1. Ted A. Bonebrake, M.D.
Case Study

2. Initial Presentation
A 14 y/o female is brought to the emergency department by her mother after being found unresponsive at home. She had been ill the day before with nausea and vomiting, but was not running a fever. Her parents had kept her home from school that day.
When her mother came home at lunchtime to check on her, she was very lethargic and not responding coherently.

3. Initial Presentation
By the time she arrived at the hospital, she had to be brought in to the ED on a gurney.
Initial evaluation showed O2 sat 100% on room air, pulse 126, respirations 30, BP 92/68, temperature F.
She appears pale, mucous membranes are dry and she only responds to painful stimuli.
Exam shows diffuse abdominal tenderness with guarding.

4. Initial Workup and Treatment
Differential diagnosis?
What initial treatment would you suggest?
What labs would you order?
Any xrays or additional studies?

5. Laboratory Data CBC BMP WBC 23,500 Hgb 14.2 g/dL Hct 45%
Platelets 425,000
BMP
Sodium 126
Potassium 5.2
Chloride 87
CO2 <5
BUN 32
Creatinine 1.5
Glucose 1,376

6. Laboratory Data Arterial Blood Gases Urine pH 7.19 Po2 100 mm Hg
HCO3 7.5 mmo/L
Pco2 20 mm Hg
Sao2 98% (room air)
Urine
Specific gravity 1.015
Ketones 4+
Leukocytes few
Glucose 4+
Nitrates 0
RBCs many

7. Diabetic Ketoacidosis
Diabetic ketoacidosis (DKA) is an acute metabolic complication of diabetes characterized by hyperglycemia, hyperketonemia, and metabolic acidosis. DKA occurs mostly in type 1 diabetics.
It causes nausea, vomiting, and abdominal pain and can progress to cerebral edema, coma, and death.
DKA is diagnosed by detection of hyperketonemia and anion gap metabolic acidosis in the presence of hyperglycemia.
Treatment involves volume expansion, insulin replacement, and prevention of hypokalemia.

8. Diabetic Ketoacidosis
Diagnosis
Epidemiology
Pathophysiology
Treatment
Initial (emergency) treatment
Ongoing management and monitoring
Prognosis

9. Diabetic Ketoacidosis-Diagnosis
Symptoms and signs of DKA
Nausea & vomiting
Abdominal pain--particularly in children
Lethargy and somnolence
Kussmaul respirations
Hypotension
Tachycardia
Fruity breath due to exhaled acetone
Fever +/- if present may signify underlying infection
In the absence of timely treatment, DKA progresses to coma and death.

10. Diabetic Ketoacidosis-Diagnosis
Arterial pH
Serum ketones
Calculation of anion gap
Electrolytes, BUN and creatinine, glucose, ketones, and osmolarity should be measured
Urine ketones
Patients who appear significantly ill and those with positive ketones should have ABG measurement.
DKA is diagnosed by an arterial pH < 7.30 with an anion gap > 12 and serum ketones in the presence of hyperglycemia.
A presumptive diagnosis can be made when urine glucose and ketones are strongly positive.

11. Diabetic Ketoacidosis-Diagnosis
Calculation Anion Gap
AG = ([Na+] + [K+]) − ([Cl−] + [HCO3−])
Or omit potassium
AG = [Na+] − ([Cl-] + [HCO3−])

12. DKA-Differential Diagnosis
Alcoholic Ketoacidosis
Appendicitis, Acute
Hyperosmolar Coma
Hypophosphatemia
Hypothermia
Lactic Acidosis
Metabolic Acidosis
Myocardial Infarction
Pancreatitis, Acute
Pneumonia, Immunocompromised
Septic Shock
Salicylate Toxicity
Urinary Tract Infection

13. DKA-Epidemiology
DKA accounts for 50% of diabetes-related admissions in young persons and 1-2% of all primary diabetes-related admissions.
DKA frequently is observed during the diagnosis of type 1 diabetes and often indicates this diagnosis.
While the exact incidence is not known, it is estimated to be 1 out of 2000.

14. DKA-Epidemiology
DKA occurs primarily in patients with type 1 diabetes.
The incidence is roughly 2 episodes per 100 patient years of diabetes.
About 3% of patients with type 1 diabetes initially present with DKA.
It can occur in patients with type 2 diabetes as well; this is less common, however.

15. DKA-Epidemiology
The incidence of DKA is higher in whites because of the higher incidence of type 1 diabetes in this racial group.
The incidence of diabetic ketoacidosis (DKA) is slightly greater in females than in males for reasons that are unclear.
Recurrent DKA frequently is seen in young women with type 1 diabetes and is caused mostly by the omission of insulin treatment.

16. DKA-Epidemiology
Among persons with type 1 diabetes, DKA is much more common in young children and adolescents than it is in adults.
DKA tends to occur in individuals younger than 19 years, but it may occur in patients with diabetes at any age.
Multiple factors (eg, ethnic minority, lack of health insurance, lower body mass index, preceding infection, delayed treatment) affect the risk of developing DKA among children and young adults

17. DKA-Pathophysiology
Diabetic ketoacidosis (DKA) is a complex disordered metabolic state characterized by hyperglycemia, ketoacidosis, and ketonuria.
DKA occurs as a consequence of absolute or relative insulin deficiency that is accompanied by an increase in counter-regulatory hormones (ie, glucagon, cortisol, growth hormone, epinephrine).
The hormonal imbalance enhances hepatic gluconeogenesis, glycogenolysis, and lipolysis.

18. DKA-Pathophysiology
Hepatic gluconeogenesis, glycogenolysis secondary to insulin deficiency, and counter-regulatory hormone excess result in severe hyperglycemia
Lipolysis increases serum free fatty acids.
Hepatic metabolism of free fatty acids as an alternative energy source (ketogenesis) results in accumulation of acidic intermediate and end metabolites (ketones).
Ketones include acetone, beta-hydroxybutyrate, and acetoacetate.

19. DKA-Pathophysiology
Increased concentration of ketones initially leads to a state of ketonemia.
Extracellular and intracellular body buffers can limit ketonemia in its early stages, as reflected by a normal arterial pH associated with a base deficit and a mild anion gap.

20. DKA-Pathophysiology
When the accumulated ketones exceed the body's capacity to extract them, ketonuria results.
If the situation is not treated promptly, this leads to clinical metabolic acidosis (ketoacidosis)
Respiratory compensation for the acidosis results in rapid shallow breathing (Kussmaul respirations)

21. DKA-Pathophysiology
Ketones induce nausea and vomiting that aggravate fluid and electrolyte loss already existing in DKA.
Acetone produces the fruity breath odor that is characteristic of ketotic patients.
Hyperglycemia, osmotic diuresis, serum hyperosmolarity, and metabolic acidosis result in severe electrolyte disturbances.
The most characteristic disturbance is total body potassium loss

22. DKA-Pathophysiology
Potassium loss is caused by a shift of potassium from the intracellular to the extracellular space in an exchange with hydrogen ions that accumulate extracellularly in acidosis.
Potassium is lost in urine because of osmotic diuresis.
Patients with initial hypokalemia are considered to have severe total body potassium depletion.
High serum osmolarity drives water from intracellular to extracellular space causing dilutional hyponatremia.
Sodium also is lost in the urine.

23. Hyperglycemia-Pathophysiology
In the absence of insulintissues such as muscle, fat, and liver do not take up glucose.
Counterregulatory hormones, such as glucagon, growth hormone, and catecholamines, enhance triglyceride breakdown into free fatty acids and gluconeogenesis.
This causes the elevation in serum glucose level in DKA.
Beta-oxidation of these free fatty acids leads to increased formation of ketone bodies.

24. Hyperglycemia-Pathophysiology
Metabolism in DKA shifts from the normal fed state characterized by carbohydrate metabolism to a fasting state characterized by fat metabolism.
This results in metabolic acidosis as the ketone bodies produced by beta-oxidation of free fatty acids deplete extracellular and cellular acid buffers.
Osmotic diuresis depletes sodium, potassium, phosphates, and water, as well as ketones and glucose.

25. DKA-Dehydration
Typical free water loss in DKA is approximately 6 liters or nearly 100 mL/kg of body weight.
Half of this amount is derived from intracellular fluid and precedes signs of dehydration.
The other half is from extracellular fluid and is responsible for signs of dehydration.

26. DKA-Electrolyte Loss Typical overall electrolyte loss:
mEq/L of potassium
mEq/L of sodium
mEq/L of chloride.
The combination of serum hyperosmolarity, dehydration, and acidosis result in increased osmolarity in brain cells that clinically manifests as an alteration in the level of consciousness.

27. DKA-Etiology
The most common causes for diabetic ketoacidosis (DKA) are:
Underlying or concomitant infection (40%)
Missed insulin treatments (25%)
Newly diagnosed, previously unknown diabetes (15%)
Other causes make up roughly 20% in the various scenarios.

28. Causes of DKA in Type I DM
Initial presentation of type 1 diabetes (25% of patients)
Poor compliance with insulin
Omission of insulin injections
Lack of patient/guardian education
Result of psychological stress, particularly in adolescents
Bacterial infection and intercurrent illness
Brittle diabetes
Insulin infusion catheter blockage
Mechanical failure of the insulin infusion pump
Idiopathic

29. Causes of DKA in Type II DM
Intercurrent illness
Myocardial infarction
Pneumonia
Prostatitis
UTI
Medications
Corticosteroids
Pentamidine, clozapine

30. DKA in Pregnancy
DKA also occurs in pregnant women, either with preexisting diabetes or with diabetes diagnosed during pregnancy.
Physiologic changes unique to pregnancy provide a background for the development of DKA.
DKA in pregnancy is a medical emergency, as mother and fetus are at risk for morbidity and mortality.

31. DKA-Pathophysiology
Many of the underlying pathophysiologic disturbances in DKA are directly measurable and need to be monitored throughout the course of treatment.
Close attention to clinical laboratory data allows for management of the underlying acidosis and hyperglycemia
This can prevent common, potentially lethal complications such as hypoglycemia, hyponatremia, and hypokalemia.

32. DKA-Definition Diabetic ketoacidosis Severe DKA
Blood glucose over 300 mg/dL
Bicarbonate level less than 15 mEq/L
pH less than 7.30
ketonemia and ketonuria
Severe DKA
pH less than 7.1
Bicarbonate less than 5 mEq/L.

33. DKA-Management
Serial laboratory tests are critical, including potassium, glucose, electrolytes, and, if necessary, phosphorus.
Initial workup should include aggressive volume, glucose, and electrolyte management.

34. DKA-Management Considerations
High serum glucose levels may lead to dilutional hyponatremia.
High triglyceride levels may lead to factitious low glucose levels.
High levels of ketone bodies may lead to factitious elevation of creatinine levels.
Extracellular shift of potassium leads to normal or elevated serum potassium, despite severely depleted total body potassium.

35. DKA-Management ICU or monitored bed
IVF NS TRA 1000cc/hr for total 20cc/kg
Insulin Drip at 0.1 cc/kg/hr
Blood tests for glucose every 1-2 h until patient is stable, then every 6 h
Serum electrolyte determinations every 1-2 h until patient is stable, then every 4-6 h
Initial arterial blood gas (ABG) measurements, followed with bicarbonate as necessary

36. DKA Management-Ketones
Blood beta-hydroxybutyrate levels measured by a reagent strip and serum ketone levels assessed by the nitroprusside reaction are equally effective in diagnosing DKA in uncomplicated cases.
The Acetest and Ketostix products measure blood and urine acetone and acetoacetic acid.
They do not measure the more common ketone body, beta-hydroxybutyrate
The patient may have paradoxical worsening as the latter is converted into the former during treatment.

37. DKA Mangement-Ketones
Specific testing for beta-hydroxybutyrate can be performed by many laboratories.
Diagnosis of ketonuria requires adequate renal function.
Ketonuria may last longer than the underlying tissue acidosis.

38. DKA Management-Ketones
One study suggests that routine urine testing for ketones is no longer necessary to diagnose DKA.
Using capillary beta hydroxybutyrate offers a distinct advantage of avoiding unnecessary work-up.
Beta-hydroxybutyrate levels greater than 0.5 mmol/L are considered abnormal, and levels of 3 mmol/L correlate with the need for treatment for DKA.

39. DKA Management-Ketones
According to the 2011 Joint British Diabetes Societies (JBDS) guideline for the management of diabetic ketoacidosis:
Capillary blood ketones should be measured in order to monitor the response to DKA treatment.
The method of choice is bedside measurement of blood ketones using a ketone meter.
In the absence of blood ketone measurement, venous pH and bicarbonate should be used together with bedside blood glucose monitoring to evaluate treatment response

40. DKA Management-ABG’s
In patients with DKA, arterial blood gases (ABGs) frequently show typical manifestations of metabolic acidosis, low bicarbonate, and low pH (< 7.2).
Venous pH may be used for repeat pH measurements.
Brandenburg and Dire found that pH on venous blood gas in patients with DKA was 0.03 lower than pH on ABG.
Because this difference is relatively reliable and not of clinical significance, there is almost no reason to perform the more painful ABG.
End tidal CO2 has been reported as a way to assess acidosis as well.

41. DKA Management-Electrolytes
Serum potassium levels initially are high or within the reference range in patients with DKA.
This is due to the extracellular shift of potassium in spite of severely depleted total body potassium.
This needs to be checked frequently, as values drop very rapidly with treatment.
An ECG may be used to assess the cardiac effects of extremes in potassium levels.
The serum sodium level usually is low in affected patients.
The osmotic effect of hyperglycemia moves extravascular water to the intravascular space.
For each 100 mg/dL of glucose over 100 mg/dL, the serum sodium level is lowered by approximately 1.6 mEq/L.
When glucose levels fall, the serum sodium level rises by a corresponding amount.
Additionally, serum chloride levels and phosphorus levels always are low in these patients.

42. DKA Management-Potassium
If the potassium level is greater than 6 mEq/L, do not administer potassium supplement.
If the potassium level is mEq/L, administer 10 mEq/h of potassium chloride.
If the potassium level is mEq/L, administer 20 mEq/h of potassium chloride.
Monitor serum potassium levels hourly, and the infusion must be stopped if the potassium level is greater than 5 mEq/L.

43. DKA Management-Potassium
The monitoring of serum potassium must continue even after potassium infusion is stopped in the case of (expected) recurrence of hypokalemia.
In severe hypokalemia, not starting insulin therapy is advisable unless potassium replacement is under way; this is to avert potentially serious cardiac dysrhythmia that may result from hypokalemia.
Potassium replacement should be started with initial fluid replacement if potassium levels are normal or low. Add mEq/L of potassium chloride to each liter of fluid once the potassium level is less than 5.5 mEq/L. Potassium can be given as follows: two thirds as KCl, one third as KPO4.

44. DKA Management-CBC, BMP
Even in the absence of infection, the CBC count shows an increased white blood cell (WBC) count in patients with diabetic ketoacidosis. High WBC counts (>15 X 109/L) or marked left shift may suggest underlying infection.
BUN frequently is increased in patients with diabetic ketoacidosis.

45. DKA Management-Osmolarity
Plasma osmolarity usually is increased (>290 mOsm/L) in patients with diabetic ketoacidosis.
If plasma osmolarity cannot be measured directly, it may be calculated with the following formula: plasma osmolarity = 2 (Na + K) + BUN/3 + glucose/18.
Urine osmolarity also is increased in affected patients.
Patients with diabetic ketoacidosis who are in a coma typically have osmolalities greater than 330 mOsm/kg H2 O.
If the osmolality is less than this in a patient who is comatose, search for another cause.

46. DKA Management-Other Lab
Urine and blood culture findings help to identify any possible infecting organisms in patients with diabetic ketoacidosis.
Elevated amylase may be seen in patients with diabetic ketoacidosis, even in the absence of pancreatitis.
If the patient is at risk for hypophosphatemia (eg, poor nutritional status, chronic alcoholism), then the serum phosphorous level should be determined.

47. DKA Management-Imaging
Chest radiography should be used to rule out pulmonary infection such as pneumonia.
An MRI is helpful in detecting early cerebral edema; it should be ordered only if altered consciousness is present.[
The threshold should be low for obtaining a head CT scan in children with diabetic ketoacidosis who have altered mental status, as this may be caused by cerebral edema.
Many of the changes may be seen late on head imaging and should not delay administration of hypertonic saline or mannitol in those pediatric cases where cerebral edema is suspected.

48. DKA Management-EKG
DKA may be precipitated by a cardiac event, and the physiological disturbances of DKA may cause cardiac complications.
An ECG should be performed every 6 hours during the first day, unless the patient is monitored. An ECG may reveal signs of acute myocardial infarction that could be painless in patients with diabetes, particularly in those with autonomic neuropathy.
An ECG is also a rapid way to assess significant hypokalemia or hyperkalemia. T-wave changes may produce the first warning sign of disturbed serum potassium levels. Low T wave and apparent U wave always signify hypokalemia, while peaked T wave is observed in hyperkalemia.

49. DKA Complications
Cerebral edema is a serious, major complication that may evolve at any time during treatment of DKA and primarily affects children. It is the leading cause of DKA mortality in children.
Deterioration of the level of consciousness in spite of improved metabolic state usually indicates the occurrence of cerebral edema.
MRI usually is used to confirm the diagnosis.
Cerebral edema that occurs at initiation of therapy tends to worsen during the course of treatment.
Mannitol or hypertonic saline should be available if cerebral edema is suspected.

50. DKA Complications
0.5-1 g/kg intravenous mannitol may be given over the course of 20 minutes and repeated if no response is seen in minutes.
If no response to mannitol occurs, hypertonic saline (3%) may be given at 5-10 mg/kg over the course of 30 minutes.
Clinical cerebral edema is rare and carries the highest mortality rate.
Although mannitol and dexamethasone (2-4 mg q6-12h) frequently are used in this situation, no specific medication has proven useful in such instances.
Recent research by Glaser et al indicated that cerebral edema occurs in 1% of children with DKA, with a mortality rate of 21% and neurologic sequelae in another 21% of patients.

51. DKA Complications
Cardiac dysrhythmia may occur secondary to severe hypokalemia and/or acidosis either initially or as a result of therapy in patients with DKA.
Usually, correction of the cause is sufficient to treat cardiac dysrhythmia, but if it persists, consultation with a cardiologist is mandatory.
Performing cardiac monitoring on patients with DKA during correction of electrolytes always is advisable.

52. DKA Complications
Pulmonary edema may occur for the same reasons as cerebral edema in patients with diabetic ketoacidosis.
Be cautious of possible overcorrection of fluid loss, though it occurs only rarely.
Although initial aggressive fluid replacement is necessary in all patients, particular care must be taken in those with comorbidities such as renal failure or congestive heart failure.
Diuretics and oxygen therapy often suffice for the management of pulmonary edema.

53. DKA Complications
Nonspecific myocardial injury may occur in severe DKA, which is associated with minute elevations of myocardial biomarkers (troponin T and CK-MB) and initial ECG changes compatible with myocardial infarction (MI).
Acidosis and very high levels of free fatty acids could cause membrane instability and biomarker leakage.
Coronary arteriography usually is normal, and patients tend to recover fully without further evidence of ischemic heart disease.
The presence of minute biomarker elevations and ECG changes do not necessarily signify MI in DKA.

54. DKA Complications Hypoglycemia Hypokalemia
In patients with diabetic ketoacidosis, hypoglycemia may result from inadequate monitoring of glucose levels during insulin therapy.
Hypokalemia
Hypokalemia is a complication that is precipitated by failing to rapidly address the total body potassium deficit brought out by rehydration and insulin treatment, which not only reduces acidosis but directly facilitates potassium reentry into the cell.

55. DKA-Management
Managing DKA in the ICU during the first hours always is advisable.
When treating patients with DKA, the following points must be considered and closely monitored:
Correction of fluid loss with intravenous fluids
Correction of hyperglycemia with insulin
Correction of electrolyte disturbances, particularly potassium loss
Correction of acid-base balance
Treatment of concurrent infection, if present
It is essential to maintain extreme vigilance for any concomitant process, such as infection, cerebrovascular accident, myocardial infarction, sepsis, or deep venous thrombosis.

56. DKA-Management
When the blood glucose falls below 14 mmol/l (250 mg/dl), 10% glucose should be added to allow the fixed-rate insulin to be continued.
If already taking, long-acting insulin analogues such as insulin glargine (Lantus) should be continued in usual doses.
The diabetes specialist team should be involved as soon as possible

57. DKA Management-Daily Insulin
Once the patient is stable, transfer to regular hospital bed.
If new onset DM, calculate daily insulin dose
0.3 units/kg/day for patients who are lean, on hemodialysis, frail and elderly, insulin-sensitive, or at risk for hypoglycemia
0.4 units/kg/day for a patient at normal weight
0.5 units/kg/day for overweight patients
0.6 units/kg/day or more for patients who are obese, on high-dose steroids or insulin-resistant

58. DKA Management-Daily Insulin
Between 40% and 50% of that total dose should be administered as basal, using Lantus or other long-acting insulin.
The remainder is divided to be given as short-acting insulin (Humalog) prior to each meal.
Check sugars in the AM fasting and 2 hours after each meal to evaluate the regimen.

59. DKA-Prognosis The overall mortality rate for DKA is 2% or less.
The presence of deep coma at the time of diagnosis, hypothermia, and oliguria are signs of poor prognosis.
The prognosis of properly treated patients with diabetic ketoacidosis is excellent, especially in younger patients if intercurrent infections are absent.
The worst prognosis usually is observed in older patients with severe intercurrent illnesses (eg, myocardial infarction, sepsis, or pneumonia), especially when these patients are treated outside an intensive care unit.

60. DKA-Prognosis
When DKA is treated properly, it rarely produces residual effects.
With modern fluid management, the mortality rate of DKA is about 2% per episode.
Before the discovery of insulin in 1922, the mortality rate was 100%.
In the last 20 years, mortality rates from DKA have markedly decreased, from 7.96% to 0.67%.[10]

61. DKA-Prognosis
DKA accounts for 14% of all hospital admissions of patients with diabetes and 16% of all diabetes-related fatalities.
A fetal mortality rate as high as 30% is associated with DKA.
The rate is as high as 60% in diabetic ketoacidosis with coma.
Fetal death typically occurs in women with overt diabetes, but it may occur with gestational diabetes.
In children younger than 10 years, diabetic ketoacidosis causes 70% of diabetes-related fatalities.

62. DKA-Prognosis Regular follow up Management of risk factors
Patient/parent education