diabetic ketoacidosis thesis

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• Ann Med Surg (Lond)
• v.85(6); 2023 Jun
• PMC10289692

Comprehensive review of diabetic ketoacidosis: an update

Chukwuka elendu.

a Federal Medical Center, Owerri

Johnson A. David

i VN Karazin National University, Kharkiv, Ukraine

Abasi-O. Udoyen

j Pirogov Medical University, Rossijskij nacional’nyj issledovatel’skij medicinskij universitet imeni N I Pirogova, Russia

Emmanuel O. Egbunu

d University of Ilorin Teaching Hospital

Ifeanyichukwu C. Ogbuiyi-Chima

e Babcock University

Lilian O. Unakalamba

f Rivers State University Teaching Hospital, Portharcourt

Awotoye I. Temitope

g Lagos University Teaching Hospital

Jennifer O. Ibhiedu

Amos o. ibhiedu, promise u. nwosu.

h Abia State University, Nigeria

Mercy O. Koroyin

k Bromley Healthcare

Chimuanya Eze

Adeyemo i. boluwatife, omotayo alabi.

c Redeemer’s University

Olisa S. Okabekwa

b University of Nigeria Teaching Hospital, Ituku Ozalla

John O. Fatoye

Habiba i. ramon-yusuf.

l University Hospital Lewisham, UK

Associated Data

Data will be made available by the authors upon reasonable request.

The most frequent hyperglycemic emergency and the leading cause of death in people with diabetes mellitus is diabetic ketoacidosis (DKA). DKA is common in people with type 1 diabetes, while type 2 diabetes accounts for roughly one-third of occurrences. Although DKA mortality rates have generally decreased to low levels, they are still significant in many underdeveloped nations. In industrialized countries, its mortality rate ranges from 2 to 5%, but in underdeveloped nations, it ranges from 6 to 24%. Therefore, it is always lethal if misdiagnosed or improperly treated. According to specific research, DKA can be present at the time of type 1 diabetes onset in 25 to 30% of cases and in 4 to 29% of young people with type 2 diabetes mellitus, and its features include hyperglycemia, metabolic acidosis, and ketosis with its triggering factors commonly being infections, newly discovered diabetes, and failure to start insulin therapy. Less than 20% of DKA patients present comatose, and patients with different levels of consciousness can present at other times. A close association between abnormalities found during a mental status evaluation and osmolality seems to exist. Hospital admission is necessary for vigorous intravenous fluid therapy, insulin therapy, electrolyte replacement, diagnosis and treatment of the underlying triggers, and routine monitoring of the patient’s clinical and laboratory conditions to manage DKA properly. Appropriate discharge plans should include actions to prevent a DKA recurrence and the proper selection and administration of insulin regimens.

Introduction and background

• Diabetic ketoacidosis is the most frequent hyperglycemic emergency.
• Diabetic ketoacidosis is the leading cause of death in people with diabetes mellitus.
• DKA is common in people with type 1 diabetes.

Diabetic ketoacidosis is a grievous complication of diabetes that occurs when there is a lack of insulin in the body, resulting in elevated blood glucose levels and the production of ketones. Diabetic ketoacidosis is a medical emergency that requires immediate treatment, as it can lead to life-threatening complications such as cerebral edema, acute respiratory distress syndrome, and sepsis 1 . It is becoming more prevalent worldwide, particularly among type 1 diabetic children and adolescents 1 . While insulin therapy and patient education have improved, diabetic ketoacidosis remains a common cause of hospitalization and is associated with notable morbidity and mortality 2 , 3 . Among the immediate treatment options for severe diabetic ketoacidosis is a multidisciplinary approach that emphasizes correcting fluid and electrolyte imbalances, restoring insulin sensitivity, and preventing complications. Primary care aims to prevent the progression of diabetic ketoacidosis and minimize the risk of cerebral edema, a rare but potentially fatal complication 4 , 5 . A recent publication has shed light on the pathophysiology of diabetic ketoacidosis, including the role of insulin deficiency, altered glucose metabolism, and acid-base disturbances 3 . Technological advances and monitoring techniques have also allowed for more precise management of fluid and electrolyte imbalances, insulin therapy, and other adjunctive therapies 5 . The management of severe diabetic ketoacidosis is not without challenges. For example, insulin therapy can rapidly drop blood glucose levels, increasing the risk of hypoglycemia.

Similarly, fluid therapy can lead to fluid overload and other complications, particularly in patients with underlying comorbidities 2 . To adequately address these challenges, there is a need for a comprehensive review of immediate care for severe diabetic ketoacidosis 4 . Such a review would synthesize current research findings, provide evidence-based recommendations, and highlight areas where further research is needed.

This review aims to comprehensively analyze the current state of immediate care for severe diabetic ketoacidosis. It will cover the pathophysiology, clinical manifestations, and management of diabetic ketoacidosis, focusing on evidence-based interventions. Furthermore, the study will highlight the challenges associated with immediate care for severe diabetic ketoacidosis and provide recommendations for addressing these challenges. It will be an essential resource for healthcare professionals managing severe diabetic ketoacidosis. This review can improve patient outcomes and reduce the morbidity and mortality associated with severe diabetic ketoacidosis by providing evidence-based guidance.

Methodology

This comprehensive review compiles and evaluates recurrent and dominant topics discussed in the literature regarding the epidemiology, pathophysiology, and emergent therapy for patients with diabetic ketoacidosis, a complication of type 1 diabetes (T1DM) and less frequently type 2 diabetes (T2DM). To attain the purpose of the study, the authors undertook an exhaustive and advanced Pubmed search. Pubmed is an electronic database that serves as a search engine and gives access to more than 35 million MEDLINE articles that can be cited (medical, biomedical, nursing, life sciences, etc.). We used Boolean operators to combine the search terms and phrases; epidemiology, pathophysiology, diagnosis, and emergent therapy for patients with diabetic ketoacidosis. We also entered the vital alternative terms into the search for a broader reach. The review was limited to articles published within the past decade (2012–2022) and was not restricted to a specific region. We used only English language articles from academic journals with peer review. In addition, the study included articles with both abstracts and full texts to facilitate screening. Thirty-seven articles popped up after the filters were applied. After reading through the abstracts of the initial results to screen for eligibility, six papers were eventually selected since they also provided the most recent discussions regarding the topic.

Definition and epidemiology

Diabetic ketoacidosis is a severe acute metabolic complication of diabetes mellitus characterized by hyperglycemia, hyperketonaemia, and metabolic acidosis. Patients have high insulin requirements, eventually depleting their body insulin 5 . This insulin deficiency leads to an excessive breakdown of fat, resulting in an excessive build-up of ketone bodies. Despite improvements in diabetic patients’ self-care, DKA still accounts for 14% of all hospital admissions of diabetic patients and 16% of all deaths linked to diabetes 4 . DKA commonly exists in people with type 1 diabetes, and about 3% of type 1 diabetes patients initially present with DKA; the incidence is two episodes per 100 patient-years of diabetes. Patients with type 2 diabetes can also develop it, though this is less typical 6 , 7 . Although the incidence of diabetic ketoacidosis in developing nations is unknown, it may be greater than in developed countries 8 . Whites have a greater prevalence of type 1 diabetes, contributing to the higher incidence of DKA in this racial group. For unknown causes, females are slightly more likely than males to develop DKA. Young ladies with type 1 diabetes frequently experience recurrent DKA, which is primarily brought on by failing to administer insulin therapy 6 , 9 . DKA is much more frequent in young children and teenagers than in adults among people with type 1 diabetes; however, patients with diabetes may experience DKA at any age. Intervention is feasible between the onset of symptoms and the development of DKA, although numerous factors (such as ethnic minority, lack of health insurance, lower BMI, preceding infection, delayed treatment, etc.) influence the risk of DKA among children and young people 9 .

Pathophysiology

The abnormal physiology seen in a diabetic patient with ketoacidosis is due to absolute or relative insulin deficiency with the rise in hormones that put the body in a catabolic state and cause insulin resistance leading to hyperglycemia, hyperketonemia, hyperosmolarity, and electrolyte imbalances. These hormones include; glucagon, growth hormone, and catecholamines (epinephrine and norepinephrine) 10 . The event that most commonly precipitates diabetic ketoacidosis is usually a loss of insulin activity or increased demand for insulin, which can occur due to missed insulin doses, improper administration of insulin, or the presence of infections in a diabetic patient 11 . It can lead to an inability to transport glucose intracellularly; when this occurs, most cells cannot utilize glucose for energy, so intracellular hunger and starvation begin. Most cells shift to free fatty acids (FFA) as an energy source 12 , 13 . Without insulin, there becomes a plethora of FFA in the bloodstream because insulin impedes the lipolysis of adipocytes into glycerol and FFA 8 . These abundantly circulating FFA are taken to the liver and transported to its mitochondria for oxidation; then, ketone bodies are formed, including beta-hydroxybutyrate, acetone, and acetoacetate. Insulin checks the biochemical process, but excessive ketone production results from insufficient insulin 14 . In uncomplicated diabetes or starvation, triglycerides usually predominate ketones. The ketones produced do not overwhelm the body’s ability to get rid of them, putting it in a state of ketosis 15 . Glucagon, catecholamines, cortisol, and growth hormone also significantly increase blood glucose through gluconeogenesis and glycogenolysis 15 . The release of these hormones can also be a response to stress, which can take the form of infections (i.e., urinary tract infections and respiratory tract infections, especially the lower tract); trauma; myocardial infarction; acute pancreatitis; burns; surgery; strokes; substance abuse; and so on 16 . These stressors cause a release in inflammatory cytokines that increase insulin counter-regulatory hormones like glucagon, catecholamines, cortisol, and growth hormone 17 . These hormones put the body in a catabolic state, causing more lipolysis and proteolysis to synthesize glucose, which worsens hyperglycemia 18 .

The commonest precipitants of diabetic ketoacidosis are poor compliance with insulin therapy, infections, and a new diagnosis of diabetes 19 . The most common precipitating factor of diabetic ketoacidosis in type 1 diabetes patients is nonadherence to treatment, while infections are the most common precipitant in type 2 diabetes patients 20 . Other causes are vascular events (e.g., acute coronary syndrome, cerebrovascular accidents, critical limb ischemia, bowel ischemia, and shock); excessive alcohol intake; illicit drugs such as cocaine and methamphetamine; antipsychotic drugs, for example, clozapine, risperidone, and olanzapine 19 .

Laboratory abnormalities and diagnosis

In 2003, the American Diabetes Association modified the diagnostic criteria of DKA by introducing severity categories of mild, moderate, and severe, as displayed in Table ​ Table1 1 2 , 21 .

Diagnostic criteria and severity of diabetic ketoacidosis

Abnormal changes in laboratory values give a significant clue of what exactly happens in patients with suspected diabetic ketoacidosis 2 , 21 – 23 .

The diagnosis of DKA consists of a triad of hyperglycemia, ketonemia, and metabolic acidosis.

All patients with positive ketones, constitutional symptoms, or suspicion of DKA and significantly elevated blood glucose levels [>13.9 mmol/l (>250 mg/dl)] should have electrolytes and blood gases checked to look for an anion gap metabolic acidosis 2 . Significantly in type 1 diabetes, DKA can develop within hours if you stop insulin injections or an insulin pump malfunctions 21 . The new American Diabetes Association definition of DKA includes a blood glucose level of 13.9 mmol/l (250 mg/dl) 2 . Many studies show that DKA is infrequent at lower levels except in situations with poor oral intake or pregnancy 22 . It is also essential to consider DKA in differential diagnoses for patients with anion gap metabolic acidosis. Check serum glucose even when the patient has no history of diabetes 15 . Consider DKA if the serum glucose is more significant than 13.9 mmol/l (250 mg/dl), but an elevated glucose level alone is insufficient to diagnose DKA. Suspect DKA in patients with diabetes with a concurrent infection, stroke, myocardial infarction, or other serious illness 13 . These intercurrent illnesses should be sought and treated aggressively 13 . Similarly, it is vital to consider DKA when patients with diabetes experience nausea and vomiting, even if the blood sugar level is less than 13.9 mmol/l (250 mg/dl) 10 . Euglycemic DKA occurs more often in patients who have not eaten but continue taking insulin 12 . A blood sugar level of less than 13.9 mmol/l (250 mg/dl) occurs in 1–7% of reported DKA cases and seems more common in patients with hepatic dysfunction or in those who are in patients 11 . Several drugs, such as glucocorticoids or thiazides, are well-known causes of hyperglycemia that may lead to DKA. Clinicians should also consider DKA in patients taking atypical antipsychotic drugs who present with hyperglycemia 23 . Atypical antipsychotic drugs have increased the frequency of diabetes, glucose intolerance, and DKA. The healthcare provider should measure such patients’ anion gap and ketone levels. Another type of antipsychotic drug must be chosen to help resolve this complication 24 , 25 . The presentation of a patient with DKA varies substantially depending on the severity of the episode 5 . Mild or moderately ill patients may describe vague symptoms of fatigue, lethargy, poor appetite, or headache. In type 1 diabetes, the history of polyuria and polydipsia may be relatively recent, but in type 2 diabetes, these symptoms may have been building for weeks to months 8 . Nausea, vomiting, and abdominal pain are commonly seen in DKA and may be related to the combined effects of dehydration, hypokalemia, ketonemia, and delayed gastric emptying 24 . Signs of dehydration, including poor skin turgor, decreased axillary sweat, or postural hypotension, may be present on physical examination 2 . Kussmaul respirations (a pattern of deep breathing and hyperventilation in response to metabolic acidosis) may be present 5 . Patients’ breath may smell fruity due to increased acetone from ketonemia, but the absence of this finding does not rule out DKA. One examination aspect that can be confusing is abdominal tenderness, which may resolve with the treatment of DKA or reflect a more acute abdominal process that precipitates DKA 19 . Abdominal pain correlates with the level of acidosis 15 . The physical examination should identify potential precipitating factors, such as infections or cardiovascular events. Patients may have mental status changes ranging from mild lethargy to delirium or coma. The most severe cases have features like hypotension, tachycardia, and coma 20 . Capillary blood ketone measurement is a relatively new quantitative and enzymatic test that determines levels of 3-β-hydroxybutyrate, one of the three ketone bodies 13 . The equipment is similar to that patients use for home blood glucose determination, but it requires specific strips. However, checking capillary blood ketones is much more expensive than checking urine ketones, and further clinical studies are needed to define the most appropriate role for β-hydroxybutyrate monitoring 24 . If clinical suspicion of DKA is high, a negative urine dipstick for ketones does not exclude DKA. Clinicians should know that urine test sticks do not measure β-hydroxybutyrate, the predominant ketone. Acetoacetate measured on the dipstick may not be high until later during the illness 23 . Arterial blood gas assessment is generally considered the most reliable method to evaluate the degree of acidosis in DKA, but a venous pH may be a more practical alternative. The average anion gap is 7–9 mmol/l but is ~25 mmol/l in DKA 2 . Rarely do patients with DKA have mixed acidosis and alkalosis with a pH close to normal. However, this unexpected laboratory result should not affect the treatment of DKA 17 . Determination of the arterial blood gas may be optional. Most DKA guidelines indicate that hyperglycemia of more than 13.9 mmol/l is necessary for diagnosing DKA; however, this is not an absolute requirement, as there are reports about DKA without hyperglycemia 20 . DKA without hyperglycemia is reported chiefly during pregnancy and in patients with prolonged vomiting or starvation 9 . It can also occur in patients with liver failure or alcohol abusers 9 . Ketone bodies are produced in the liver from acetyl-CoA liberated during lipolysis from fatty acids. For DKA to develop, an absolute or relative insulin deficiency must be present. Three ketone bodies are produced: acetone (resulting in the fruity odor of DKA patients), acetoacetate, and β-hydroxybutyrate (β-OHB). β-OHB is the most prominent contributor to metabolic acidosis in patients with DKA 18 . Acetone does not contribute to acidosis and is not usually measured as such. Acetoacetate can be measured in the urine with a urine dipstick utilizing the nitroprusside reaction 10 . As DKA resolves, β-OHB is oxidized to acetoacetate. Therefore, if only a urine ketone dipstick procedure is done, it might give the impression that the condition is not improving. Blood ketones can be measured with a point of care (bedside) meter utilizing capillary finger prick blood 10 . This measures β-OHB directly and accurately 11 , 12 . The American Diabetic Association recommends that the blood ketone measurement of β-OHB is preferable to urine measurement for diagnosing and monitoring DKA 8 . An arterial pH of less than 7.3 should be present in diagnosing DKA. The measurement of pH or serum bicarbonate is essential for the diagnosis and estimation of the severity of DKA 4 . The pH is also an important measure to assess improvement and treatment adjustment. A venous pH determination would probably be sufficient unless respiratory function must also be evaluated 12 . The venous pH is, on average, 0.03 lower than the arterial pH 23 .

Differential diagnosis

Diabetic ketoacidosis may have a diverse and complex presentation, which makes it share many similarities in the way and manner it presents compared to other common pathologies; hence, other common pathologies may mimic diabetic ketoacidosis 1 . It is, therefore, essential to rule out other pathologies with similar presentations whenever a case of diabetic ketoacidosis is suspected. Differentials include; starvation ketoacidosis, pancreatitis, alcoholic ketoacidosis, lactic acidosis, uremia, overdose on diabetic medication, hyperosmolar hyperglycemic nonketotic syndrome, and myocardial infarction 2 .

Therapy goals in patients with hyperglycemic crises include improving the circulatory volume and tissue perfusion, gradual reduction of serum glucose and osmolality, correcting electrolyte imbalance, and identifying and promptly treating co-morbid precipitating causes. Successful treatment of DKA requires frequent monitoring of patients regarding the above goals by clinical and laboratory parameters. Table ​ Table2 2 below illustrates the initial management of patients with diabetic ketoacidosis 2 , 26 .

Detailed management of patients with diabetic ketoacidosis

A patient with diabetic ketoacidosis might have normal potassium levels before the initiation of treatment; the medical practitioner should take caution to prevent severe hypokalemia after initiating insulin therapy. Table ​ Table3 3 shows endocrine society’s clinical practice guideline for hospitalized patients with diabetes 2 , 26 – 29 .

Endocrine society’s clinical practice guideline for hospitalized patients with diabetes

This guideline addresses several crucial aspects of care precise for inpatient management of noncritically ill patients with diabetes or newly recognized hyperglycemia that can potentially improve clinical outcomes in the hospital and following discharge. This guideline addresses and updates some of the standards of care for glycemic management for noncritically ill-hospitalized adult patients with diabetes 30 .

Conclusions

Diabetic ketoacidosis is often a severe medical emergency that results in a complication of diabetes. When the diagnosis of diabetic ketoacidosis is made, the blood glucose level is higher than 250 mg/dl, the bicarbonate level is less than 15 mmol/l, the arterial pH is less than 7.3, and there is ketonuria or ketonemia. It occurs primarily in patients with type 1 diabetes. The incidence is roughly two episodes per 100 patient-years of diabetes, with about 3% of patients with type 1 diabetes initially presenting with diabetic ketoacidosis. It can occur in patients with type 2 diabetes as well; however, this is less common. Diabetic ketoacidosis usually occurs due to absolute or relative insulin lack accompanied by increased glucagon, cortisol, growth hormone, and epinephrine. This insulin deficiency enhances hepatic gluconeogenesis, glycogenolysis, and lipolysis leading to severe hyperglycemia, ketoacidosis, and ketonuria.

In most cases, there are precipitating factors, which could be: underlying infection, missed insulin treatment, previously unknown diabetes, surgical stress, etcetera. Prompt diagnosis and treatment are essential to improve patient outcomes. Treatment involves fluid resuscitation, insulin administration to correct hyperglycemia, correction of acidosis, electrolyte imbalances, and treatment of underlying causes or precipitants. The prognosis of adequately treated patients is excellent.

Ethics statement

It was exempted and waived at my institution.

Patient consent

Patient consent was waived due to the minimal risk nature of the observational chart review study.

Sources of funding

All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.

Authors’ contributions

The author and co-authors played important roles to actualize this article as shown below: C.E.: conceptualization, visualization, supervision, oversight and leadership, writing of the original draft; J.A.D.: conceptualization, validation, writing of the original draft, methodology; A.-O.U.: resources, software, visualization; E.O.E.: conceptualization, validation, resources, methodology; I.C.O.-C.: resource and journal review, formal analysis, writing of the original draft; L.O.U.: writing of the original draft, data creation, project administration; A.I.T.: writing of the article, data curation, leadership; J.O.I.: writing of the article, reviewing and revising the text; A.O. I.: project administration, editing, concept rephrasing; P.U.N.: literature search, writing, and editing; M.O.K.: editing, concept rephrasing, and editing; C.E.: drafting and revising the article; A.I.B.: concept rephrasing and maintenance of data research integrity; O.A.: preparation, typing, editing; O.S.O.: methodology and drafting of conclusion; F.O.J.: project administration, review, and editing; H.I.R.-Y.: editing, concept rephrasing, and editing.

Conflicts of interest

In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.

Research registration unique identifying number (UIN)

Chukwuka Elendu, E-mail: .moc.oohay@akuwkuhcudnele

Provenance and peer review

Commissioned, externally peer reviewed.

Data availability statement

Institutional review board statement.

The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Board of the Mayo Clinic (IRB ID: 21-007698).

Informed consent statement

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Published online 23 May 2023

Hypokalaemic complications in diabetic ketoacidosis: Clinical and conceptual approaches for improved diagnosis and management

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Conclusions, acknowledgments, acidosis: the prime determinant of depressed sensorium in diabetic ketoacidosis.

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Ebenezer A. Nyenwe , Laleh N. Razavi , Abbas E. Kitabchi , Amna N. Khan , Jim Y. Wan; Acidosis: The Prime Determinant of Depressed Sensorium in Diabetic Ketoacidosis. Diabetes Care 1 August 2010; 33 (8): 1837–1839. https://doi.org/10.2337/dc10-0102

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The etiology of altered sensorium in diabetic ketoacidosis (DKA) remains unclear. Therefore, we sought to determine the origin of depressed consciousness in DKA.

We analyzed retrospectively clinical and biochemical data of DKA patients admitted in a community teaching hospital.

We recorded 216 cases, 21% of which occurred in subjects with type 2 diabetes. Mean serum osmolality and pH were 304 ± 31.6 mOsm/kg and 7.14 ± 0.15, respectively. Acidosis emerged as the prime determinant of altered sensorium, but hyperosmolarity played a synergistic role in patients with severe acidosis to precipitate depressed sensorium (odds ratio 2.87). Combination of severe acidosis and hyperosmolarity predicted altered consciousness with 61% sensitivity and 87% specificity. Mortality occurred in 0.9% of the cases.

Acidosis was independently associated with altered sensorium, but hyperosmolarity and serum “ketone” levels were not. Combination of hyperosmolarity and acidosis predicted altered sensorium with good sensitivity and specificity.

Diabetic ketoacidosis (DKA) is frequently associated with altered mental status, which is correlated with the severity of the disease and prognosis ( 1 ). However, the etiology of depressed sensorium in DKA remains uncertain and controversial ( 2 , 3 ). Putative factors in the pathogenesis of diabetic ketoacidotic coma include cerebral hypoperfusion due to circulatory collapse and cerebral thrombosis ( 4 ), reduced cerebral glucose and oxygen utilization ( 1 , 5 ), acidosis ( 6 , 7 ), hyperosmolarity ( 8 , 9 ), and direct toxic effect of ketone bodies ( 2 ). Cerebral edema remains an important precipitant of altered consciousness in DKA, especially in children.

Different studies have yielded conflicting results regarding the role of these etiologic factors in the pathogenesis of altered mentation in patients with DKA. Hence, the origin of clouded sensorium in DKA remains to be fully elucidated. We undertook to study the etiology of depressed consciousness in patients admitted with DKA at the Regional Medical Center in Memphis.

We performed a retrospective analysis of patients admitted with DKA between October 2003 and October 2008. DKA was diagnosed based on American Diabetes Association criteria ( 10 ). Demographic and biochemical data were extracted from the medical records of the patients including serum pH, bicarbonate, sodium, potassium, blood urea nitrogen (BUN), serum creatinine, osmolality, “ketones,” arterial pO 2 and pCO 2 , as well as level of consciousness. Serum effective osmolality was calculated as reported before ( 10 ).

Patients were categorized by mental status into alert versus altered (semi-comatose and comatose).

Statistical analysis

For comparison of variables among groups, univariate analysis was performed. To identify the independent determinants of level of consciousness, multivariate linear model analysis was applied. The groups were characterized using means ± SD and compared by Student's t test for continuous variables and χ 2 test for discrete variables using SAS 9.1.3 software. Using quartiles of pH and serum osmolality as predictors of depressed consciousness, we generated a receiver operating characteristic curve from which we derived the sensitivity and specificity of these independent variables in predicting the presence of depressed sensorium in patients presenting with DKA.

Quartiles of pH were as follows: 6.92–7.03, 7.04–7.15, 7.16–7.25, and 7.26–7.40, while quartiles of serum osmolality were as follows: 231–287, 287.4–301, 301.2–315, and 316–431.

The Institution Review Board of the University of Tennessee Health Science Center approved this study.

We recorded 216 cases of DKA in patients aged 37.7 ± 12.4 years, 57.9% of whom were males, whereas 21 and 15% had type 2 diabetes and new-onset diabetes, respectively. Average blood glucose level was 658.6 ± 276.0 mg/dl, whereas mean serum osmolality and pH were 304 ± 31.6 mOsm/kg and 7.14 ± 0.15, respectively. Serum sodium and potassium were 131.6 ± 6.5 and 5.4 ± 3.5 mEq, respectively. The clinical and biochemical characteristics of the patients according to mental status are shown in Table 1 . Variables that demonstrated a significant difference between the two groups were entered into a multiple regression model shown in supplemental Table 1 (available in an online appendix at http://care.diabetesjournals.org/cgi/content/full/dc10-0102/DC1 ). As can be seen, only pH emerged as an independent determinant of level of consciousness in this cohort of patients with DKA.

Clinical and biochemical characteristics of the patients at presentation

*Statistically significant.

To further elucidate the influence of acidosis measured by arterial pH and effective serum osmolality on the level of consciousness at presentation, we determined the odds ratio of depressed sensorium in all 216 subjects by quartiles of pH and osmolality (see supplemental Fig. 1 in the online appendix). Supplemental Fig. 1 clearly demonstrates that arterial pH is the prime determinant of mental status in DKA, which appeared to act synergistically with hyperosmolarity to produce depressed consciousness. In patients with severe acidosis (lowest pH quartile ≤7.03), the odds ratio for altered sensorium was 1 if serum osmolality was in the lowest quartile (≤287), but increased almost threefold to 2.8 among patients in the highest quartile of osmolality (≥316). However, in the absence of severe acidosis, worsening hyperosmolarity was not significantly associated with altered sensorium (odds ratio <1). Therefore, although acidosis was required for depressed sensorium to occur, the likelihood of altered mentation was higher in the presence of elevated serum osmolality. A total of 45 patients (20.8%) were in the lowest pH quartile, while 52 patients (24.1%) were in the highest osmolality quartile (≥316 mOsm/kg). Fifteen subjects (6.9%) had a combination of low pH and high osmolality. This latter category represented the patients with the highest likelihood of having depressed level of consciousness (odds ratio 2.81). Mortality, which was recorded in 0.9% of the cases, occurred in patients who had presented with severe acidosis and sepsis. The combination of severe acidosis and hyperosmolarity predicted altered sensorium with sensitivity of 61% and specificity of 87% (supplemental Table 2 and supplemental Fig. 2).

We have demonstrated that acidosis measured by arterial pH at presentation is the prime determinant of mental status in DKA. Severe acidosis appeared to act in concert with hyperosmolarity in a synergistic manner to produce depressed sensorium in these patients. Therefore, a combination of acidosis and hyperosmolarity at presentation may identify a subset of patients with severe DKA (7% in this study) who may benefit from more aggressive treatment and monitoring. Identifying this class of patients, who are at a higher risk for poorer prognosis, may be helpful in triaging them, thus further improving the outcome.

The dominant effect of acidosis on mental status obtained in this study is consistent with the findings of other clinical studies ( 6 , 7 ).

Some studies have reported that depressed sensorium in DKA is attributable to elevated serum osmolality ( 8 , 9 ). However, despite some biochemical similarities between these two hyperglycemic crises, there are notable differences that may suggest different pathogenic mechanisms. We observed that hyperosmolarity, which was associated with depressed sensorium in a univariate model, did not prove to be an independent predictor of altered sensorium in a multivariate analysis. However, in the presence of hypertonicity, the likelihood of altered mental status was increased in patients with severe acidosis. Studies that reported hyperosmolarity as the sole etiology of altered consciousness DKA did not perform logistic regression ( 8 ) as we have done. This could be a confounding factor, since up to 30% of patients with DKA may have high serum osmolality ( 9 , 11 ).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

No potential conflicts of interest relevant to this article were reported.

E.A.N.: research design, data collection, statistical analysis, manuscript writing, and review of manuscript. L.N.R.: data extraction and collation, statistical analysis, and manuscript writing. A.E.K.: research design, manuscript writing, and critical review of manuscript for intellectual content. A.N.K.: data extraction and collation and manuscript writing. J.Y.W.: statistical analysis and manuscript writing.

We acknowledge the efforts of the following residents in internal medicine and fellows in endocrinology who assisted with data collection: Jevaria Ahmed, MD, Swaroopa Bartakke, MD, Malini Gupta-Ganguli, MD, Omid Rad Pour, MD, Amanda Long, DO, and Sadiya Zaidi, MD.

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Clinical Profile of Diabetic Ketoacidosis: A Prospective Study in a Tertiary Care Hospital

Affiliation.

• 1 Assistant Professor, Department of Emergency Medicine, Dayanand Medical College and Hospital , Ludhiana, India .
• PMID: 26266145
• PMCID: PMC4525534
• DOI: 10.7860/JCDR/2015/8586.5995

Background: Diabetic ketoacidosis, a well-known and major acute metabolic complication classically occurs in young patients with type 1 diabetes. However, it may occur in patients with type 2 Diabetes Mellitus too.

Objective: Aim of this study was to look into the clinical profile, precipitating factors and clinical outcome in the patients presenting with Diabetic ketoacidosis in the Emergency of a Tertiary care hospital.

Design: The study was a prospective study conducted over a period of two years in Kasturba Medical College, Manipal Karnataka, India.

Materials and methods: Clinical profile of 60 diabetic patients admitted in the Emergency with the diagnosis of Diabetic ketoacidosis were analysed.

Results: Out of 60 patients, 12 were of Type 1 and 48 were Type 2 Diabetes Mellitus. Mean duration of diabetes was 8.65 years. Only 14 (23.3%) patients were taking regular treatment for Diabetes Mellitus whereas 32 (53.33%) patients were on irregular treatment and eight (13.33%) were not on any treatment at all. Among 12 Type 1 Diabetic patients, six patients were freshly diagnosed to be diabetic when they presented with Diabetic ketoacidosis complication. Nausea and vomiting (63.33%) were the most common symptoms of these patients. Infections (73.33%) were the most common precipitating factor for Diabetic ketoacidosis. Mean fluid requirement on first day of therapy was 3.51 liters. Mortality of 10% was seen.

Conclusion: Diabetic ketoacidosis is a fatal acute metabolic complication of Diabetes Mellitus with heterogeneous clinical presentation. Early diagnosis and treatment can avoid morbidity & mortality.

Keywords: Diabetes mellitus; Emphysematous pyelonephritis; Hyperglycaemia; Ketosis; Non-compliance.

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Diabetic ketoacidosis among adult patients with diabetes mellitus admitted to emergency unit of Hawassa university comprehensive specialized hospital

• Asres Bedaso   ORCID: orcid.org/0000-0001-7859-0264 1 ,
• Zewdie Oltaye 1 ,
• Ephrem Geja 1 &
• Mohammed Ayalew 1  

BMC Research Notes volume  12 , Article number:  137 ( 2019 ) Cite this article

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This study was aimed to assess the prevalence and associated factors of diabetic ketoacidosis among adult patients admitted in emergency department of Hawassa university comprehensive specialized hospital. An institution based retrospective cross-sectional study design was conducted among 195 adult patients aged 16 years and above with known or previously unknown diabetes cases presented in the emergency unit.

In our study from the total 195 patients medical record reviewed 78 (40%) developed DKA. Out of the total reviewed medical record 55 (28.2%) and 23 (11.8%) were with type-1 and type 2 diabetes mellitus respectively. From acute complication of diabetes, diabetic ketoacidosis was a leading cause 78 (77%) followed by hypoglycemia 14 (14%) and hyperosmolar hyperglycemic state (9%). During multiple logistic regression analysis age and hypertension were found to have significant association with diabetic ketoacidosis.

Introduction

Diabetes is a group of metabolic disorder characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both [ 1 ]. Diabetes mellitus DM) is a group of common metabolic disorders that share the phenotype of hyperglycemia, which are caused by a complex interaction of genetics and environmental factors. It is the leading cause of end-stage renal disease, traumatic lower extremity amputations, and adult blindness. In Ethiopia study shows the prevalence of DKA among acute complication of DM was 68.3% and 71% in Dessie and Jimma respectively [ 2 ].

The major classifications of diabetes are type-1 diabetes which is caused by β-cell destruction and type-2 diabetes that results from insulin resistance. Type-1 DM covers 5–10% of all diabetes and type-2 DM covers 90–95% of all diabetes [ 3 ]. Diabetes and its complications are major causes of early death in most countries, with cardiovascular disease being the leading cause of death among people with diabetes [ 4 ].

Diabetes mellitus leads to acute and chronic complications include diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic state, and hypoglycemia during treatment. Diabetic ketoacidosis (DKA) is one of the most serious acute complications of DM. Ketoacidosis occurs when stored triglyceride broken down into fatty acid which serves as alternate sources of fuel, which causes elevation of blood ketone leads to ketoacidosis [ 5 ].

The common causes of DKA are missed dose of insulin, illness or infection, and undiagnosed or untreated diabetes. The main clinical features of DKA are hyperglycemia, dehydration, electrolyte loss, and acidosis [ 6 ]. Diabetic ketoacidosis (DKA) occurs commonly in people who have type 1 diabetes. However, people who have type 2 diabetes may also develop diabetic ketoacidosis [ 7 ].

In Africa, 19.8 million people or 4.9% are estimated to have diabetes in 2013 [ 8 ]. In Ethiopia, WHO estimates the number of cases of diabetics to be about 800,000 in 2000 and projected that it would increase to about 1.8 million by the year 2030 [ 9 ]. The same studies conducted in Ethiopia from 1970 to 2011 suggested that DM prevalence in the country was about 2%, rising to > 5% in persons aged ≥ 40 years in certain settings [ 10 ]. A more recent nationwide World Health Organization (WHO) Steps survey among 2153 persons in Ethiopia found the DM prevalence to be 6.5% [ 11 ].

DKA is one of the most fatal acute complications among DM patient. Its mortality rate ranges from 2 to 5 percent in developed countries and 6 to 24 percent in developing countries. If it misdiagnosed or mistreated, it is 100% fatal [ 12 ]. In some studies it has been reported that DKA can be present in 25% to 30% of type 1 diabetes cases at onset and from 4 to 29% in youth with type-2 diabetes [ 13 ].

Several studies were conducted on diabetes mellitus and its complication, but few studies were done on the prevalence and factors associated with DKA among Ethiopian patients. As a result of this information’s are scant to promote better health service to prevent mortality due to DKA in Ethiopia.

Methods and materials

Study design, area and period.

Institution based retrospective cross-sectional study design was conducted at Hawassa university comprehensive specialized hospital from February 01–30/2018. Hawassa is the capital city of SNNPR of Ethiopia, which is 273 km far from South of Addis Ababa. The hospital gives service for about 18 million people of SNNPR and neighboring areas of Oromia regional state. It has 350 beds for admitted patients. The hospital provides different service through inpatient and outpatient level. The hospital’s emergency unit gives services for approximately 10,000 patients per year. The emergency unit has more than 33 beds and 10 rooms for emergency admission.

All adult DM patients who visited Hawassa university comprehensive specialized hospital emergency unit from January, 2016 to January, 2018 were the source population. Diabetes patients, who visited adult emergency unit of Hawassa university comprehensive specialized hospital from January, 2016 to January, 2018 and those who fulfill the inclusion criteria were the study population.

Sample size and sampling technique

Single population proportion formula was used to calculate sample size with the assumption of, 5% margin of error, 95% confidence interval and 71% proportion of DKA from a study conducted in Jimma University teaching hospital [ 2 ]. Since the source population was < 10,000, we used a correction formula, adding 10% non response rate, the final sample size was 195.

Systematic random sampling technique was used to select the record of the study subjects. The record of the study subjects were selected based on constant interval K = 2 calculated from total DM case admitted at emergency unit from 1/2016 to 1/2018 in chronological order, which were 400 divided by the sample size of the study 195. The first patient was selected by a lottery method with in the first two medical record number and all patient charts in K interval was included in the study until the calculated sample size was obtained.

Data collection instrument and data collection technique

A structured and adapted questionnaire was used and pre-test was conducted in Adare hospital 5% of the sample size. The data was collected using structured questionnaire. The collected data were entered and analyzed using SPSS version 20. Binary and multiple logistic regression analysis was used to see the association between outcome and explanatory variables. During multiple logistic regression, the strength of association was measured by odds ratio with 95%CI and P-value less than 0.05 was considered as statistically significant.

Operational definition

Short-acting insulin treat: 30 min–1 h of onset (length of time before insulin reaches bloodstream).

Intermediate acting: 1.5–4 h of onset (length of time before insulin reaches bloodstream).

Long-acting: 0.8–4 h of onset (length of time before insulin reaches bloodstream).

Socio demographic characteristics

There were total of 400 adult patients who were admitted with DM in emergency room of Hawassa university comprehensive specialized referral hospital during two years period (January/2016–January/2018). Of these 400 patients, 195 diabetic cases were reviewed. 125 (64.1%) of the study subjects were male and 52 (26.7%) were within the age group of 25–34 (Table 1 ).

Prevalence of diabetic ketoacidosis among patients with DM

Among the reviewed 195 diabetic patients medical record, 114 (58.46) were type 1 DM and 81 (41.54%) were type 2 DM. From the total 195 patients, type-1 DM with DKA was 55 (28.2%) and type-2 DM with DKA was 23 (11.8%) (Table 2 ).

Also from the total reviewed 195 records, 128 (65.6%) were known DM and 67 (34.4%) were newly diagnosed, among them, known DM with DKA were 36 (46.15%) and newly diagnosed DM cases with DKA were 42 (53.85%) (Additional file 1 ).

Acute and chronic complications of DM

Among acute complication of DM, DKA was the leading causes 78 (77%), followed by hypoglycemia 14 (14%), and hyperosmolar hyperglycemic state (HHS) 9 (9%). The most common chronic complication was DFU (diabetic foot ulcer) 60%, followed by retinopathy 27%, and nephropathy 13%.

Anti diabetic medication profile

Most DKA patients 59 (75.64%), commonly taking short acting agents, followed by intermediate acting 19 (24.36%) (Additional file 2 ).

Sign and symptom of DKA/DM/

In this study the frequently reported presenting symptoms of DKA or DM were 3P (polydipsia, polyuria, polyphagia) (50.3%), followed by 2P (polyuria and polydipsia) (29.2%), others (15.9%), and weight loss 1.5%.

Factors associated with DKA

During multiple logistic regression analysis age, duration of DM with DKA and hypertension, found to the significant factors for developing DKA. Age groups between 15–24 and 25–34 years and HTN have significant association with developing DKA among patients (Table 3 ).

The prevalence of diabetic ketoacidosis among DM patients in this study was 40%. It is close to former studies conducted in Italy (40.3%) [ 14 ] and Collared university (38.6%) [ 12 ]. However, low prevalence has been reported in the a previous studies conducted in Cambridge University (18–22%) [ 6 ], Nigeria (12.2%) [ 4 ], and England (22.5–23.9%). The variation might be due to the socio-cultural differences in health seeking behavior, a change in feeding and overall life style emanating from increasing urbanization and economic development in the region.

In this study the prevalence of DKA in type 1 DM and type 2 DM was 28.7% and 11.28% respectively. The current finding was in line with studies conducted in Colorado American university [ 13 ], prevalence of DKA in type one diabetes and type 2 was 25–30% and 4–29% respectively.

In our study, among newly diagnosed DM case, 53.85% of cases present with DKA. This figure is more than what observed in England (22.5 to 23.9%) [ 15 ]. The variation might be due to socioeconomic status, race/ethnicity variation.

In the current study the prevalence of DKA among acute complications of diabetes is 77%. The finding was higher than the previous studies done in Dessie (68.3%) [ 2 ]. The variation might be due to the different study design used and different socio-demographic characteristics of clients.

In the study younger age was significantly associated with DKA, the finding was in line with studies conducted in Jima referral hospital [ 2 ], Colorado university [ 13 ] and findings in four countries England, Wales, Austria, US and Germany [ 16 ]. Another study conducted in Cambridge university indicated that age had significantly associated with diabetic ketoacidosis [ 6 ].

In this study being male, and being younger age group were significantly associated with DKA, similar to previous finding in Italy [ 14 ]. Ketosis-prone diabetes mellitus (KPDM ) was more frequent in men compared to women and in obese compared to non-obese participants. Gender differences in KPDM may be associated with a different impact of obesity in men and women. Although multiple factors (e.g., ethnic minority, lack of health insurance, lower body mass index, preceding infection, delayed treatment) affect the risk of developing DKA among children and young adults, intervention is possible between symptom onset and development of DKA [ 6 ].

The prevalence of DKA among diabetes observed in this study was 40%. The study found that diabetic ketoacidosis is more common in male and young adults’ particular between the ages of 25–34 years.

Since the study is cross sectional, it cannot identify cause and effect relationship.

Abbreviations

adjusted odds ratio

confidence interval

crudes odds ration

diabetic foot ulcer

diabetic ketoacidosis

diabetes mellitus

Gregorian calendar

hyperosmolar hyperglycemic state

hypertension

ketosis prone diabetes mellitus

medical record number

Southern Nations Nationalities and Peoples Region

United States

World Health Organization

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Authors’ contributions

AB and ZO participated in the conception, design of the study, reviewing the proposal, data analysis and report writing. MA and EG participated in data analysis and report writing. AB prepared the manuscript for publication. All authors read and approved the final manuscript.

Acknowledgements

We would like to thank Hawassa University comprehensive specialized hospital staffs for their strong support during data collection.

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

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Ethical approval was obtained from the Institutional Review Board of Hawassa University College of medicine and Health Sciences. Permission to carry out the study was also obtained from the hospital on behalf of the patients. All records of patient were kept confidential and anonymous. Filled out questionnaires were carefully handled and access to results was kept strictly.

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Additional files

Additional file 1..

Profile of patients Type-1 and Type-2 diabetes with DKA among patient visited to Hawassa university comprehensive specialized hospital emergency room from January 2016 to January 2018 GC.

Additional file 2.

Anti diabetic medication profile of patients T1 & T2 diabetes with DKA versus without DKA among patient visited to Hawassa university comprehensive specialized hospital emergency room from January 2016 to January 2018 GC.

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Diabetic, Alcoholic, and Starvation Ketoacidosis

• Alluru S. Reddi 2  
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Ketones are acetone, acetoacetic acid (acetoacetate), and β-hydroxybutyric acid (BHB). Of these, only acetoacetetate and BHB cause acidosis, whereas acetone does not cause acidosis. Acetone is formed by nonenzymatic decarboxylation of acetoacetate and does not contribute any acid load to the body (Fig. 32.1). Clinically, metabolic acidosis due to ketone overload is caused by diabetes, alcohol, and starvation. Therefore, this chapter focuses on diabetic, alcoholic, and starvation ketoacidosis.

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Reddi, A.S. (2023). Diabetic, Alcoholic, and Starvation Ketoacidosis. In: Fluid, Electrolyte and Acid-Base Disorders. Springer, Cham. https://doi.org/10.1007/978-3-031-25810-7_32

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Initial management of diabetic ketoacidosis and prognosis according to diabetes type: a French multicentre observational retrospective study

• Adrien Balmier 1 , 2 ,
• Fadia Dib 3 , 4 , 5 ,
• Arnaud Serret-Larmande 6 ,
• Etienne De Montmollin 7 , 8 ,
• Victorine Pouyet 9 ,
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• Bruno Megarbane 12 , 13 ,
• Abirami Thiagarajah 1 , 9 ,
• Didier Dreyfuss 1 , 8 ,
• Jean-Damien Ricard 1 , 8 &
• Damien Roux   ORCID: orcid.org/0000-0002-6103-6416 1 , 8  

Annals of Intensive Care volume  9 , Article number:  91 ( 2019 ) Cite this article

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Guidelines for the management of diabetic ketoacidosis (DKA) do not consider the type of underlying diabetes. We aimed to compare the occurrence of metabolic adverse events and the recovery time for DKA according to diabetes type.

Multicentre retrospective study conducted at five adult intermediate and intensive care units in Paris and its suburbs, France. All patients admitted for DKA between 2013 and 2014 were included. Patients were grouped and compared according to the underlying type of diabetes into three groups: type 1 diabetes, type 2 or secondary diabetes, and DKA as the first presentation of diabetes. Outcomes of interest were the rate of metabolic complications (hypoglycaemia or hypokalaemia) and the recovery time.

Of 122 patients, 60 (49.2%) had type 1 diabetes, 28 (22.9%) had type 2 or secondary diabetes and 34 (27.9%) presented with DKA as the first presentation of diabetes (newly diagnosed diabetes). Despite having received lower insulin doses, hypoglycaemia was more frequent in patients with type 1 diabetes (76.9%) than in patients with type 2 or secondary diabetes (50.0%) and in patients with newly diagnosed diabetes (54.6%) ( p  = 0.026). In contrast, hypokalaemia was more frequent in the latter group (82.4%) than in patients with type 1 diabetes (57.6%) and type 2 or secondary diabetes (51.9%) ( p  = 0.022). The median recovery times were not significantly different between groups.

Conclusions

Rates of metabolic complications associated with DKA treatment differ significantly according to underlying type of diabetes. Decreasing insulin dose may limit those complications. DKA treatment recommendations should take into account the type of diabetes.

Diabetic ketoacidosis (DKA) is a severe acute event in diabetes mellitus characterized by dehydration, hyperglycaemia and metabolic acidosis due to ketone hyperproduction. Although historically observed almost exclusively in type 1 diabetes in a context of absolute insulin deficiency, DKA has been increasingly described in type 2 diabetes in the last decades [ 1 , 2 , 3 ]. DKA may frequently reveal diabetes mellitus (DKA as first presentation of diabetes).

The pathophysiology of DKA involves severe insulin deficiency and increased levels of counterregulatory hormones (glucagon, catecholamines, cortisol and growth hormone), leading to hyperglycaemia, osmotic diuresis and production of ketone bodies (acetoacetate, 3-beta-hydroxybutyrate and acetone). This results in metabolic acidosis with increased anion gap. Osmotic diuresis explains losses of water, sodium, potassium and phosphate [ 4 , 5 ].

Diabetic ketoacidosis is, thus, defined by the association of ketonemia ≥ 3 mmol/l or ketonuria ≥ 3+, blood glucose > 11 mmol/l (or known diabetes mellitus), venous plasma bicarbonates (HCO 3 − ) < 15 mmol/l and/or venous pH < 7.30. The four key points of DKA patient management are (i) admission in a high dependency unit if presence of at least one severity criterium, (ii) rehydration with isotonic saline, (iii) intravenous insulin therapy, and (iv) potassium supplementation [ 6 , 7 ]. Severity criterium defined by international guidelines include neurological, hemodynamic, pulmonary or biological criterium [ 6 ].

Vascular filling followed by insulin therapy is the cornerstone of DKA management. Numerous studies have reported a high incidence of potentially serious adverse events of insulin therapy such as hypoglycaemia and hypokalaemia during DKA management [ 8 , 9 , 10 , 11 ]. A national survey of DKA management conducted in 2014 in the UK showed rates of 55% of hypokalaemia (at least one episode below 4.0 mmol/l) and 27% of hypoglycaemia (at least one episode) during the 1st day after admission [ 8 ].

So far, DKA management in patients with type 2 has been similar to that in patients with type 1 diabetes, although the underlying pathophysiology and clinical profile differ between the two populations, with significant insulin resistance, older age and more prevalent comorbidities in type 2. This undifferentiated approach is not based upon evidence and remains to be demonstrated as appropriate. Since insulin resistance is an important part of type 2 diabetes pathophysiology, we hypothesized that patients with type 2 diabetes are less susceptible to such potentially harmful adverse events. No study has addressed this question. Therefore, in this study, we aimed to compare the metabolic events and the recovery time in adult patients hospitalized for DKA, according to the type of underlying diabetes. We also assessed to what extent the therapeutic management of DKA in the participating centers respected the guidelines [ 6 ].

Study design

This is a French multicentre retrospective cohort study of patients admitted for DKA in five adult intensive care units in Paris and its suburb, between January 1, 2013 and December 31, 2014. All participating units were closed units. All medical decisions were, thus, taken by the intensivists in charge. Patients with DKA were identified in the PMSI database (Programme de Médicalisation des Systèmes d’Information) using the ICD 10 codes. All adult patients admitted for DKA as the main diagnoses were included. Patients under 15 years, those with another cause of acidosis and those with hyperglycemic hyperosmolar state were not included. They were, thus, grouped and compared according to the underlying type of diabetes in three groups: patients with known type 1 diabetes (group 1), patients with known type 2 or secondary diabetes (group 2), or patients with DKA as first presentation of diabetes (group 3). Type of diabetes was based on medical files, medical history and treatment regimens. Since it was difficult based on our data to differentiate type 2 diabetes and secondary diabetes, we included these patients in the same group. The study was approved by the Institutional Review Board of Bichat Hospital (approval number: 2018-008).

Data collection

The following data were recorded from the medical records: demographics and clinical characteristics, the underlying type of diabetes, presence of chronic complications such as microangiopathy (retinopathy, nephropathy or neuropathy), macroangiopathy (cardiovascular disease with coronary arteries, brain or lower limb artery diseases) or chronic renal failure (creatinine clearance below 15 ml/min per 1.73 m 2 ), laboratory data (obtained from capillary, blood and urine sampling) and treatments administered within the 48 first hours following hospital admission.

Outcome variables

Metabolic adverse events during the first 48 h were defined as: hypoglycaemia (at least one episode of blood glucose lower than 4 mmol/l), severe hypoglycaemia (at least one blood glucose lower than 2.9 mmol/l) and hypokalaemia (at least one episode of serum potassium less than 3.5 mmol/l).

Diabetic ketoacidosis resolution time was defined as the interval in hours between the first vascular filling to treat the DKA (performed either in pre-hospital (mobile medical team), in the emergency room or in the ICU) and DKA resolution defined as the occurrence of: the first blood ketone < 0.5 mmol/l, or the first negative ketonuria (0 or 1 cross), or the discharge time from the ICU, which ever came first.

Biological measurements

The initial blood glucose level was measured either in a venous sample or, if not available, on a capillary glucose test. In the latter case, if the hyperglycaemia measurement threshold was attained, the value of 35 mmol/l was assigned (hyperglycaemia measurement threshold of the capillary glucose meter). Initial ketonemia was the first ketonemia measured either on venous blood in the laboratory or by capillary ketone test. For severity assessment, the anion gap at admission is calculated according to the following formula: (Na +  + K + ) − (Cl −  + HCO 3 − ).

Statistical analysis

Quantitative variables were presented using median and interquartile ranges, while qualitative variables using numbers and percentages. The three groups were compared on all continuous variables using one-way analysis of variance (ANOVA) tests and Kruskal–Wallis tests as appropriate; they were compared on all qualitative variables using Chi-square and Fisher’s exact tests as appropriate. If significant differences occurred between groups, then paired comparisons were performed using Mann–Whitney U -tests and Chi-square tests as appropriate. All p -values were 2-sided, and significance was set at p  < 0.05. Analyses were performed using R version 3.3.0 and SAS (version 9.3, SAS institute Inc., Cary North Carolina).

Baseline characteristics

During the study period, 122 patients were admitted to the five participating centers for DKA treatment. Sixty patients (49.2%) had a history of type 1 diabetes, 28 (22.9%) a history of type 2 or secondary diabetes, and 34 (27.9%) had no known history of diabetes. Five pregnant women were included: two patients with a type 1 diabetes and three patients with this episode of DKA revealing a diabetes. Patients were hospitalized in adult intermediate care unit in 61.5% of cases and in adult intensive care unit in 38.5% of cases. Of note, 10 patients between 15 and 18 years old were admitted in our adult units. This is general practice in France where patients older than 15 are considered as adults.

Patient’s characteristics, precipitating causes of DKA and biological results on admission are shown in Table  1 . Patients with type 1 diabetes were younger and had a lower weight than other groups ( p  < 0.0001 and p  < 0.01 as compared to patients with type 2 or secondary diabetes and patients with DKA revealing diabetes, respectively). Patients with type 2 or secondary diabetes had more diabetic chronic complications than other groups ( p  < 0.01 for both). Plasma protein and haemoglobin concentrations (as a marker of dehydration) were higher in patients with newly diagnosed diabetes ( p  < 0.001 and p  < 0.01 as compared to type 1 diabetes and type 2 or secondary diabetes, respectively). Sex ratio was not different between groups. According to French law, it is not allowed to report patient ethnicity. Hence, this parameter was not recorded.

Treatment management

Table  2 presents the characteristics of treatment management (vascular filling and insulin therapy) during the first 48 h. Intravenous insulin therapy was started at the same time as vascular filling in 45.5% of cases. In 47.3% of cases, insulin was started after the beginning of vascular filling. Insulin was administered before the start of filling in 7.3% of cases. Normalized to body weight, patients with type 1 diabetes and patients with newly diagnosed diabetes received a lower insulin dosage (an average of 0.079 U/kg/h and 0.083 U/kg/h, respectively) than patients with type 2 or secondary diabetes (0.104 U/kg/h, p  < 0.01 and p  < 0.05, respectively) during the first 6 h of management. In contrast, patients with type 1 diabetes and patients with newly diagnosed diabetes received significantly higher volume of saline during the 1st day as compared to patients with type 2 or secondary diabetes ( p  < 0.05 for both). Although guidelines do not recommend sodium bicarbonate, a few patients received this crystalloid solution (Table  2 ).

Metabolic events and mortality

The rate of hypoglycaemia and profound hypoglycaemia during the first 48 h was significantly higher among patients with type 1 diabetes as compared to patients with type 2 or secondary diabetes (76.9% vs. 50.0%, p  = 0.016 and 40.4% vs. 18.5%; p  = 0.032, respectively) and to patients with newly diagnosed diabetes (76.9% vs. 54.5%; p  = 0.032 and 40.4% vs. 18.2%; p  = 0.049, respectively). Twenty-eight (82.4%) patients with DKA as revealing presentation of diabetes had at least one episode of hypokalaemia during the first 48 h of management, an incidence significantly higher than the one observed in patients with type 1 diabetes ( n  = 34, 57.6%, p  = 0.015) and type 2 or secondary diabetes ( n  = 14, 51.9%, p  = 0.011). Hypophosphatemia below 0.3 mmol/l was observed in 24 patients (21.4%) without statistical differences between groups. Exhaustive report of metabolic events is depicted in Additional file 1 : Table S1. Overall, these complications mandated intravenous or oral supplementation of glucose, potassium or phosphate. Insulin infusion has to be temporarily stopped in 23.4% of the patients. However, no neurological or cardiovascular effects of these metabolic complications were reported in medical files.

One patient with type 2 diabetes died; he was a 74-year-old man with a history of chronic calcific pancreatitis and pleural mesothelioma.

Resolution time

The resolution times were not statistically different between groups (type 1 diabetes: 16 h [IQR = 11–26]; type 2 or secondary diabetes: 14 h [IQR = 8–23] and patients with newly diagnosed diabetes: 16 h [IQR = 12–28]; N  = 91).

Adequacy to UK recommendations regarding admission

Since no French recommendations regarding DKA management were published, we used the UK guidelines to evaluate the adequacy of admission in intermediate or intensive care unit using severity criteria [ 6 ]. One-hundred and twenty-one patients (99.2%) had at least one intermediate and intensive care unit admission criteria according to the UK guidelines. The details of these criteria are presented for the entire population in Table  3 .

This study reports management and complications of DKA depending of underlying type of diabetes, including newly diagnosed diabetes. Its main findings can be summarized in three points. First, we confirm that there is a significant prevalence of patients with type 2 or secondary diabetes with DKA hospitalized in intermediate and intensive care units; patients with type 2 or secondary diabetes being older with higher body weight and more chronic complications of diabetes. Second, we notice a higher incidence of hypoglycaemic events during DKA treatment in patients with type 1 diabetes despite being treated with lower insulin doses; observation compatible with the hypothesis of a lower level of insulin resistance in patients with type 1 diabetes as compared to patients with type 2 diabetes. And third, we observe a higher incidence of hypokalaemia in patients with newly diagnosed diabetes, in a context of more severe dehydration on admission (higher haemoglobin and plasma protein concentrations).

Despite the increasing occurrence in patients with type 2 or secondary diabetes and differences in pathophysiology between type 1 diabetes and type 2 or secondary diabetes, guidelines for management of DKA do not distinguish these patients [ 6 ]. In view of the differences observed in our study, the appropriateness of currently recommended management of DKA, not considering the type of underlying diabetes, may be questioned.

Many previous studies have shown that DKA occurs increasingly in patients with type 2 diabetes [ 1 , 12 , 13 ]. In our cohort, the proportion of type 2 or secondary diabetes among all DKA patients (23%) was similar to other recent publications, confirming in France what was previously observed in the US and the UK. Accordingly, Newton et al. [ 1 ] found 21.7% of type 2 diabetes in a cohort of 138 patients admitted for moderate to severe DKA. Barski et al. [ 12 ] observed 17.4% of patients with type 2 diabetes in their cohort of 201 patients. As observed in other studies, the characteristics of these patients differed significantly from those with type 1 diabetes: patients with type 2 or secondary diabetes were older, had more chronic complications of diabetes (microangiopathy or macroangiopathy, chronic renal failure), had higher incidence of cancers and higher body mass index.

Precipitating causes of DKA confirmed what was already observed worldwide with a predominance of poor adherence to treatment in patients with type 1 diabetes and a significant role of infection which concerned about 25% of the patients with DKA [ 14 ].

Patients in all three groups had comparable blood glucose on admission. Although patients with type 1 diabetes received lower insulin doses than patients with type 2 or secondary diabetes and lower than those recommended in the UK guidelines [ 6 ], they had more episodes of hypoglycaemia (including profound hypoglycaemia). In contrast, patients with type 2 or secondary diabetes received an initial dose of insulin in accordance with the UK recommendations. This result suggests that, in our units, clinicians already considered the type of underlying diabetes in the management of DKA. In addition, it suggests that a decreased dose of insulin, either at its initiation or when glucose level decreased below a determined threshold as proposed by other authors [ 14 ], could help in preventing this frequent complication.

Interestingly, a non-inferiority randomized controlled trial (RCT) comparing reduced dose of insulin (0.05 UI/kg/h) with standard recommended dose (0.10 UI/kg/h) in children with DKA including almost exclusively patients with type 1 diabetes reported significantly less metabolic events in the group receiving the reduced dose of insulin, without altering the recovery time [ 15 ]. It is reasonable to think that a similar effect would be observed in a DKA episode among adult patients with type 1 diabetes.

The nationwide survey on the management of DKA in the UK by Dhatariya et al. [ 8 ] did not differentiate patients by type of diabetes. Comparing our study populations at admission, it reveals that our patients were slightly more severe with higher blood glucose level (32 vs. 28.7 mmol/l) and lower bicarbonate concentration (6.5 vs. 11.3 mmol/l). In the study by Dhatariya et al., 27.6% of patients had at least one episode of hypoglycaemia during the first 24 h. The threshold for diagnosing hypoglycaemia was not clearly indicated. In our study, 51.4 and 20.5% of patients had at least one episode of blood glucose lower than 4 and 2.9 mmol/l, respectively. Similarly, while Dhatariya et al. reported that 55% of patients developed an hypokalaemia during the first 24 h, we observed that 63.3% of our patients presented at least one episode of serum potassium less than 3.5 mmol/l during the first 48 h of management [ 8 ]. Overall, it appears that the rate of metabolic events during DKA care remains high.

The recovery time in our study was quite similar to the one reported by Dhatariya et al. [ 8 ] (16.0 vs. 18.7 h). In our study, the recovery time was not different between the three groups. This could be explained either by the fact that patients with type 2 or secondary diabetes received more insulin, compensating for the increased insulin resistance of this population, or because a low dose of insulin is sufficient to block lipolysis, release of free fatty acids and production of ketone bodies. This is concordant with the absence of difference in recovery time observed in type 1 diabetes paediatric patients in the RCT of Nallasamy et al. [ 15 ] despite halved dose in the experimental group.

The results reported in the group of patients developing a DKA as first presentation of diabetes also bring new insights. This group of newly diagnosed diabetes is heterogeneous, including both young and older patients. Since no prior history of diabetes was known in these patients, DKA evolved probably for a longer time before diagnosis. This is suggested by the higher severity of extracellular dehydration than in the other two groups (significantly higher plasma protein and haemoglobin concentrations). It can be argued that water and sodium loss correlated with potassium losses, explaining the higher incidence of hypokalaemia among patients of this group. In a paediatric study by Lopes et al. [ 16 ], there were also a greater number of hypokalaemia episodes in the group of patients with newly diagnosed diabetes.

All but one patients of the present study were correctly referred to an ICU in regard to UK recommendations (at least one criterium of severity) [ 6 ]. The elevation of the anion gap beyond 16 mmol/l was the most frequent factor leading to ICU hospitalization (98.2% of patients). However, since elevated anion gap above 16 mmol/l mainly confirms the presence of ketone bodies and does not systematically reflect the severity of DKA, we believe this criterion is not useful to identify the most severe patients; it is rather a diagnostic criterion of the DKA. A threshold greater than 16 would probably be more discriminating. Unfortunately, since a large proportion of patients admitted in our ICUs were transferred from emergency department of other hospital or directly from home (using French mobile emergency medical service), it is not possible to evaluate the total number of patients hospitalized for a DKA, and thus the proportion of patients referred to our units.

In our study, a few patients received intravenous hyperosmolar sodium bicarbonate. This treatment is not recommended in international guidelines and should be avoided since it may be associated with an increased risk of cerebral oedema [ 17 , 18 ]. It underlines the need for French recommendations on DKA management that have not been produced until now.

This study has limitations. First and foremost, it is retrospective. If type 1 diabetes was well documented in patients’ files, it was difficult to differentiate accurately type 2 diabetes from secondary diabetes. In this context we decided to include these patients in a single group (type 2 and secondary diabetes). Second, practices and monitoring were not strictly similar among study centers, and patients’ files were either computerized or paper based, thus conferring heterogeneity of data availability. Third, due to sample size limitations, we were unable to perform multivariate analysis to fully investigate the role of the type of diabetes (with adjustment for confounding variables) in the occurrence of hypoglycaemia following management of DKA.

We found a greater incidence of hypoglycaemia in patients with type 1 diabetes during DKA management, as compared to patients with type 2 or secondary diabetes, despite lower insulin doses. Patients with unknown diabetes (DKA as first presentation of diabetes) appeared to have more severe extracellular dehydration and developed more hypokalaemia episodes than DKA patients with previously diagnosed diabetes. Since no difference was observed for the time to achieve resolution of DKA, reducing insulin doses in patients with type 1 diabetes as well as in patients with DKA as the first presentation of diabetes would likely help prevent metabolic complications. Randomized controlled studies comparing reduced insulin doses to standard care in these patients are required to improve DKA care.

Availability of data and materials

All data are conserved at the “Unite de Recherche Clinique” at Bichat hospital, Paris, under the supervision of Dr Fadia Dib.

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Adrien Balmier, Abirami Thiagarajah, Didier Dreyfuss, Jean-Damien Ricard & Damien Roux

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Design: DR, FD, JDR, AB, DD; data collection: AB, EDM, VP, BS, BM, AT; analysis: FD, DR, AB, ASL; writing manuscript: AB, DR, FD, JDR. All authors read and approved the final manuscript.

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Additional file 1: table s1..

Metabolic complications (hypoglycaemia, hypokalaemia, hypophosphatemia) according to the type of diabetes.

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Balmier, A., Dib, F., Serret-Larmande, A. et al. Initial management of diabetic ketoacidosis and prognosis according to diabetes type: a French multicentre observational retrospective study. Ann. Intensive Care 9 , 91 (2019). https://doi.org/10.1186/s13613-019-0567-y

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• Diabetic ketoacidosis
• Hypoglycaemia
• Hypokalaemia
• Critical care
• Type 1 diabetes
• Type 2 diabetes

Diabetic ketoacidosis

On this page, when to see a doctor, risk factors, complications.

Diabetic ketoacidosis is a serious complication of diabetes.

The condition develops when the body can't produce enough insulin. Insulin plays a key role in helping sugar — a major source of energy for muscles and other tissues — enter cells in the body.

Without enough insulin, the body begins to break down fat as fuel. This causes a buildup of acids in the bloodstream called ketones. If it's left untreated, the buildup can lead to diabetic ketoacidosis.

If you have diabetes or you're at risk of diabetes, learn the warning signs of diabetic ketoacidosis and when to seek emergency care.

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• A Book: The Essential Diabetes Book
• Assortment of Health Products from Mayo Clinic Store

Diabetic ketoacidosis symptoms often come on quickly, sometimes within 24 hours. For some, these symptoms may be the first sign of having diabetes. Symptoms might include:

• Being very thirsty
• Urinating often
• Feeling a need to throw up and throwing up
• Having stomach pain
• Being weak or tired
• Being short of breath
• Having fruity-scented breath
• Being confused

More-certain signs of diabetic ketoacidosis — which can show up in home blood and urine test kits — include:

• High blood sugar level
• High ketone levels in urine

If you feel ill or stressed or you've had a recent illness or injury, check your blood sugar level often. You might also try a urine ketone test kit you can get at a drugstore.

Contact your health care provider right away if:

• You're throwing up and can't keep down food or liquid
• Your blood sugar level is higher than your target range and doesn't respond to home treatment
• Your urine ketone level is moderate or high

Seek emergency care if:

• Your blood sugar level is higher than 300 milligrams per deciliter (mg/dL), or 16.7 millimoles per liter (mmol/L) for more than one test.
• You have ketones in your urine and can't reach your health care provider for advice.
• You have many symptoms of diabetic ketoacidosis. These include excessive thirst, frequent urination, nausea and vomiting, stomach pain, weakness or fatigue, shortness of breath, fruity-scented breath, and confusion.

Remember, untreated diabetic ketoacidosis can lead to death.

From Mayo Clinic to your inbox

Sugar is a main source of energy for the cells that make up muscles and other tissues. Insulin helps sugar enter the cells in the body.

Without enough insulin, the body can't use sugar to make the energy it needs. This causes the release of hormones that break down fat for the body to use as fuel. This also produces acids known as ketones. Ketones build up in the blood and eventually spill over into the urine.

Diabetic ketoacidosis usually happens after:

• An illness. An infection or other illness can cause the body to make higher levels of certain hormones, such as adrenaline or cortisol. These hormones work against the effects of insulin and sometimes cause diabetic ketoacidosis. Pneumonia and urinary tract infections are common illnesses that can lead to diabetic ketoacidosis.
• A problem with insulin therapy. Missed insulin treatments can leave too little insulin in the body. Not enough insulin therapy or an insulin pump that doesn't work right also can leave too little insulin in the body. Any of these problems can lead to diabetic ketoacidosis.

Other things that can lead to diabetic ketoacidosis include:

• Physical or emotional trauma
• Heart attack or stroke
• Pancreatitis
• Alcohol or drug misuse, particularly cocaine
• Certain medicines, such as corticosteroids and some diuretics

The risk of diabetic ketoacidosis is highest if you:

• Have type 1 diabetes
• Often miss insulin doses

Sometimes, diabetic ketoacidosis can occur with type 2 diabetes. In some cases, diabetic ketoacidosis may be the first sign of having diabetes.

Diabetic ketoacidosis is treated with fluids, electrolytes — such as sodium, potassium and chloride — and insulin. Perhaps surprisingly, the most common complications of diabetic ketoacidosis are related to this lifesaving treatment.

Possible complications of the treatments

Treatment complications include:

• Low blood sugar, also known as hypoglycemia. Insulin allows sugar to enter cells. This causes the blood sugar level to drop. If the blood sugar level drops too quickly, the drop can lead to low blood sugar.
• Low potassium, also known as hypokalemia. The fluids and insulin used to treat diabetic ketoacidosis can cause the potassium level to drop too low. A low potassium level can affect the heart, muscles and nerves. To avoid this, potassium and other minerals are usually given with fluid replacement as part of the treatment of diabetic ketoacidosis.
• Swelling in the brain, also known as cerebral edema. Adjusting the blood sugar level too quickly can cause the brain to swell. This appears to be more common in children, especially those with newly diagnosed diabetes.

Untreated, diabetic ketoacidosis can lead to loss of consciousness and, eventually, death.

There are many ways to prevent diabetic ketoacidosis and other diabetes complications.

• Manage your diabetes. Make healthy eating and physical activity part of your daily routine. Take diabetes medicines or insulin as directed.
• Monitor your blood sugar level. You might need to check and record your blood sugar level at least 3 to 4 times a day, or more often if you're ill or stressed. Careful monitoring is the only way to make sure that your blood sugar level stays within your target range.
• Adjust your insulin dosage as needed. Talk to your health care provider or diabetes educator about how to make your insulin dosage work for you. Consider factors such as your blood sugar level, what you eat, how active you are, and whether you're ill. If your blood sugar level begins to rise, follow your diabetes treatment plan to return your blood sugar level to your target range.
• Check your ketone level. When you're ill or stressed, test your urine for excess ketones with a urine ketones test kit. You can buy test kits at a drugstore. If your ketone level is moderate or high, contact your health care provider right away or seek emergency care. If you have low levels of ketones, you may need to take more insulin.
• Be prepared to act quickly. If you think you have diabetic ketoacidosis because your blood sugar is high and you have too many ketones in your urine, seek emergency care.

Diabetes complications are scary. But don't let fear keep you from taking good care of yourself. Follow your diabetes treatment plan carefully. Ask your diabetes treatment team for help when you need it.

Oct 06, 2022

• DKA (ketoacidosis) and ketones. American Diabetes Association. https://diabetes.org/diabetes/dka-ketoacidosis-ketones. Accessed Sept. 17, 2022.
• Diabetic ketoacidosis (DKA). Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetic-ketoacidosis-dka?query=Diabetic ketoacidosis (DKA). Accessed Sept. 17, 2022.
• Hirsch IB, et al. Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis. https://www.uptodate.com/contents/search. Accessed Sept. 17, 2022.
• Hirsch IB, et al. Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment. https://www.uptodate.com/contents/search. Accessed Sept. 17, 2022.
• Ferri FF. Diabetic ketoacidosis. In: Ferri's Clinical Advisor 2023. Elsevier; 2023. https://www.clinicalkey.com. Accessed Sept. 17, 2022.
• Evans K. Diabetic ketoacidosis: Update on management. Clinical Medicine. 2019; doi:10.7861/clinmed.2019-0284.
• Diseases & Conditions
• Diabetic ketoacidosis symptoms & causes

Associated Procedures

• Chest X-rays
• Electrocardiogram (ECG or EKG)

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