Mohammed Hassan-Ali, MSc

Case

A 32-year-old Hispanic man presented to the ED with complications associated with diabetes mellitus (DM), the symptoms of which started approximately 3 days prior to arrival. The patient reported feelings of fatigue, dry mouth, increased thirst, and frequent urination. He denied sweating, nausea, chest pain, shortness of breath, diarrhea, or blood in his urine; he also denied blurry vision or dizziness.

During history intake, the patient informed the emergency physician (EP) that he had been diagnosed with DM and hyperglycemia earlier that day by his primary care physician, who had immediately referred the patient to the ED for urgent management. The patient’s own medical history was noncontributory; however, his father’s history was notable for DM and chronic renal failure. The patient further stated that he was not on any medications. Regarding his social history, he denied cigarette smoking and noted only occasional alcohol consumption.

The patient’s vital signs on presentation were: blood pressure (BP), 116/74 mm Hg; heart rate, 113 beats/minute; respiratory rate, 26 breaths/minute; and temperature, 97.8°F. Oxygen saturation was 97% on room air. On physical examination, the patient was severely anxious, with tachycardia and respiratory distress. He was obese, with a body mass index of 30.9 kg/m² (height, 5 feet, 4 inches; weight, 180 lb).

At admission, a finger-stick glucose test revealed an elevated level. Laboratory studies included a complete blood count with differential, arterial blood gas measurement, blood cultures, comprehensive metabolic profile, lactic acid test, serum troponin I level, random glucose test, ketone panel, and urinalysis (Table 1). Laboratory glucose level was 1,890 mg/dL. A chest X-ray and an electrocardiogram were also ordered.

The patient was started on an intravenous (IV) bolus of 0.9% normal saline (2 L at 20 mL/kg). After a consultation with endocrinology, he was then given a maintenance dose of normal saline IV at 250 cc/h and an IV insulin drip at 0.1 U/kg/h following a bolus of 8 units of insulin IV. His glucose levels were carefully monitored via hourly finger-stick glucose testing.

Although the patient’s condition stabilized, he collapsed while walking to the bathroom. He had agonal respirations and no pulse. Resuscitation efforts were started with bag-valve-mask ventilation, along with emergent advanced cardiac life support (ACLS) treatment, the protocol of which included epinephrine administration (x2) IV push 5 minutes apart, 2 ampules of sodium bicarbonate (50 mEq each) IV push, and calcium gluconate 10% (x1) 10 mL (1 g) IV push. A pulse was re-established, and the patient was intubated.

The patient was diagnosed with diabetic ketoacidosis (DKA) and admitted to the intensive care unit where repeat laboratory evaluation was ordered. Additional pharmacological management included IV administration of dopamine, norepinephrine, phenylephrine, vasopressin, antibiotics (azithromycin, meropenem, and vancomycin), pantoprazole, and subcutaneous heparin.

During treatment, the patient coded a second time and was revived according to ACLS protocols. Shortly thereafter, he coded a third time, but resuscitation efforts failed. Pathology reported no biological cause of death, and the coroner closed the case as death due to DM-related complications.

Diabetic Ketoacidosis

Diabetic ketoacidosis is a major complication of DM.⁴ Although the condition usually occurs in type 1 DM, it can also develop in type 2 DM. Diabetic ketoacidosis may be an inciting event leading to the eventual diagnosis of DM, but can also develop during a concurrent illness such as a urinary tract infection or an eating disorder.⁵ Risk factors for DKA include patients with type 1 or type 2 DM, a family history of DM, obesity, and nonwhite patients whose ethnic background places them at increased risk.⁶ Hispanic,  black, and African American patients are at a greater risk of developing DKA and are more likely to develop “ketosis-prone” type 2 DM.⁷

Patients who do not fit into the definitive categories of type 1 or 2 DM can be classified under ketosis-prone DM.^7,8 Diabetic ketoacidosis acts as the inciting event for the disease and evolves into severe β-cell dysfunction, hence blurring the lines between the archetypal DM categories. Fifty percent of ketosis-prone DM patients are A-β+ (absent autoantibodies, present β-cell function), which indicates that the dysfunction can be partially reversed. Reversal of the condition is largely based on long-term β-cell reserves, which are dependent on tight glycemic control and insulin dependence. Higher incidences of the A-β+ variant of ketosis-prone diabetes are seen in the male population and are often unprovoked.^9-11

Etiology

Diabetic ketoacidosis is the result of either a decrease or absence of insulin in the body (Table 2).⁴ Without insulin modulating exogenous glucose intake and endogenous glucose production (via glucagon, glycogenolysis, and gluconeogenesis), high levels of glucose are found in the circulation, leading to prominent hyperglycemia (>250 mg/dL or >13.8 mmol/L).⁶ This environment causes the body to switch from carbohydrate metabolism to fatty acid metabolism. As a result, acidic ketone bodies such β-hydroxybutyrate and acetoacetate are produced. These physiological changes in the body cause the signs and symptoms typically found in DKA.

 

Signs and Symptoms

Over a period of 24 hours, symptoms such as nausea, vomiting, increased thirst, and polyuria develop due to dehydration caused by osmotic diuresis and glucosuria.⁵ Patients may also present with hypotension and tachycardia. Confusion, deep gasping breaths or Kussmaul respirations, and metabolic acidosis result from hyperventilation and failure to compensate for the increased serum concentration of ketone bodies. Ketone production leads to a fruit-like odor in the patient’s breath and ketonuria in the urinalysis. In DKA, laboratory values will indicate metabolic acidosis and abnormal serum electrolytes. In both DM and DKA, increased urea and creatinine due to dehydration, increased ketones, and the presence of diabetic nephropathy are useful indicators of impaired kidney function.¹²

Management and Treatment

Diabetic ketoacidosis can be managed and reversed, especially when recognized and treated early.^6,13 Dehydration in DKA can be corrected with IV fluid replacement. Normal saline (0.9%) can be started at 15 to 20 mL/kg/h or 1 L/h. As the patient’s vital signs stabilize, IV fluids can be titrated to a lower dose of 250 to 500 mL/h. Monitoring BP and electrolytes are key at this point as alterations in sodium levels and glucose levels may require switching to half-normal saline and/or dextrose.

The hyperglycemic state of patients with DKA is managed by IV insulin. An initial bolus of 0.1 U/kg/h can be given, but should only be administered when potassium levels are greater than 3.3 mmol/L.¹⁴ If adequate perfusion can be maintained, then 0.14 U/kg/h can be used instead of a bolus. Glucose levels must be monitored; once the levels decrease to approximately 200 mg/dL, the infusion rate of insulin should be titrated down to 0.05 to 0.1 U/kg/h. Dextrose is then added to maintain glucose levels at approximately 150 to 200 mg/dL.

Electrolytes, especially potassium, must be monitored closely in patients with DKA. Insulin leads to the shift of potassium into cells. The lack of insulin keeps potassium in the extracellular space. Due to osmotic diuresis, potassium is lost in the urine, leading to hypokalemia. Potassium levels in patients with DKA should be maintained at a level between 4 to 5 mmol/L. Patients with potassium levels between 3.3 to 5.2 mmol/L can be started on IV potassium between 20 to 30 mmol/h. If the patient is severely hypokalemic (<3.3 mmol/L), insulin should be withheld, and only IV potassium should be given at a rate of 20 to 30 mmol/h.

Bicarbonate levels can also be managed as acidosis can lead to both neurological and cardiac complications. If the patient’s pH is less than 6.9, the American Diabetes Association recommends starting 100 mmol of sodium bicarbonate in 400 mL sterile water (in addition to potassium chloride at 200 mL/h) for 2 hours. Dosing should be repeated every 2 hours until the patient’s pH is greater than 6.9.

In uncomplicated cases of DKA, the condition is resolved when a patient’s pH is greater than 7.3; glucose level is less than 200 mg/dL; and bicarbonate level is greater than or equal to 18 mmol/L. After patients become hemodynamically stable, they can be discharged and managed at home with a combination of intermediate- or long-acting insulin as well as short- or rapid-acting insulin.

Complications and Mortality

Diabetic ketoacidosis can cause sudden and fluctuating changes in the body. Therefore, it is very important to monitor a patient’s laboratory values very carefully and frequently to avoid any pitfalls. Since patients can present with hyponatremia due to the osmotic draw of glucose in the blood,¹³ sodium levels may have to be corrected. The corrected serum sodium can be calculated by adding 1.6 mmol/L for every 100 mg/dL of glucose (when finger-stick readings are above 200 mg/dL).¹⁵ Patients with DKA can also present with leukocytosis (even in the absence of infection) and hypertriglyceridemia (due to impaired lipoprotein lipase).¹⁵ Serum creatine may be elevated due to blood acetoacetate levels.¹⁵

Interestingly, there are other acute conditions that can mimic DKA.¹⁵ For example, chronic ethanol abuse can lead to ketoacidosis. Unlike DKA, however, alcoholic ketoacidosis does not have profound hyperglycemia, which can help differentiate the two during initial assessment.

Complications due to DKA can arise comprising the patient’s health, including hypoglycemia, hypokalemia, rhabdomyolysis, acute renal failure, pulmonary edema, and shock.¹⁶ Cerebral edema is seen in up to 1% of DKA patients,¹⁵ the cause of which may be due to the severity of the acidosis, high glucose levels, and rapid hydration. Even when cerebral edema is reduced, patients are often neurologically impaired. Mortality rates from DKA deaths due to cerebral edema can be as high as 24%.¹³ In the United States, over 100,000 patients with DM per year are admitted to the hospital for DKA, and 9% of patients with DM suffer from DKA-related complications postdischarge.¹⁵ With current treatment protocols, mortality rates for DKA-associated deaths are now down to 1%.^6,15

 

Diabetes ketoacidosis-related deaths are usually the result of the following: a triad of DKA symptoms (hyperglycemia, hyperketonemia, and metabolic acidosis),  another underlying comorbid condition (eg, myocardial infarction, sepsis, acute respiratory distress syndrome), or the release of biological markers (ie, catecholamines).^14,15,17 Thus, as previously stated, the management of potassium levels is important as both hyperkalemia and hypokalemia can lead to fatal arrthythmias.¹⁵

Direct mortality from DKA has dropped significantly over the past 20 years, from 8% to less than 1%.⁶ The US Centers for Disease Control and Prevention has observed a downward trend in death and estimates that 2,417 patients died in 2009 due to DKA,¹⁸ and recent postmortem studies have revealed new insights into DKA-related deaths.¹⁹ Blood and vitreous acetone concentrations are strong indicators for predeath hyperglycemia and ketosis (if there are no underlying comorbid and/or pharmacological provocations). Blood acetone levels greater than 0.01 g/dL antemortem are suggestive of DKA. It is recommended that these tests should be performed in sudden deaths which have no biological or anatomical cause of death. Postmortem diagnosis of DKA is made with the following criteria: history of DM, increased vitreous glucose concentrations, and elevated blood/vitreous/urine acetone concentrations (>200 mg/dL). If results of the abovementioned parameters are inconclusive, measurement of lactic acid postmortem is thought to further support a diagnosis of DKA.¹⁹

Patient Counseling and Education

Approximately 33% of patients whose death was associated with DKA had no personal  history of DM.¹⁹ This statistic emphasizes the importance of taking a thorough history, physical examination, blood glucose evaluation, and educating patients about the signs and symptoms of DM and DKA.

Patient counseling and education are important, especially in patients whose racial/ethnic background places them at increased risk of developing DM (eg, patients of black or African American, American Indian, Alaskan Native, Asian American, Hispanic, Native Hawaiian, or Pacific Islander descent).^20,21 Strategies for preventive management include advocating regular glucose monitoring as well as dietary and lifestyle modifications. In patients with DM, successful management of the condition and its comorbidities can help prevent DKA and associated mortality.

Conclusion

As this case demonstrates, despite prompt diagnosis and management, patients with DKA—especially those with uncontrolled, undiagnosed, or advanced DM—are associated with fatal outcomes. In many cases, however, DKA can be successfully managed and reversed, especially when the condition is recognized early. Management includes not only IV therapy to adjust fluid and insulin levels, but also restoring electrolyte balance (especially potassium and bicarbonate). Frequent and careful evaluation of laboratory values is vital to the successful treatment of DKA, as there are numerous pitfalls and complications that the emergency physician can encounter. Patients who either have or are at an increased risk of developing DM or DKA may benefit from preventive measures, including regular glucose monitoring and appropriate diet and lifestyle modifications.

Mr Hassan-Ali is a fourth-year medical student at Windsor University School of Medicine, St Kitts, West Indies. Dr Raziuddin is an internist and an emergency medicine physician at Weiss Memorial, Thorek Memorial, and Westlake Hospitals, Chicago, Illinois.

Case

A 32-year-old Hispanic man presented to the ED with complications associated with diabetes mellitus (DM), the symptoms of which started approximately 3 days prior to arrival. The patient reported feelings of fatigue, dry mouth, increased thirst, and frequent urination. He denied sweating, nausea, chest pain, shortness of breath, diarrhea, or blood in his urine; he also denied blurry vision or dizziness.

During history intake, the patient informed the emergency physician (EP) that he had been diagnosed with DM and hyperglycemia earlier that day by his primary care physician, who had immediately referred the patient to the ED for urgent management. The patient’s own medical history was noncontributory; however, his father’s history was notable for DM and chronic renal failure. The patient further stated that he was not on any medications. Regarding his social history, he denied cigarette smoking and noted only occasional alcohol consumption.

The patient’s vital signs on presentation were: blood pressure (BP), 116/74 mm Hg; heart rate, 113 beats/minute; respiratory rate, 26 breaths/minute; and temperature, 97.8°F. Oxygen saturation was 97% on room air. On physical examination, the patient was severely anxious, with tachycardia and respiratory distress. He was obese, with a body mass index of 30.9 kg/m² (height, 5 feet, 4 inches; weight, 180 lb).

At admission, a finger-stick glucose test revealed an elevated level. Laboratory studies included a complete blood count with differential, arterial blood gas measurement, blood cultures, comprehensive metabolic profile, lactic acid test, serum troponin I level, random glucose test, ketone panel, and urinalysis (Table 1). Laboratory glucose level was 1,890 mg/dL. A chest X-ray and an electrocardiogram were also ordered.

The patient was started on an intravenous (IV) bolus of 0.9% normal saline (2 L at 20 mL/kg). After a consultation with endocrinology, he was then given a maintenance dose of normal saline IV at 250 cc/h and an IV insulin drip at 0.1 U/kg/h following a bolus of 8 units of insulin IV. His glucose levels were carefully monitored via hourly finger-stick glucose testing.

Although the patient’s condition stabilized, he collapsed while walking to the bathroom. He had agonal respirations and no pulse. Resuscitation efforts were started with bag-valve-mask ventilation, along with emergent advanced cardiac life support (ACLS) treatment, the protocol of which included epinephrine administration (x2) IV push 5 minutes apart, 2 ampules of sodium bicarbonate (50 mEq each) IV push, and calcium gluconate 10% (x1) 10 mL (1 g) IV push. A pulse was re-established, and the patient was intubated.

The patient was diagnosed with diabetic ketoacidosis (DKA) and admitted to the intensive care unit where repeat laboratory evaluation was ordered. Additional pharmacological management included IV administration of dopamine, norepinephrine, phenylephrine, vasopressin, antibiotics (azithromycin, meropenem, and vancomycin), pantoprazole, and subcutaneous heparin.

During treatment, the patient coded a second time and was revived according to ACLS protocols. Shortly thereafter, he coded a third time, but resuscitation efforts failed. Pathology reported no biological cause of death, and the coroner closed the case as death due to DM-related complications.

Diabetic Ketoacidosis

Diabetic ketoacidosis is a major complication of DM.⁴ Although the condition usually occurs in type 1 DM, it can also develop in type 2 DM. Diabetic ketoacidosis may be an inciting event leading to the eventual diagnosis of DM, but can also develop during a concurrent illness such as a urinary tract infection or an eating disorder.⁵ Risk factors for DKA include patients with type 1 or type 2 DM, a family history of DM, obesity, and nonwhite patients whose ethnic background places them at increased risk.⁶ Hispanic,  black, and African American patients are at a greater risk of developing DKA and are more likely to develop “ketosis-prone” type 2 DM.⁷

Patients who do not fit into the definitive categories of type 1 or 2 DM can be classified under ketosis-prone DM.^7,8 Diabetic ketoacidosis acts as the inciting event for the disease and evolves into severe β-cell dysfunction, hence blurring the lines between the archetypal DM categories. Fifty percent of ketosis-prone DM patients are A-β+ (absent autoantibodies, present β-cell function), which indicates that the dysfunction can be partially reversed. Reversal of the condition is largely based on long-term β-cell reserves, which are dependent on tight glycemic control and insulin dependence. Higher incidences of the A-β+ variant of ketosis-prone diabetes are seen in the male population and are often unprovoked.^9-11

Etiology

Diabetic ketoacidosis is the result of either a decrease or absence of insulin in the body (Table 2).⁴ Without insulin modulating exogenous glucose intake and endogenous glucose production (via glucagon, glycogenolysis, and gluconeogenesis), high levels of glucose are found in the circulation, leading to prominent hyperglycemia (>250 mg/dL or >13.8 mmol/L).⁶ This environment causes the body to switch from carbohydrate metabolism to fatty acid metabolism. As a result, acidic ketone bodies such β-hydroxybutyrate and acetoacetate are produced. These physiological changes in the body cause the signs and symptoms typically found in DKA.

 

Signs and Symptoms

Over a period of 24 hours, symptoms such as nausea, vomiting, increased thirst, and polyuria develop due to dehydration caused by osmotic diuresis and glucosuria.⁵ Patients may also present with hypotension and tachycardia. Confusion, deep gasping breaths or Kussmaul respirations, and metabolic acidosis result from hyperventilation and failure to compensate for the increased serum concentration of ketone bodies. Ketone production leads to a fruit-like odor in the patient’s breath and ketonuria in the urinalysis. In DKA, laboratory values will indicate metabolic acidosis and abnormal serum electrolytes. In both DM and DKA, increased urea and creatinine due to dehydration, increased ketones, and the presence of diabetic nephropathy are useful indicators of impaired kidney function.¹²

Management and Treatment

Diabetic ketoacidosis can be managed and reversed, especially when recognized and treated early.^6,13 Dehydration in DKA can be corrected with IV fluid replacement. Normal saline (0.9%) can be started at 15 to 20 mL/kg/h or 1 L/h. As the patient’s vital signs stabilize, IV fluids can be titrated to a lower dose of 250 to 500 mL/h. Monitoring BP and electrolytes are key at this point as alterations in sodium levels and glucose levels may require switching to half-normal saline and/or dextrose.

The hyperglycemic state of patients with DKA is managed by IV insulin. An initial bolus of 0.1 U/kg/h can be given, but should only be administered when potassium levels are greater than 3.3 mmol/L.¹⁴ If adequate perfusion can be maintained, then 0.14 U/kg/h can be used instead of a bolus. Glucose levels must be monitored; once the levels decrease to approximately 200 mg/dL, the infusion rate of insulin should be titrated down to 0.05 to 0.1 U/kg/h. Dextrose is then added to maintain glucose levels at approximately 150 to 200 mg/dL.

Electrolytes, especially potassium, must be monitored closely in patients with DKA. Insulin leads to the shift of potassium into cells. The lack of insulin keeps potassium in the extracellular space. Due to osmotic diuresis, potassium is lost in the urine, leading to hypokalemia. Potassium levels in patients with DKA should be maintained at a level between 4 to 5 mmol/L. Patients with potassium levels between 3.3 to 5.2 mmol/L can be started on IV potassium between 20 to 30 mmol/h. If the patient is severely hypokalemic (<3.3 mmol/L), insulin should be withheld, and only IV potassium should be given at a rate of 20 to 30 mmol/h.

Bicarbonate levels can also be managed as acidosis can lead to both neurological and cardiac complications. If the patient’s pH is less than 6.9, the American Diabetes Association recommends starting 100 mmol of sodium bicarbonate in 400 mL sterile water (in addition to potassium chloride at 200 mL/h) for 2 hours. Dosing should be repeated every 2 hours until the patient’s pH is greater than 6.9.

In uncomplicated cases of DKA, the condition is resolved when a patient’s pH is greater than 7.3; glucose level is less than 200 mg/dL; and bicarbonate level is greater than or equal to 18 mmol/L. After patients become hemodynamically stable, they can be discharged and managed at home with a combination of intermediate- or long-acting insulin as well as short- or rapid-acting insulin.

Complications and Mortality

Diabetic ketoacidosis can cause sudden and fluctuating changes in the body. Therefore, it is very important to monitor a patient’s laboratory values very carefully and frequently to avoid any pitfalls. Since patients can present with hyponatremia due to the osmotic draw of glucose in the blood,¹³ sodium levels may have to be corrected. The corrected serum sodium can be calculated by adding 1.6 mmol/L for every 100 mg/dL of glucose (when finger-stick readings are above 200 mg/dL).¹⁵ Patients with DKA can also present with leukocytosis (even in the absence of infection) and hypertriglyceridemia (due to impaired lipoprotein lipase).¹⁵ Serum creatine may be elevated due to blood acetoacetate levels.¹⁵

Interestingly, there are other acute conditions that can mimic DKA.¹⁵ For example, chronic ethanol abuse can lead to ketoacidosis. Unlike DKA, however, alcoholic ketoacidosis does not have profound hyperglycemia, which can help differentiate the two during initial assessment.

Complications due to DKA can arise comprising the patient’s health, including hypoglycemia, hypokalemia, rhabdomyolysis, acute renal failure, pulmonary edema, and shock.¹⁶ Cerebral edema is seen in up to 1% of DKA patients,¹⁵ the cause of which may be due to the severity of the acidosis, high glucose levels, and rapid hydration. Even when cerebral edema is reduced, patients are often neurologically impaired. Mortality rates from DKA deaths due to cerebral edema can be as high as 24%.¹³ In the United States, over 100,000 patients with DM per year are admitted to the hospital for DKA, and 9% of patients with DM suffer from DKA-related complications postdischarge.¹⁵ With current treatment protocols, mortality rates for DKA-associated deaths are now down to 1%.^6,15

 

Diabetes ketoacidosis-related deaths are usually the result of the following: a triad of DKA symptoms (hyperglycemia, hyperketonemia, and metabolic acidosis),  another underlying comorbid condition (eg, myocardial infarction, sepsis, acute respiratory distress syndrome), or the release of biological markers (ie, catecholamines).^14,15,17 Thus, as previously stated, the management of potassium levels is important as both hyperkalemia and hypokalemia can lead to fatal arrthythmias.¹⁵

Direct mortality from DKA has dropped significantly over the past 20 years, from 8% to less than 1%.⁶ The US Centers for Disease Control and Prevention has observed a downward trend in death and estimates that 2,417 patients died in 2009 due to DKA,¹⁸ and recent postmortem studies have revealed new insights into DKA-related deaths.¹⁹ Blood and vitreous acetone concentrations are strong indicators for predeath hyperglycemia and ketosis (if there are no underlying comorbid and/or pharmacological provocations). Blood acetone levels greater than 0.01 g/dL antemortem are suggestive of DKA. It is recommended that these tests should be performed in sudden deaths which have no biological or anatomical cause of death. Postmortem diagnosis of DKA is made with the following criteria: history of DM, increased vitreous glucose concentrations, and elevated blood/vitreous/urine acetone concentrations (>200 mg/dL). If results of the abovementioned parameters are inconclusive, measurement of lactic acid postmortem is thought to further support a diagnosis of DKA.¹⁹

Patient Counseling and Education

Approximately 33% of patients whose death was associated with DKA had no personal  history of DM.¹⁹ This statistic emphasizes the importance of taking a thorough history, physical examination, blood glucose evaluation, and educating patients about the signs and symptoms of DM and DKA.

Patient counseling and education are important, especially in patients whose racial/ethnic background places them at increased risk of developing DM (eg, patients of black or African American, American Indian, Alaskan Native, Asian American, Hispanic, Native Hawaiian, or Pacific Islander descent).^20,21 Strategies for preventive management include advocating regular glucose monitoring as well as dietary and lifestyle modifications. In patients with DM, successful management of the condition and its comorbidities can help prevent DKA and associated mortality.

Conclusion

As this case demonstrates, despite prompt diagnosis and management, patients with DKA—especially those with uncontrolled, undiagnosed, or advanced DM—are associated with fatal outcomes. In many cases, however, DKA can be successfully managed and reversed, especially when the condition is recognized early. Management includes not only IV therapy to adjust fluid and insulin levels, but also restoring electrolyte balance (especially potassium and bicarbonate). Frequent and careful evaluation of laboratory values is vital to the successful treatment of DKA, as there are numerous pitfalls and complications that the emergency physician can encounter. Patients who either have or are at an increased risk of developing DM or DKA may benefit from preventive measures, including regular glucose monitoring and appropriate diet and lifestyle modifications.

Mr Hassan-Ali is a fourth-year medical student at Windsor University School of Medicine, St Kitts, West Indies. Dr Raziuddin is an internist and an emergency medicine physician at Weiss Memorial, Thorek Memorial, and Westlake Hospitals, Chicago, Illinois.

Case

A 32-year-old Hispanic man presented to the ED with complications associated with diabetes mellitus (DM), the symptoms of which started approximately 3 days prior to arrival. The patient reported feelings of fatigue, dry mouth, increased thirst, and frequent urination. He denied sweating, nausea, chest pain, shortness of breath, diarrhea, or blood in his urine; he also denied blurry vision or dizziness.

During history intake, the patient informed the emergency physician (EP) that he had been diagnosed with DM and hyperglycemia earlier that day by his primary care physician, who had immediately referred the patient to the ED for urgent management. The patient’s own medical history was noncontributory; however, his father’s history was notable for DM and chronic renal failure. The patient further stated that he was not on any medications. Regarding his social history, he denied cigarette smoking and noted only occasional alcohol consumption.

The patient’s vital signs on presentation were: blood pressure (BP), 116/74 mm Hg; heart rate, 113 beats/minute; respiratory rate, 26 breaths/minute; and temperature, 97.8°F. Oxygen saturation was 97% on room air. On physical examination, the patient was severely anxious, with tachycardia and respiratory distress. He was obese, with a body mass index of 30.9 kg/m² (height, 5 feet, 4 inches; weight, 180 lb).

At admission, a finger-stick glucose test revealed an elevated level. Laboratory studies included a complete blood count with differential, arterial blood gas measurement, blood cultures, comprehensive metabolic profile, lactic acid test, serum troponin I level, random glucose test, ketone panel, and urinalysis (Table 1). Laboratory glucose level was 1,890 mg/dL. A chest X-ray and an electrocardiogram were also ordered.

The patient was started on an intravenous (IV) bolus of 0.9% normal saline (2 L at 20 mL/kg). After a consultation with endocrinology, he was then given a maintenance dose of normal saline IV at 250 cc/h and an IV insulin drip at 0.1 U/kg/h following a bolus of 8 units of insulin IV. His glucose levels were carefully monitored via hourly finger-stick glucose testing.

Although the patient’s condition stabilized, he collapsed while walking to the bathroom. He had agonal respirations and no pulse. Resuscitation efforts were started with bag-valve-mask ventilation, along with emergent advanced cardiac life support (ACLS) treatment, the protocol of which included epinephrine administration (x2) IV push 5 minutes apart, 2 ampules of sodium bicarbonate (50 mEq each) IV push, and calcium gluconate 10% (x1) 10 mL (1 g) IV push. A pulse was re-established, and the patient was intubated.

The patient was diagnosed with diabetic ketoacidosis (DKA) and admitted to the intensive care unit where repeat laboratory evaluation was ordered. Additional pharmacological management included IV administration of dopamine, norepinephrine, phenylephrine, vasopressin, antibiotics (azithromycin, meropenem, and vancomycin), pantoprazole, and subcutaneous heparin.

During treatment, the patient coded a second time and was revived according to ACLS protocols. Shortly thereafter, he coded a third time, but resuscitation efforts failed. Pathology reported no biological cause of death, and the coroner closed the case as death due to DM-related complications.

Diabetic Ketoacidosis

Diabetic ketoacidosis is a major complication of DM.⁴ Although the condition usually occurs in type 1 DM, it can also develop in type 2 DM. Diabetic ketoacidosis may be an inciting event leading to the eventual diagnosis of DM, but can also develop during a concurrent illness such as a urinary tract infection or an eating disorder.⁵ Risk factors for DKA include patients with type 1 or type 2 DM, a family history of DM, obesity, and nonwhite patients whose ethnic background places them at increased risk.⁶ Hispanic,  black, and African American patients are at a greater risk of developing DKA and are more likely to develop “ketosis-prone” type 2 DM.⁷

Patients who do not fit into the definitive categories of type 1 or 2 DM can be classified under ketosis-prone DM.^7,8 Diabetic ketoacidosis acts as the inciting event for the disease and evolves into severe β-cell dysfunction, hence blurring the lines between the archetypal DM categories. Fifty percent of ketosis-prone DM patients are A-β+ (absent autoantibodies, present β-cell function), which indicates that the dysfunction can be partially reversed. Reversal of the condition is largely based on long-term β-cell reserves, which are dependent on tight glycemic control and insulin dependence. Higher incidences of the A-β+ variant of ketosis-prone diabetes are seen in the male population and are often unprovoked.^9-11

Etiology

Diabetic ketoacidosis is the result of either a decrease or absence of insulin in the body (Table 2).⁴ Without insulin modulating exogenous glucose intake and endogenous glucose production (via glucagon, glycogenolysis, and gluconeogenesis), high levels of glucose are found in the circulation, leading to prominent hyperglycemia (>250 mg/dL or >13.8 mmol/L).⁶ This environment causes the body to switch from carbohydrate metabolism to fatty acid metabolism. As a result, acidic ketone bodies such β-hydroxybutyrate and acetoacetate are produced. These physiological changes in the body cause the signs and symptoms typically found in DKA.

 

Signs and Symptoms

Over a period of 24 hours, symptoms such as nausea, vomiting, increased thirst, and polyuria develop due to dehydration caused by osmotic diuresis and glucosuria.⁵ Patients may also present with hypotension and tachycardia. Confusion, deep gasping breaths or Kussmaul respirations, and metabolic acidosis result from hyperventilation and failure to compensate for the increased serum concentration of ketone bodies. Ketone production leads to a fruit-like odor in the patient’s breath and ketonuria in the urinalysis. In DKA, laboratory values will indicate metabolic acidosis and abnormal serum electrolytes. In both DM and DKA, increased urea and creatinine due to dehydration, increased ketones, and the presence of diabetic nephropathy are useful indicators of impaired kidney function.¹²

Management and Treatment

Diabetic ketoacidosis can be managed and reversed, especially when recognized and treated early.^6,13 Dehydration in DKA can be corrected with IV fluid replacement. Normal saline (0.9%) can be started at 15 to 20 mL/kg/h or 1 L/h. As the patient’s vital signs stabilize, IV fluids can be titrated to a lower dose of 250 to 500 mL/h. Monitoring BP and electrolytes are key at this point as alterations in sodium levels and glucose levels may require switching to half-normal saline and/or dextrose.

The hyperglycemic state of patients with DKA is managed by IV insulin. An initial bolus of 0.1 U/kg/h can be given, but should only be administered when potassium levels are greater than 3.3 mmol/L.¹⁴ If adequate perfusion can be maintained, then 0.14 U/kg/h can be used instead of a bolus. Glucose levels must be monitored; once the levels decrease to approximately 200 mg/dL, the infusion rate of insulin should be titrated down to 0.05 to 0.1 U/kg/h. Dextrose is then added to maintain glucose levels at approximately 150 to 200 mg/dL.

Electrolytes, especially potassium, must be monitored closely in patients with DKA. Insulin leads to the shift of potassium into cells. The lack of insulin keeps potassium in the extracellular space. Due to osmotic diuresis, potassium is lost in the urine, leading to hypokalemia. Potassium levels in patients with DKA should be maintained at a level between 4 to 5 mmol/L. Patients with potassium levels between 3.3 to 5.2 mmol/L can be started on IV potassium between 20 to 30 mmol/h. If the patient is severely hypokalemic (<3.3 mmol/L), insulin should be withheld, and only IV potassium should be given at a rate of 20 to 30 mmol/h.

Bicarbonate levels can also be managed as acidosis can lead to both neurological and cardiac complications. If the patient’s pH is less than 6.9, the American Diabetes Association recommends starting 100 mmol of sodium bicarbonate in 400 mL sterile water (in addition to potassium chloride at 200 mL/h) for 2 hours. Dosing should be repeated every 2 hours until the patient’s pH is greater than 6.9.

In uncomplicated cases of DKA, the condition is resolved when a patient’s pH is greater than 7.3; glucose level is less than 200 mg/dL; and bicarbonate level is greater than or equal to 18 mmol/L. After patients become hemodynamically stable, they can be discharged and managed at home with a combination of intermediate- or long-acting insulin as well as short- or rapid-acting insulin.

Complications and Mortality

Diabetic ketoacidosis can cause sudden and fluctuating changes in the body. Therefore, it is very important to monitor a patient’s laboratory values very carefully and frequently to avoid any pitfalls. Since patients can present with hyponatremia due to the osmotic draw of glucose in the blood,¹³ sodium levels may have to be corrected. The corrected serum sodium can be calculated by adding 1.6 mmol/L for every 100 mg/dL of glucose (when finger-stick readings are above 200 mg/dL).¹⁵ Patients with DKA can also present with leukocytosis (even in the absence of infection) and hypertriglyceridemia (due to impaired lipoprotein lipase).¹⁵ Serum creatine may be elevated due to blood acetoacetate levels.¹⁵

Interestingly, there are other acute conditions that can mimic DKA.¹⁵ For example, chronic ethanol abuse can lead to ketoacidosis. Unlike DKA, however, alcoholic ketoacidosis does not have profound hyperglycemia, which can help differentiate the two during initial assessment.

Complications due to DKA can arise comprising the patient’s health, including hypoglycemia, hypokalemia, rhabdomyolysis, acute renal failure, pulmonary edema, and shock.¹⁶ Cerebral edema is seen in up to 1% of DKA patients,¹⁵ the cause of which may be due to the severity of the acidosis, high glucose levels, and rapid hydration. Even when cerebral edema is reduced, patients are often neurologically impaired. Mortality rates from DKA deaths due to cerebral edema can be as high as 24%.¹³ In the United States, over 100,000 patients with DM per year are admitted to the hospital for DKA, and 9% of patients with DM suffer from DKA-related complications postdischarge.¹⁵ With current treatment protocols, mortality rates for DKA-associated deaths are now down to 1%.^6,15

 

Diabetes ketoacidosis-related deaths are usually the result of the following: a triad of DKA symptoms (hyperglycemia, hyperketonemia, and metabolic acidosis),  another underlying comorbid condition (eg, myocardial infarction, sepsis, acute respiratory distress syndrome), or the release of biological markers (ie, catecholamines).^14,15,17 Thus, as previously stated, the management of potassium levels is important as both hyperkalemia and hypokalemia can lead to fatal arrthythmias.¹⁵

Direct mortality from DKA has dropped significantly over the past 20 years, from 8% to less than 1%.⁶ The US Centers for Disease Control and Prevention has observed a downward trend in death and estimates that 2,417 patients died in 2009 due to DKA,¹⁸ and recent postmortem studies have revealed new insights into DKA-related deaths.¹⁹ Blood and vitreous acetone concentrations are strong indicators for predeath hyperglycemia and ketosis (if there are no underlying comorbid and/or pharmacological provocations). Blood acetone levels greater than 0.01 g/dL antemortem are suggestive of DKA. It is recommended that these tests should be performed in sudden deaths which have no biological or anatomical cause of death. Postmortem diagnosis of DKA is made with the following criteria: history of DM, increased vitreous glucose concentrations, and elevated blood/vitreous/urine acetone concentrations (>200 mg/dL). If results of the abovementioned parameters are inconclusive, measurement of lactic acid postmortem is thought to further support a diagnosis of DKA.¹⁹

Patient Counseling and Education

Approximately 33% of patients whose death was associated with DKA had no personal  history of DM.¹⁹ This statistic emphasizes the importance of taking a thorough history, physical examination, blood glucose evaluation, and educating patients about the signs and symptoms of DM and DKA.

Patient counseling and education are important, especially in patients whose racial/ethnic background places them at increased risk of developing DM (eg, patients of black or African American, American Indian, Alaskan Native, Asian American, Hispanic, Native Hawaiian, or Pacific Islander descent).^20,21 Strategies for preventive management include advocating regular glucose monitoring as well as dietary and lifestyle modifications. In patients with DM, successful management of the condition and its comorbidities can help prevent DKA and associated mortality.

Conclusion

As this case demonstrates, despite prompt diagnosis and management, patients with DKA—especially those with uncontrolled, undiagnosed, or advanced DM—are associated with fatal outcomes. In many cases, however, DKA can be successfully managed and reversed, especially when the condition is recognized early. Management includes not only IV therapy to adjust fluid and insulin levels, but also restoring electrolyte balance (especially potassium and bicarbonate). Frequent and careful evaluation of laboratory values is vital to the successful treatment of DKA, as there are numerous pitfalls and complications that the emergency physician can encounter. Patients who either have or are at an increased risk of developing DM or DKA may benefit from preventive measures, including regular glucose monitoring and appropriate diet and lifestyle modifications.

Mr Hassan-Ali is a fourth-year medical student at Windsor University School of Medicine, St Kitts, West Indies. Dr Raziuddin is an internist and an emergency medicine physician at Weiss Memorial, Thorek Memorial, and Westlake Hospitals, Chicago, Illinois.