dysfunction, skeletal muscle weakness, respiratory failure or hemolytic anemia arise [ 13 , 18 , 32 , 41 ]. In these instances, potassium or sodium phosphate supplementation (20–30 mEq/L) may be added to replacement fluids over several hours [ 1 , 18 ] with close monitoring of serum calcium and phosphate levels [ 18 , 41 ]. Alternatively, in patient tolerating oral intake with mild deficits, oral phosphate (2.5–3.5 g/day in 2–3 divided doses may be administered [ 1 ]. Prospective randomized trials have failed to demonstrate a measurable clinical benefit with phosphate therapy in amelioration of the duration of DKA, insulin requirements, hyperglycemia or effect on morbidity and mortality [ 32 , 41 ].

Complications

The most widely recognized complications of DKA treatment include exogenous insulin-induced hypoglycemia and hypokalemia. The effect of bicarbonate therapy may also worsen hypokalemia. These complications may be avoided with the use of dextrose-containing solutions when blood glucose falls below 250 mg/dL with a concomitant reduction in the rate of insulin delivery as well as the addition of potassium to replacement fluids [ 18 , 28 ]. Additionally, abrupt discontinuation of intravenous insulin therapy after resolution of DKA without overlapping subcutaneous insulin coverage may precipitate hyperglycemia [ 13 ].

Although rare in adult patients, cerebral edema is a complication of DKA treatment with significant morbidity and mortality [ 16 , 18 , 23 ]. Its hallmarks include rapid deterioration in the level of consciousness and headache. Other manifestations include seizure, bradycardia, incontinence, respiratory arrest, and eventual brain-stem herniation. Theoretically, cerebral edema develops when water is osmotically driven into the central nervous system; plasma osmolality declines too rapidly during replacement of sodium and water deficits in DKA treatment [ 13 ]. Gradual correction of the hyperosmolar state in addition to adding dextrose to intravenous fluids when blood glucose falls below 250 mg/dL may avert this risk.

Hypoxemia and noncardiogenic pulmonary edema may result secondary to falling colloid osmotic pressure and subsequent increase in lung water content and diminished lung compliance [ 13 ]. A rare but highly morbid complication of DKA is ARDS [ 42 ]. Ominous signs include a widened A-a gradient, dyspnea, hypoxemia, rales or infiltrates during routine resuscitation as well as severe acidemia [ 42 ]. Lastly, vascular thrombosis may occur in the setting of critical illness and low dose heparin or low molecular weight heparin should be considered for prophylaxis [ 16 ].

Once a patient is successfully treated and transitioned to a subcutaneous insulin regimen the focus should turn to prevention of future episodes. Efforts should be made to ensure the patient has a grasp of their condition, close physician follow-up, and access to their medications. Patient education should occur as soon as the patient is well enough to participate. Inpatient education should include an assessment of the patients understanding of diabetes, information regarding physiology of diabetes, and overall treatment goals. The medical team should review sick-day plans with patients. The patient should be more vigilant on days with fevers, vomiting, or diarrhea. Sick-day plans should include more frequent monitoring of blood sugars, every 4–6 h, and checking for ketones. This should allow the patient to detect ketosis early and allow delivery of increased doses of insulin as planned by their specialist to prevent severe hyperglycemia. The patient should also be encouraged to continue nutrition and fluid intake and to seek medical attention if they are unable to tolerate oral intake. If symptoms of DKA are present or hyperglycemia with sustained capillary blood sugars greater than 240 mg/dL medical attention should be sought [ 43 ]. Patients should be discharged on cost-effective regimens with close follow up with their primary care providers.

With the combination of interdisciplinary collaboration and standardized care the mortality of DKA has decreased significantly in the past few decades [ 32 ]. The challenges for current practitioners include triaging DKA patients to the appropriate level of care and educating patients to avert repeat episodes of DKA. The potential cost saving associated with caring for less severe DKA patients in medical floors must be weighed with staffing ratios. The prevention of DKA will require further study and collaboration between inpatient and outpatient practitioners, as well as patient education.

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Perilli, G., Saraceni, C., Daniels, M.N. et al. Diabetic Ketoacidosis: A Review and Update. Curr Emerg Hosp Med Rep 1 , 10–17 (2013). https://doi.org/10.1007/s40138-012-0001-3

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Introduction, epidemiology, pathogenesis, clinical aspects, signs and symptoms, laboratory/diagnostic findings, timing of initial and subsequent laboratory evaluation, radiologic findings, diabetic ketoacidosis.

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Drs Cashen and Petersen have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.

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Katherine Cashen , Tara Petersen; Diabetic Ketoacidosis. Pediatr Rev August 2019; 40 (8): 412–420. https://doi.org/10.1542/pir.2018-0231

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Clinicians should be aware of the etiology and clinical presentation of diabetic ketoacidosis.

Clinicians should understand the appropriate management and risks associated with treatment of children with diabetic ketoacidosis.

After completing this article, readers should be able to:

Understand the etiology of diabetic ketoacidosis (DKA).

Understand the basic clinical presentation, diagnostic tests, and management of DKA.

Recognize the risks associated with fluid and electrolyte therapy in patients with DKA.

Understand the causes of recurrent DKA.

Diabetic ketoacidosis (DKA) occurs when there is a relative or absolute decrease in circulating insulin levels in relation to an increase in counterregulatory hormone levels. In response to this imbalance, normal physiologic mechanisms are exaggerated, resulting in hyperglycemia, hyperosmolality, ketosis, and acidosis. ( 1 ) The biochemical criteria for the diagnosis of DKA are hyperglycemia (blood glucose level >200 mg/dL [>11.1 mmol/L]), venous pH less than 7.3 or serum bicarbonate level less than 15 mEq/L (<15 mmol/L), and ketonemia (blood β-hydroxybutyrate concentration ≥3 mmol/L) or moderate or severe ketonuria. ( 1 )( 2 )( 3 )

Overall, the most common cause of DKA is new-onset type 1 diabetes mellitus (T1DM). DKA can also be seen in children with T1DM and infection, other intercurrent illness, or inadequate insulin administration. Children with type 2 diabetes mellitus (T2DM) may also present in DKA. High-dose corticosteroids, atypical antipsychotic agents, diazoxide, and immunosuppressive medications have been reported to precipitate DKA in patients without a diagnosis of T1DM. ( 4 )( 5 )

Treatment of DKA involves careful fluid resuscitation, insulin administration, electrolyte replacement, and close monitoring for signs of cerebral edema. This review focuses on the epidemiology, pathogenesis, diagnosis, management, and morbidity of DKA. We highlight diagnostic criteria, risk factors, treatment, and the risks associated with fluid and electrolyte therapy in these patients.

Diabetes is one of the most common chronic diseases in the United States. In 2009, at least 192,000 children in the United States had a diagnosis of diabetes, and the population incidence for DKA hospitalizations continues to increase, with 188,965 total admissions in 2014. ( 6 ) Approximately 11% of these admissions for DKA were in children younger than 17 years. ( 7 ) Despite an overall increase in hospital admissions, both hospital length of stay and mortality have decreased, with mortality decreasing to 0.33%. ( 7 )

Nearly 30% of children with a new diagnosis of T1DM present with DKA and 10% of children with a new diagnosis of T2DM present with DKA. ( 8 )( 9 ) Risk factors for DKA on initial diagnosis are younger age (<2 years), delayed diagnosis, and lower socioeconomic status. ( 2 ) In children with known T1DM, the risk of DKA is 1% to 10% per patient year, and risk factors for DKA include insulin omission, previous episodes of DKA, inadequate dosing of insulin, and infection. ( 2 )( 9 )( 10 ) In recurrent DKA, psychological considerations play a major role, including stress of chronic disease, rebellion against authority, fear of weight gain, and eating disorders, which have all been implicated as contributing factors. Increased risk of recurrence of DKA has also been reported in peripubertal and adolescent girls and children with challenging social situations or limited access to medical services. ( 2 )( 9 )

DKA occurs when serum insulin concentrations are inadequate due to an absolute deficiency (as in the setting of progressive pancreatic β-cell failure due to autoimmune destruction in undiagnosed T1DM) or relative deficiency (stress, infection, inadequate insulin intake) in relation to elevated counterregulatory hormone levels (catecholamines, cortisol, glucagon, and growth hormone).

Figure 1 depicts the pathophysiology of DKA. The combination of insulin deficiency and increased counterregulatory hormone levels leads to gluconeogenesis and glycogenolysis with increased glucose production and decreased peripheral glucose utilization. This causes hyperglycemia, hyperosmolality, increased lipolysis, and ketogenesis. When the renal threshold for glucose is exceeded (∼170–200 mg/dL [∼9.4–11.1 mmol/L]), glucosuria and hyperketonemia cause osmotic diuresis, dehydration, and electrolyte wasting (including sodium, potassium, magnesium, calcium, and phosphate loss). ( 11 )( 12 ) This further stimulates stress hormone production, and if insulin, fluid, and electrolytes are not replaced, then worsening dehydration, metabolic and lactic acidosis, and even death can occur.

Pathophysiology of diabetic ketoacidosis. (Reprinted with permission from Wolfsdorf JI, Glaser N, Agus M, et al. ISPAD Clinical Practice Consensus Guidelines 2018: diabetic ketoacidosis and the hyperglycemic hyperosmolar state. Pediatr Diabetes . 2018;19[suppl 27]:155–177.)

The pathogenesis of cerebral edema is incompletely understood. Multiple mechanisms have been suggested, and controversy exists about whether intravenous fluid administration rate and content contribute. Earlier theories suggested that rapid rehydration with hypotonic fluid and resultant fluid shifts due to a rapid decrease in osmolality between the extravascular and intravascular intracranial compartment explained the development of cerebral edema. Newer theories suggest that cerebral hypoperfusion with reperfusion injury, neuroinflammation, and vasogenic edema play a role, as does increased permeability of the blood brain barrier. A recent randomized controlled trial performed at 13 large pediatric centers, the Pediatric Emergency Care Applied Research Network (PECARN) DKA FLUID Study, compared the effects of the rate and content of intravenous fluid administration on neurologic outcomes in children with DKA. ( 13 ) In this study, only 0.9% of patients had clinically apparent brain injury, and there was no difference in neurologic outcome between the groups, suggesting that the rate of infusion is not associated with increased neurologic injury. ( 13 ) The rate of clinically apparent brain injury has remained static despite improved treatment and monitoring pathways, which suggests that the mechanism is multifactorial and that providers still have much to learn to fully understand this complex pathophysiology.

Demographic factors associated with an increased risk of cerebral edema include younger age (<5 years old), new onset of diabetes, longer duration of symptoms (often associated with severe dehydration), and severe acidosis.

The classic clinical signs of DKA include polyuria, polydipsia, polyphagia, and weight loss. A good history and physical examination are necessary to prevent misdiagnosis in children who do not have classic presenting symptoms, and, even with classic signs, inexperienced providers may misdiagnose DKA. Clinical signs may progress rapidly and include vomiting, abdominal pain, dehydration, weakness, and lethargy. Abdominal pain and ileus can result from potassium depletion, acidosis, and poor splanchnic perfusion. Abdominal pain may be severe enough to mimic an acute abdomen in the initial phase of DKA. Dehydration causes tachycardia, delayed capillary refill time, poor skin turgor, and dry mucus membranes. Ketoacidosis stimulates both central and peripheral chemoreceptors that control respiration, resulting in Kussmaul respiration (rapid fast deep breathing) in an attempt to decrease P co 2 and compensate for the metabolic acidosis. In addition, ketoacidosis may result in a fruity odor to the breath. Despite severe dehydration, children generally maintain their blood pressure, likely due to increased plasma catecholamines and increased release of antidiuretic hormone in relation to high serum osmolality. ( 2 ) Eventually, when compensatory mechanisms are overwhelmed, children with severe DKA may present with hypotension, shock, and altered mental status.

The most feared complication of DKA is severe neurologic injury and development of cerebral edema. Warning signs and symptoms of developing brain injury include headache, bradycardia, irritability, increased drowsiness, altered mental status, cranial nerve palsies, new abnormal neurologic signs on examination, hypertension, unresponsiveness, and coma. The Glasgow Coma Scale (GCS) ( Table 1 ) may be used to provide more objectivity when assessing mental status. ( 14 ) Recent studies have used multiple scores or a change in GCS score to assess decline in mental status in children with DKA and have shown an association between GCS score and cerebral edema on neuroimaging. ( 13 ) However, the GCS is limited because it has not been well validated as a predictor of short- or long-term outcome in pediatric DKA and, thus, should be used in conjunction with a complete neurologic examination. ( 13 )( 14 )

Glasgow Coma Scale

NA=not applicable.

In addition to the aforementioned history and physical examination findings, it is important to investigate potential precipitants of DKA, including, but not limited to, intercurrent infection, malfunctioning insulin pump, ingestion of medications or substances, and pregnancy.

Laboratory values necessary for diagnosing DKA are hyperglycemia (blood glucose level >200 mg/dL [>11.1 mmol/L]), venous pH less than 7.3 or serum bicarbonate level less than 15 mEq/L (<15 mmol/L), ketonemia (blood β-hydroxybutyrate concentration ≥3 mmol/L), and ketonuria. ( 1 )( 2 )( 3 ) The severity of DKA is categorized as mild (pH <7.3 or serum bicarbonate level <15 mEq/L [<15 mmol/L]), moderate (pH <7.2 or serum bicarbonate level <10 mEq/L [<10 mmol/L]), or severe (pH <7.1 or serum bicarbonate level <5 mEq/L [<5 mmol/L]). ( 15 )

Serum electrolytes with calculation of an increased anion gap [Na−(Cl+HCO 3 )] greater than 12 ± 2 mEq/L is consistent with DKA. Note that this gap is attributable to the presence of serum ketones and not to other etiologies of anion gap metabolic acidosis (such as lactic acidosis, salicylates). Children will have dilutional hyponatremia due to hyperglycemia, and the calculated corrected sodium value should be considered. Corrected sodium is calculated as measured sodium + 2 ([plasma glucose − 100] / 100) mg/dL. Elevated serum osmolality, blood urea nitrogen concentration, and creatinine level are also consistent with DKA. Due to known urinary losses in the setting of glucosuria, serum calcium, phosphate, and magnesium levels are also important to monitor. In addition, an electrocardiogram should be considered in the setting of high serum potassium levels given the associated risk of ventricular arrhythmia.

A complete blood cell count with leukocytosis is commonly seen and by itself may not indicate infection. Cultures or radiographic imaging for the source of infection should be considered if the clinical history or physical examination findings are suggestive.

Findings on laboratory testing that have been associated with the development of cerebral edema are elevated serum blood urea nitrogen level, severe acidosis, and severe hypocapnia. ( 2 ) A failure of the corrected sodium level to rise with treatment, or a further decrease in serum sodium level, has been associated with cerebral edema as well. Additional laboratory tests may be warranted as the clinical examination and history findings dictate.

At the time of initial presentation, blood glucose levels, serum electrolyte levels, pH (via blood gas), and the presence of urine or blood ketones will confirm the diagnosis of DKA. Patients presenting in DKA with a new diagnosis of diabetes should undergo additional laboratory testing to assist with the evaluation of their underlying pathophysiology. This testing is inclusive of hemoglobin A1c, thyroperoxidase antibodies, thyrotropin, free thyroxine, tissue transglutaminases, immunoglobulin A, total immunoglobulin A, islet cell antibody, insulin antibody, and glutamic acid decarboxylase antibody.

Serial laboratory testing with hourly capillary blood glucose concentrations and frequent (every 2–4 hours) serum electrolyte, blood gas, blood urea nitrogen, calcium, magnesium, phosphate, and β-hydroxybutyrate levels should be performed. Note that capillary blood glucose levels may be inaccurate in the presence of poor peripheral circulation and severe acidosis, thereby limiting this collection method in measuring extremely high blood glucose concentrations. In these circumstances, capillary samples may need to be cross-checked against venous glucose samples. ( 2 )

Head computed tomography can be used to evaluate the brain parenchyma for radiologic signs of cerebral edema ( Fig 2 ). In some cases, the radiation exposure of computed tomography may outweigh the benefit of the study. Magnetic resonance imaging may be valuable to identify cerebral edema in the setting of acute alteration in mental status for ischemic stroke, dural sinus thrombosis, and other associated neurologic injuries. Imaging is an adjunct to clinical examination findings and should not delay emergency treatment.

Computed tomographic scan showing effacement of the cerebral sulci consistent with cerebral edema.

Initial treatment of DKA should follow the guidelines of Pediatric Advanced Life Support. Management should be in a center with expertise in managing pediatric DKA. If a child needing emergency care does not present to a center with this expertise, consultation with an expert in the management of pediatric DKA is strongly recommended. Initial testing as described in the Laboratory/Diagnostic Findings subsection may be necessary, and thorough clinical examination and history are important in determining precipitating factors, estimating the severity of dehydration, and assessing mental status.

After initial life support, a child with DKA should receive care in a unit that has both experienced nurses and physicians trained in the serial monitoring and management of DKA in children and adolescents. Within this care arena, providers should follow a protocolized approach for pediatric DKA management. In addition, to provide the best and safest care, the medical team needs to have access to a laboratory that can provide frequent and timely measurements of biochemical variables. Patients with severe DKA inclusive of prolonged duration of symptoms, compromised circulation, or depressed level of consciousness should be considered for treatment in an ICU (pediatric if available) or in a unit with equivalent staffing and resources. ( 2 )

The overall goals of treatment are to correct dehydration and acidosis and reverse ketosis, with gradual correction of hyperosmolality and hyperglycemia. Initial management includes fluid resuscitation with isotonic fluid. Note that fluid replacement should begin before starting insulin therapy. In children with hypovolemic shock (inadequate tissue perfusion from decreased intravascular volume), fluid resuscitation with isotonic saline (0.9% sodium chloride), and 20-mL/kg fluid boluses should be rapidly infused, with reassessment after each bolus. ( 2 ) In children with dehydration without shock, initial fluid resuscitation should begin with an isotonic saline fluid bolus, typically 10 mL/kg over 30 to 60 minutes. Calculation of fluid administration, including replacement from losses and maintenance fluid requirements, should be estimated over 24 to 48 hours, and 0.45% to 0.9% saline, or a balanced salt solution, may be used (Ringer’s lactate, Hartmann solution, or Plasma-Lyte). ( 2 )( 13 ) The International Society for Pediatric and Adolescent Diabetes Consensus Statement has been recently modified to reflect that 0.45% to 0.9% saline may be used based on findings from the PECARN DKA FLUID Study. ( 2 )( 13 ) Patients with DKA are typically 5% to 10% dehydrated. The mean time to correction of DKA was approximately 12 hours in a study of 635 patients. ( 16 ) Thus, although calculations of fluid administration should be made to replace fluid over 24 to 48 hours, most patients will correct before the 24- to 48-hour mark and will be able to restore the remaining fluid deficit via enteral replacement.

As noted previously herein, initiation of insulin therapy should follow initial fluid replacement. Initial insulin infusion rates of 0.05 to 0.1 U/kg per hour are recommended depending on the clinical scenario and degree of hyperosmolality. A continuous insulin infusion should be maintained until resolution of DKA. A small randomized controlled trial in children younger than 12 years showed that low-dose insulin (0.05 U/kg per hour) was comparable with higher dose (0.1 U/kg per hour) in terms of rate of glucose decrease and resolution of acidosis but did not suggest that higher-dose insulin was harmful. ( 17 ) The expected rate of decrease of blood glucose is 36 to 90 mg/dL per hour (2–5 mmol/L per hour). Dextrose may be added to the intravenous fluid if the rate of decrease drops faster than expected. Table 2 shows an example of the 2-bag technique for intravenous fluid replacement. If the blood glucose level falls more quickly than expected and DKA has not resolved despite the addition of up to 12.5% of dextrose peripherally, then a reduction in the insulin dose delivered should be considered. When the patient has corrected and is no longer in DKA, has improved sensorium, and is able to tolerate oral intake, he or she should be transitioned to oral food and subcutaneous insulin.

Example of 2-Bag Technique for Intravenous Replacement and Fluid Requirement

Each intravenous fluid bag should have equal electrolyte levels depending on institutional preference and protocol (eg, 30 mEq/L [30 mmol/L] of potassium acetate + 10 mEq/L [10 mmol/L] of potassium phosphate). The rate of infusion will depend on the calculated maintenance and replacement of the remaining deficit based on institutional protocol. Each child requires specific individual treatment and assessment, and adjustments to treatments should be made based on careful monitoring. D 10 =10% dextrose, NaCl=sodium chloride.

Potassium should be replaced as soon as the patient has urine output and laboratory values confirm that the child is not hyperkalemic. Despite initially normal or elevated levels of serum potassium, children with DKA typically have a total body deficit of potassium with intracellular potassium depletion due to shifts of potassium to the extracellular space and loss due to vomiting and osmotic diuresis. If children are hypokalemic on presentation, potassium should be replaced, and as long as the patient has adequate renal function, rehydration fluid should contain potassium. Depletion of intracellular phosphate is also seen in DKA due to losses from osmotic diuresis, and severe hypophosphatemia should be treated. Bicarbonate administration is not recommended because this has not shown benefit in the resolution of DKA, and bolus administration has been historically associated with worse outcomes. Administration of bicarbonate potentially may cause harm due to paradoxical central nervous system acidosis. Therefore, bicarbonate administration should be reserved for the treatment of severe hyperkalemia or severe acidosis (pH ≤6.9) causing impaired cardiac contractility. ( 2 ) Hyperchloremia may develop in children who undergo replacement with fluids containing large amounts of chloride. This can contribute to persistent hyperchloremic metabolic acidosis, large base deficit, and low serum bicarbonate level. Hyperchloremia should be considered in a child with low β-hydroxybutyrate levels with a non–anion gap metabolic acidosis and a low serum bicarbonate level.

Children with severe DKA and children at high risk for cerebral edema should be cared for in an ICU. Children who are severely obtunded or unconscious and cannot protect their airways should be intubated. In most circumstances, intubation should be avoided if possible because pharmacologic sedation and the subsequent elevation of P co 2 in a child with cerebral edema may progress to cerebral herniation. Central venous catheters should be avoided due to the high risk of thrombosis in these patients. If the clinical scenario deems a central venous catheter necessary, it should be removed as soon as the patient status allows. Repeated neurologic examinations (hourly, or more frequently as clinically indicated) should be performed to assess for the development of cerebral edema (new or worsening headache, bradycardia, vomiting, change in neurologic status, new cranial nerve palsies, abnormal pupillary response, hypertension, hypoventilation). ( 2 ) Treatment of cerebral edema should be started as soon as there is clinical suspicion and should not be delayed because of neuroimaging. Hypotension, hypoxia, and excessive fluid administration should be avoided. The head of the patient’s bed should be elevated to 30°, and hyperosmolar agents (mannitol or hypertonic saline [3%]) should be administered. Hypertonic saline is increasingly used in many institutions; however, controversy remains, and data are lacking to definitively dictate whether mannitol or 3% hypertonic saline is preferable in this patient population.

The mortality from DKA in children is low, and the major cause of mortality and morbidity is cerebral injury. DKA associated with central nervous system complications include neuronal changes resulting from hypoglycemia and hypoxia, dural sinus and basilar artery thrombosis, intracranial hemorrhage, cerebral infarction, and cerebral edema. Note that DKA is associated with a prothrombotic tendency in children. This is due to a combination of altered clotting factor activity and serum hyperosmolarity, which potentiate the risk of thromboembolic events, including the previously mentioned cerebral thrombosis or cerebral infarction. ( 18 )( 19 )

Clinically apparent cerebral edema occurs in 0.5% to 0.9% of patients with DKA, with high mortality. Alteration in mental status (defined as a GCS score <14) occurs more commonly and has been associated with findings of cerebral edema on neuroimaging. Neuroimaging studies in children with DKA without overt clinical signs have shown that evidence of cerebral edema occurs more frequently than clinically suspected. The pathogenesis of cerebral edema is incompletely understood, and controversy exists about whether intravenous fluid administration rate and content contribute. Historically, abrupt changes in serum osmolality have been implicated in the development of cerebral edema. ( 20 )( 21 ) Newer theories suggest that factors intrinsic to DKA, including cerebral hypoperfusion with reperfusion injury, neuroinflammation, osmotic shifts, and vasogenic edema, play a role, as does increased permeability of the blood-brain barrier, which can worsen during treatment. ( 22 ) Meticulous monitoring of clinical and laboratory response to treatment should be provided with goals to correct rehydration, gradually improve hyperglycemia and hyperosmolality, and reverse acidosis and ketosis. A causal relationship has not been determined between the administration of hypotonic fluid or a rapid reduction in serum osmolality and the development of cerebral edema. However, caution and gradual reduction in hyperglycemia and hyperosmolality are recommended. Additional research is needed to clearly define the pathogenesis of cerebral edema and whether specific treatment interventions contribute to the development of cerebral edema.

Survivors of cerebral edema after DKA have significant morbidity. Even children treated for DKA who did not have clinically apparent neurologic injury during treatment demonstrate memory deficits after recovery, suggesting that subclinical changes may contribute to morbidity. Additional reports suggest that children with altered mental status at presentation without overt clinical or radiologic findings during treatment for DKA score worse on cognitive testing, and structural and functional changes on magnetic resonance imaging persist for up to 6 months after treatment. These data suggest that measures aimed at prevention, including earlier diagnosis in patients with new-onset T1DM and improved diabetes compliance and prevention of recurrence by identifying and addressing precipitating factors, play a key role in morbidity and mortality. ( 2 )( 23 )( 24 )

In conclusion, children with DKA should be cared for in a center with expertise in managing these ill patients. Most cases of DKA are seen in children with a new diagnosis of T1DM. Recurrent DKA is more common in children with psychosocial concerns, including difficulty with access to health care, challenging social situations, and poor compliance. Treatment goals are to correct dehydration, acidosis, and ketosis and, if possible, to avoid the development of cerebral edema. Mortality is low but morbidity, especially long-term morbidity, is not well delineated, and the underlying mechanism of neurologic injury requires additional study. Prevention via earlier diagnosis and improved diabetes compliance should be targeted.

On the basis of class D evidence and consensus, children and adolescents with diabetic ketoacidosis (DKA) should be cared for in a center experienced in the treatment of DKA.

On the basis of class A evidence, goals of treatment in children with DKA are to correct dehydration, correct acidosis, and reverse ketosis.

On the basis of class A evidence, fluid replacement (deficit and maintenance) should be calculated and replaced over 24 to 48 hours.

On the basis of class B evidence, insulin therapy should start at a rate of 0.05 to 0.1 U/kg per hour after starting fluid replacement.

On the basis of class B evidence, bicarbonate administration is not recommended except for severe hyperkalemia or severe acidosis with impaired cardiac output.

To view the Teaching Slides that accompany this article, please see the Supplementary Data at https://doi.org/10.1542/pir.2018-0231.

diabetic ketoacidosis

Pediatric Emergency Care Applied Research Network

type 1 diabetes mellitus

type 2 diabetes mellitus

Competing Interests

Supplementary data.

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Incidence and prevalence of diabetic ketoacidosis (DKA) among adults with type 1 diabetes mellitus (T1D): a systematic literature review

Affiliations.

• 1 Corporate Department GlobalEpidemiology, Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany.
• 2 Global Epidemiology, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, USA.
• 3 Boehringer Ingelheim Canada, Burlington, Canada.
• 4 Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim am Rhein, Germany.
• 5 Xcenda L L C, Palm Harbor, Florida, USA.
• PMID: 28765134
• PMCID: PMC5642652
• DOI: 10.1136/bmjopen-2017-016587

Objectives: To summarise incidence and prevalence of diabetic ketoacidosis (DKA) in adults with type 1 diabetes (T1D) for the overall patient population and different subgroups (age, sex, geographical region, ethnicity and type of insulin administration).

Design: Systematic literature review (SLR).

Data sources: Medline (via PubMed) and Embase (1 January 2000 to 23 June 2016).

Study selection: Peer-reviewed observational studies with reported data on the incidence or prevalence of DKA in T1D adults were included. A single reviewer completed the study screening and selection process and a second reviewer performed an additional screening of approximately 20% of the publications; two reviewers independently conducted the quality assessment; the results were narratively synthesised.

Results: Out of 1082 articles, 19 met the inclusion and exclusion criteria, with two additional studies identified that did not specify the patient age range and are therefore not included in the SLR. Overall, eight studies reported incidence with a range of 0-56 per 1000 person-years (PYs), with one outlying study reporting an incidence of 263 per 1000 PYs. Eleven studies reported prevalence with a range of 0-128 per 1000 people. Prevalence of DKA decreased with increasing age. Subgroup analyses were performed using data from no more than two studies per subgroup. There was a higher prevalence of DKA reported in women, non-whites and patients treated with insulin injections compared with men, whites and patients using continuous subcutaneous insulin infusion pumps, respectively.

Conclusions: To our knowledge, this is the first SLR on the epidemiology of DKA in T1D adults. Despite an increasing prevalence of T1D in recent years, DKA in adults has been poorly characterised. In an era when the benefit-risk profiles of new antidiabetic therapies are being evaluated, including the potential risk of DKA, there is a clear need to better elucidate the expected rate of DKA among T1D adults.

Keywords: diabetic ketoacidosis; epidemiology; incidence; prevalence; systematic literature review; type 1 diabetes mellitus.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Publication types

• Systematic Review
• Diabetes Mellitus, Type 1 / complications*
• Diabetes Mellitus, Type 1 / drug therapy
• Diabetic Ketoacidosis / epidemiology*
• Diabetic Ketoacidosis / etiology
• Hypoglycemic Agents / administration & dosage
• Hypoglycemic Agents / therapeutic use
• Infusion Pumps
• Insulin / administration & dosage
• Insulin / therapeutic use
• Hypoglycemic Agents

Diet Review: Ketogenic Diet for Weight Loss

Finding yourself confused by the seemingly endless promotion of weight-loss strategies and diet plans? In this series , we take a look at some popular diets—and review the research behind them .

What is it?

The ketogenic or “keto” diet is a low-carbohydrate, fat-rich eating plan that has been used for centuries to treat specific medical conditions. In the 19 th century, the ketogenic diet was commonly used to help control diabetes. In 1920 it was introduced as an effective treatment for epilepsy in children in whom medication was ineffective. The ketogenic diet has also been tested and used in closely monitored settings for cancer, diabetes, polycystic ovary syndrome, and Alzheimer’s disease.

However, this diet is gaining considerable attention as a potential weight-loss strategy due to the low-carb diet craze, which started in the 1970s with the Atkins diet (a very low-carbohydrate, high-protein diet, which was a commercial success and popularized low-carb diets to a new level). Today, other low-carb diets including the Paleo, South Beach, and Dukan diets are all high in protein but moderate in fat. In contrast, the ketogenic diet is distinctive for its exceptionally high-fat content, typically 70% to 80%, though with only a moderate intake of protein.

How It Works

The premise of the ketogenic diet for weight loss is that if you deprive the body of glucose—the main source of energy for all cells in the body, which is obtained by eating carbohydrate foods—an alternative fuel called ketones is produced from stored fat (thus, the term “keto”-genic). The brain demands the most glucose in a steady supply, about 120 grams daily, because it cannot store glucose. During fasting, or when very little carbohydrate is eaten, the body first pulls stored glucose from the liver and temporarily breaks down muscle to release glucose. If this continues for 3-4 days and stored glucose is fully depleted, blood levels of a hormone called insulin decrease, and the body begins to use fat as its primary fuel. The liver produces ketone bodies from fat, which can be used in the absence of glucose. [1]

When ketone bodies accumulate in the blood, this is called ketosis. Healthy individuals naturally experience mild ketosis during periods of fasting (e.g., sleeping overnight) and very strenuous exercise. Proponents of the ketogenic diet state that if the diet is carefully followed, blood levels of ketones should not reach a harmful level (known as “ketoacidosis”) as the brain will use ketones for fuel, and healthy individuals will typically produce enough insulin to prevent excessive ketones from forming. [2] How soon ketosis happens and the number of ketone bodies that accumulate in the blood is variable from person to person and depends on factors such as body fat percentage and resting metabolic rate. [3]

What is ketoacidosis?

There is not one “standard” ketogenic diet with a specific ratio of macronutrients ( carbohydrates , protein , fat ). The ketogenic diet typically reduces total carbohydrate intake to less than 50 grams a day—less than the amount found in a medium plain bagel—and can be as low as 20 grams a day. Generally, popular ketogenic resources suggest an average of 70-80% fat from total daily calories, 5-10% carbohydrate, and 10-20% protein. For a 2000-calorie diet, this translates to about 165 grams fat, 40 grams carbohydrate, and 75 grams protein. The protein amount on the ketogenic diet is kept moderate in comparison with other low-carb high-protein diets, because eating too much protein can prevent ketosis. The amino acids in protein can be converted to glucose, so a ketogenic diet specifies enough protein to preserve lean body mass including muscle, but that will still cause ketosis.

Many versions of ketogenic diets exist, but all ban carb-rich foods. Some of these foods may be obvious: starches from both refined and whole grains like breads, cereals, pasta, rice, and cookies; potatoes, corn, and other starchy vegetables; and fruit juices. Some that may not be so obvious are beans , legumes, and most fruits. Most ketogenic plans allow foods high in saturated fat, such as  fatty cuts of meat , processed meats, lard, and butter, as well as sources of unsaturated fats , such as nuts, seeds, avocados, plant oils, and oily fish. Depending on your source of information, ketogenic food lists may vary and even conflict.

• Strong emphasis on fats at each meal and snack to meet the high-fat requirement. Cocoa butter, lard, poultry fat, and most plant fats (olive, palm, coconut oil) are allowed, as well as foods high in fat, such as avocado, coconut meat, certain nuts (macadamia, walnuts, almonds, pecans), and seeds (sunflower, pumpkin, sesame, hemp, flax).
• Some dairy foods may be allowed. Although dairy can be a significant source of fat, some are high in natural lactose sugar such as cream, ice cream, and full-fat milk so they are restricted. However, butter and hard cheeses may be allowed because of the lower lactose content.
• Protein stays moderate. Programs often suggest grass-fed beef (not grain-fed) and free-range poultry that offer slightly higher amounts of omega-3 fats, pork, bacon, wild-caught fish, organ meats, eggs, tofu, certain nuts and seeds.
• Most non-starchy vegetables are included: Leafy greens (kale, Swiss chard, collards, spinach, bok choy, lettuces), cauliflower, broccoli, Brussels sprouts, asparagus, bell peppers, onions, garlic, mushrooms, cucumber, celery, summer squashes.
• Certain fruits in small portions like berries. Despite containing carbohydrate, they are lower in “net carbs”* than other fruits.
• Other: Dark chocolate (90% or higher cocoa solids), cocoa powder, unsweetened coffee and tea, unsweetened vinegars and mustards, herbs, and spices.

Not Allowed

• All whole and refined grains and flour products, added and natural sugars in food and beverages, starchy vegetables like potatoes, corn, and winter squash.
• Fruits other than from the allowed list, unless factored into designated carbohydrate restriction. All fruit juices.
• Legumes including beans, lentils, and peanuts.
• Although some programs allow small amounts of hard liquor or low carbohydrate wines and beers, most restrict full carbohydrate wines and beer, and drinks with added sweeteners (cocktails, mixers with syrups and juice, flavored alcohols).

*What Are Net Carbs? “Net carbs” and “impact carbs” are familiar phrases in ketogenic diets as well as diabetic diets. They are unregulated interchangeable terms invented by food manufacturers as a marketing strategy, appearing on some food labels to claim that the product contains less “usable” carbohydrate than is listed. [6] Net carbs or impact carbs are the amount of carbohydrate that are directly absorbed by the body and contribute calories. They are calculated by subtracting the amount of indigestible carbohydrates from the total carbohydrate amount. Indigestible (unabsorbed) carbohydrates include insoluble fibers from whole grains, fruits, and vegetables; and sugar alcohols, such as mannitol, sorbitol, and xylitol commonly used in sugar-free diabetic food products. However, these calculations are not an exact or reliable science because the effect of sugar alcohols on absorption and blood sugar can vary. Some sugar alcohols may still contribute calories and raise blood sugar. The total calorie level also does not change despite the amount of net carbs, which is an important factor with weight loss. There is debate even within the ketogenic diet community about the value of using net carbs.

Programs suggest following a ketogenic diet until the desired amount of weight is lost. When this is achieved, to prevent weight regain one may follow the diet for a few days a week or a few weeks each month, interchanged with other days allowing a higher carbohydrate intake.

The Research So Far

The ketogenic diet has been shown to produce beneficial metabolic changes in the short-term. Along with weight loss, health parameters associated with carrying excess weight have improved, such as insulin resistance, high blood pressure, and elevated cholesterol and triglycerides. [2,7] There is also growing interest in the use of low-carbohydrate diets, including the ketogenic diet, for type 2 diabetes. Several theories exist as to why the ketogenic diet promotes weight loss, though they have not been consistently shown in research: [2,8,9]

• A satiating effect with decreased food cravings due to the high-fat content of the diet.
• A decrease in appetite-stimulating hormones, such as insulin and ghrelin, when eating restricted amounts of carbohydrate.
• A direct hunger-reducing role of ketone bodies—the body’s main fuel source on the diet.
• Increased calorie expenditure due to the metabolic effects of converting fat and protein to glucose.
• Promotion of fat loss versus lean body mass, partly due to decreased insulin levels.

The findings below have been limited to research specific to the ketogenic diet: the studies listed contain about 70-80% fat, 10-20% protein, and 5-10% carbohydrate. Diets otherwise termed “low carbohydrate” may not include these specific ratios, allowing higher amounts of protein or carbohydrate. Therefore only diets that specified the terms “ketogenic” or “keto,” or followed the macronutrient ratios listed above were included in this list below. In addition, though extensive research exists on the use of the ketogenic diet for other medical conditions, only studies that examined ketogenic diets specific to obesity or overweight were included in this list. ( This paragraph was added to provide additional clarity on 5.7.18. )

• A meta-analysis of 13 randomized controlled trials following overweight and obese participants for 1-2 years on either low-fat diets or very-low-carbohydrate ketogenic diets found that the ketogenic diet produced a small but significantly greater reduction in weight, triglycerides, and blood pressure, and a greater increase in HDL and LDL cholesterol compared with the low-fat diet at one year. [10] The authors acknowledged the small weight loss difference between the two diets of about 2 pounds, and that compliance to the ketogenic diet declined over time, which may have explained the more significant difference at one year but not at two years (the authors did not provide additional data on this).
• A systematic review of 26 short-term intervention trials (varying from 4-12 weeks) evaluated the appetites of overweight and obese individuals on either a very low calorie (~800 calories daily) or ketogenic diet (no calorie restriction but ≤50 gm carbohydrate daily) using a standardized and validated appetite scale. None of the studies compared the two diets with each other; rather, the participants’ appetites were compared at baseline before starting the diet and at the end. Despite losing a significant amount of weight on both diets, participants reported less hunger and a reduced desire to eat compared with baseline measures. The authors noted the lack of increased hunger despite extreme restrictions of both diets, which they theorized were due to changes in appetite hormones such as ghrelin and leptin, ketone bodies, and increased fat and protein intakes. The authors suggested further studies exploring a threshold of ketone levels needed to suppress appetite; in other words, can a higher amount of carbohydrate be eaten with a milder level of ketosis that might still produce a satiating effect? This could allow inclusion of healthful higher carbohydrate foods like whole grains, legumes, and fruit. [9]
• A study of 39 obese adults placed on a ketogenic very low-calorie diet for 8 weeks found a mean loss of 13% of their starting weight and significant reductions in fat mass, insulin levels, blood pressure, and waist and hip circumferences. Their levels of ghrelin did not increase while they were in ketosis, which contributed to a decreased appetite. However during the 2-week period when they came off the diet, ghrelin levels and urges to eat significantly increased. [11]
• A study of 89 obese adults who were placed on a two-phase diet regimen (6 months of a very-low-carbohydrate ketogenic diet and 6 months of a reintroduction phase on a normal calorie Mediterranean diet) showed a significant mean 10% weight loss with no weight regain at one year. The ketogenic diet provided about 980 calories with 12% carbohydrate, 36% protein, and 52% fat, while the Mediterranean diet provided about 1800 calories with 58% carbohydrate, 15% protein, and 27% fat. Eighty-eight percent of the participants were compliant with the entire regimen. [12] It is noted that the ketogenic diet used in this study was lower in fat and slightly higher in carbohydrate and protein than the average ketogenic diet that provides 70% or greater calories from fat and less than 20% protein.

Potential Pitfalls

Following a very high-fat diet may be challenging to maintain. Possible symptoms of extreme carbohydrate restriction that may last days to weeks include hunger, fatigue, low mood, irritability, constipation, headaches, and brain “fog.” Though these uncomfortable feelings may subside, staying satisfied with the limited variety of foods available and being restricted from otherwise enjoyable foods like a crunchy apple or creamy sweet potato may present new challenges.

Some negative side effects of a long-term ketogenic diet have been suggested, including increased risk of kidney stones and osteoporosis, and increased blood levels of uric acid (a risk factor for gout). Possible nutrient deficiencies may arise if a variety of recommended foods on the ketogenic diet are not included. It is important to not solely focus on eating high-fat foods, but to include a daily variety of the allowed meats, fish, vegetables, fruits, nuts, and seeds to ensure adequate intakes of fiber, B vitamins, and minerals (iron, magnesium, zinc)—nutrients typically found in foods like whole grains that are restricted from the diet. Because whole food groups are excluded, assistance from a registered dietitian may be beneficial in creating a ketogenic diet that minimizes nutrient deficiencies.

Unanswered Questions

• What are the long-term (one year or longer) effects of, and are there any safety issues related to, the ketogenic diet?
• Do the diet’s health benefits extend to higher risk individuals with multiple health conditions and the elderly? For which disease conditions do the benefits of the diet outweigh the risks?
• As fat is the primary energy source, is there a long-term impact on health from consuming different types of fats (saturated vs. unsaturated) included in a ketogenic diet?
• Is the high fat, moderate protein intake on a ketogenic diet safe for disease conditions that interfere with normal protein and fat metabolism, such as kidney and liver diseases?
• Is a ketogenic diet too restrictive for periods of rapid growth or requiring increased nutrients, such as during pregnancy, while breastfeeding, or during childhood/adolescent years?

Bottom Line

Available research on the ketogenic diet for weight loss is still limited. Most of the studies so far have had a small number of participants, were short-term (12 weeks or less), and did not include control groups. A ketogenic diet has been shown to provide short-term benefits in some people including weight loss and improvements in total cholesterol, blood sugar, and blood pressure. However, these effects after one year when compared with the effects of conventional weight loss diets are not significantly different. [10]

Eliminating several food groups and the potential for unpleasant symptoms may make compliance difficult. An emphasis on foods high in  saturated fat  also counters recommendations from the Dietary Guidelines for Americans and the American Heart Association and may have adverse effects on blood LDL cholesterol. However, it is possible to modify the diet to emphasize foods low in saturated fat such as olive oil, avocado, nuts, seeds, and fatty fish.

A ketogenic diet may be an option for some people who have had difficulty losing weight with other methods.  The exact ratio of fat, carbohydrate, and protein that is needed to achieve health benefits will vary among individuals due to their genetic makeup and body composition. Therefore, if one chooses to start a ketogenic diet, it is recommended to consult with one’s physician and a dietitian to closely monitor any biochemical changes after starting the regimen, and to create a meal plan that is tailored to one’s existing health conditions and to prevent nutritional deficiencies or other health complications. A dietitian may also provide guidance on reintroducing carbohydrates once weight loss is achieved.

A modified carbohydrate diet following the Healthy Eating Plate model may produce adequate health benefits and weight reduction in the general population. [13]

• Low-Carbohydrate Diets
• David Ludwig clears up carbohydrate confusion
• The Best Diet: Quality Counts
• Other Diet Reviews
• Paoli A, Rubini A, Volek JS, Grimaldi KA. Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. Eur J Clin Nutr . 2013 Aug;67(8):789.
• Paoli A. Ketogenic diet for obesity: friend or foe?. Int J Environ Res Public Health . 2014 Feb 19;11(2):2092-107.
• Gupta L, Khandelwal D, Kalra S, Gupta P, Dutta D, Aggarwal S. Ketogenic diet in endocrine disorders: Current perspectives. J Postgrad Med . 2017 Oct;63(4):242.
• von Geijer L, Ekelund M. Ketoacidosis associated with low-carbohydrate diet in a non-diabetic lactating woman: a case report. J Med Case Rep . 2015 Dec;9(1):224.
• Shah P, Isley WL. Correspondance: Ketoacidosis during a low-carbohydrate diet. N Engl J Med . 2006 Jan 5;354(1):97-8.
• Marcason W. Question of the month: What do “net carb”, “low carb”, and “impact carb” really mean on food labels?. J Am Diet Assoc . 2004 Jan 1;104(1):135.
• Schwingshackl L, Hoffmann G. Comparison of effects of long-term low-fat vs high-fat diets on blood lipid levels in overweight or obese patients: a systematic review and meta-analysis. J Acad Nutr Diet . 2013 Dec 1;113(12):1640-61.
• Abbasi J. Interest in the Ketogenic Diet Grows for Weight Loss and Type 2 Diabetes. JAMA . 2018 Jan 16;319(3):215-7.
• Gibson AA, Seimon RV, Lee CM, Ayre J, Franklin J, Markovic TP, Caterson ID, Sainsbury A. Do ketogenic diets really suppress appetite? A systematic review and meta‐analysis. Obes Rev . 2015 Jan 1;16(1):64-76.
• Bueno NB, de Melo IS, de Oliveira SL, da Rocha Ataide T. Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials. Br J Nutr . 2013 Oct;110(7):1178-87.
• Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, Kriketos A, Proietto J. Ketosis and appetite-mediating nutrients and hormones after weight loss. Eur J Clin Nutr . 2013 Jul;67(7):759.
• Paoli A, Bianco A, Grimaldi KA, Lodi A, Bosco G. Long term successful weight loss with a combination biphasic ketogenic mediterranean diet and mediterranean diet maintenance protocol. Nutrients . 2013 Dec 18;5(12):5205-17.
• Hu T, Mills KT, Yao L, Demanelis K, Eloustaz M, Yancy Jr WS, Kelly TN, He J, Bazzano LA. Effects of low-carbohydrate diets versus low-fat diets on metabolic risk factors: a meta-analysis of randomized controlled clinical trials. Am J Epidemiol . 2012 Oct 1;176(suppl_7):S44-54.

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