Diabetic ketoacidosis

Diabetic Ketoacidosis

I. What every physician needs to know.

Diabetic ketoacidosis (DKA) is a serious, life-threatening complication of diabetes mellitus. DKA is characterized by the triad of hyperglycemia, anion gap metabolic acidosis, and ketonemia. It is part of a spectrum of hyperglycemia on which lies hyperosmolar hyperglycemic state (HHS). Though the two are distinct entities, they do share some commonalities.

DKA is caused by the reduced effect of insulin, either due to deficit or reduction of levels, with concomitant elevation of counter regulatory hormones (glucagon, catecholamines, cortisol, and growth hormones), generally due to a precipitating stress. Increased gluconeogenesis, glycogenolysis, and decreased glucose uptake by cells leads to hyperglycemia, while insulin deficiency leads to mobilization and oxidization of fatty acids leading to ketogenesis.

Although DKA may be the initial manifestation of diabetes, it is typically precipitated by other factors. It is critical for a clinician to identify and treat these factors. Infection can be found in 40-50% of patients with hyperglycemic crisis, with urinary tract infection and pneumonia accounting for the majority of cases.

DKA is a life-threatening medical emergency with a mortality rate just under 5% in individuals under 40 years of age, but with a more serious prognosis in the elderly, who have mortality rates over 20%. Deaths may also occur as a result of hypokalemia induced arrhythmias and cerebral edema (more common in children).

II. Diagnostic confirmation: are you sure your patient has diabetic ketoacidosis?

Although the diagnosis of DKA can be suspected on clinical grounds, confirmation is based on laboratory tests including potential hydrogen (pH) level, urinalysis, and basic metabolic profile. Table I summarizes the biochemical criteria for the diagnosis and assessment of severity of DKA. Although the bicarbonate level is typically low, it may be normal or even high in patients with vomiting, diuretic use, or alkali ingestion.

Table I.

	Mild	Moderate	Severe
Plasma glucose	>250	>250	>250
Arterial pH	7.25-7.30	7.00 – <7.24	<7.00
Serum bicarbonate (mEq/L)	15-18	10 – <15	<10
Urine ketone	+	+	+
Serum ketone	+	+	+
Effective serum osmolality	Variable	Variable	Variable
Anion gap	+	+	+

A. History: Pattern Recognition.

DKA can develop rapidly, often over a period of less than 24 hours. Patients generally are known to have diabetes (mainly type 1 diabetes mellitus but can also occur in obese type 2 diabetes) and present with polyuria, polydypsia, polyphagia, weakness, and Kussmaul respiration. Nausea, vomiting and abdominal pain, often mimicking an acute abdomen, are present in 50-80% of patients. Coffee-ground emesis from hemorrhagic gastritis occurs in about 25% of vomiting patients. There is some data to suggest that abdominal pain is associated with a more severe metabolic acidosis and frequently resolves after correction of the metabolic disturbance.

B. History: Prevalence.

Data from the National Diabetes Surveillance Program of the Centers for Disease Control (CDC) show that DKA & HHS is responsible for approximately 175,000 ER visits annually and accounts for 4-9% of all hospitalizations. DKA characteristically occurs in patients with type I diabetes, but can affect patients with type 2 diabetes as well. Contrary to popular belief, the disease is more common among adults than in children.

There are number of precipitants of DKA. These include:

Infection, such as urinary tract infection and pneumonia.

Psychological stress.

Poor compliance with therapy.

Vascular, including cerebrovascular accident, myocardial infarction, and pulmonary embolism.

Pancreatitis.

Trauma.

Medications, such as corticosteroids, thiazide diuretics, and pentamidine.

Alcohol / drug abuse

Omission of insulin administration because of eating disorder or mental health disorder.

C. History: Competing Diagnoses that can Mimic Diabetic Ketoacidosis.

The differential diagnosis for DKA is relatively narrow (see Table II). For the vast majority of these conditions the classic triad of hyperglycemia, anion gap metabolic acidosis and ketonemia is absent. However, it is critical to keep in mind that the list of potential precipitants of DKA is extensive and includes many of the diseases listed below.

Feature	Differential diagnosis
Hyperglycemia	Hyperglycemic hyperosmolar state
Ketosis	Alcoholism, starvation
Anion gap metabolic acidosis	Toxic ingestion (methanol, ethylene glycol, salicylate, etc.), lactic acidosis, ketoacidosis, uremia
Abdominal pain	Appendicitis, cholecystitis, gastritis, peptic ulcer disease, pancreatitis

In hyperglycemic hyperosmolar state (HHS) there is little or no ketoacid accumulation (pH greater than 7.30), the blood glucose is extremely elevated (frequently exceeds 1000 mg/dL), and neurologic abnormalities (coma, stupor) are frequently present.

Patients with chronic alcohol abuse or starvation can also present with ketonemia. Although the acidosis can be severe in alcoholic ketoacidosis, starvation ketoacidosis generally does not cause severe acidemia and rarely presents with a serum bicarbonate level of less than 18 mEq/L.

D. Physical Examination Findings.

As with all patients, the physical examination should focus on airway, breathing, and circulation, mental status, possible precipitating events, and volume status.

Physical examination in patients with DKA is generally non-specific and reveals signs of dehydration, including loss of skin turgor, dry mucous membranes, tachycardia, and hypotension. Mental status can vary from full alertness to profound lethargy; however, less than 20% of patients who are hospitalized have loss of consciousness. Body temperature is usually normal or even low, except in the case of concomitant infection. Consciousness can be affected in more severe cases of DKA. Acetone on breath and labored Kussmaul (deep) respiration may also be present on admission, particularly in patients with severe metabolic acidosis.

E. What diagnostic tests should be performed?

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

As discussed previously the diagnosis of DKA is principally based on the history and biochemical data. As a result, patients suspected to have the condition should have a thorough laboratory evaluation. These include:

Serum glucose.

Serum electrolytes (with calculation of the anion gap), blood urea nitrogen (BUN), and serum creatinine.

Complete blood count with differential.

Urinalysis, and urine ketones by dipstick.

Urine drug screen if recurrent DKA to rule out drug abuse.

Plasma osmolality.

Serum beta-hydroxybutrate.

Arterial or venous blood gas (if urine ketones or anion gap are present).

Electrocardiogram.

Although ketonemia used to be frequently assessed through serum ketones, but in the current clinical environment serum or plasma assays for beta-hydroxybutyrate are preferred over serum ketones levels as it more accurately reflect the true ketone body level (beta-hydroxybutyrate is synthesized at a 3-fold greater rate than acetoacetate). In addition, ketosis and acidosis are not synonymous, because the increase in hydrogen ion (H+) concentration resulting from the production of ketone acids is initially buffered by bicarbonate. Thus, measurement of blood pH is important.

There are several common pitfalls in the interpretation of laboratory tests for DKA.

Patients with DKA frequently present with leukocytosis, however, a significantly elevated leukocyte count (greater than 25,000 mm³), or bandemia (greater than 10% bands) is unlikely in the absence of bacterial infection.
Serum sodium is characteristically low because of hyperglycemia, which causes an influx of water from the intracellular to the extracellular space. It is important to correct for this, which is done using the following formula:

Corrected sodium = Measured sodium + (((Serum glucose) – 100)/100) x 1.6)

or roughly 1.6 meg reduction in serum sodium for each 100 mg/dL of glucose rise.

Serum potassium is generally elevated secondary to acidemia, insulin deficiency and hypertonicity.
Serum phosphate may be normal or elevated secondary to metabolic acidosis.
Serum amylase is almost always elevated even if there is no pancreatitis. (In DKA amylase is usually of salivary origin). Lipase should always be ordered in addition to amylase to assess for pancreatitis.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Radiologic studies should not be routinely used in the diagnosis of DKA. However, they may be very important in the identification of the underlying precipitating cause. Depending on the patient’s presentation, chest or abdominal radiography may be helpful.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Although testing of blood pH is essential in the diagnosis and management of DKA, data suggest that venous blood gas values perform comparably among adult emergency department patients. Thus, a separate arterial blood gas may be unnecessary.

III. Default Management.

The treatment of DKA requires:

Correction of hypovolemia and hyperglycemia.
Replacement of electrolyte losses.
A thorough search for a precipitating cause.

Therapy is best delivered through an evidence-based protocol with frequent monitoring to ensure resolution of the metabolic disturbances. This should include blood glucose monitoring every 1-2 hours, electrolyte monitoring every 2-6 hours, and cardiac monitoring. Patients with shock may also benefit from central venous catheterization and arterial line. It is important to remember that fluid resuscitation through a standard triple-lumen central venous catheter is likely to be inadequate and additional peripheral access ought to be maintained.

The American Diabetes Association (ADA) admission guidelines are a plasma glucose concentration greater than 250mg/dL (13.9 mmol/L) with an arterial pH level below 7.30, a serum bicarbonate level of less than 15 mEq/L, and a moderate or greater level of ketones in the serum or urine. Patients with severe DKA should be admitted to the intensive care unit.

A. Immediate Management.

In patients hospitalized with DKA it is important to stabilize the patient’s airway, breathing, and circulation. Patients should have large-bore access (greater than 16 gauge) and have cardiac telemetry.

Fluid therapy

Fluids are critical in the management of DKA. Data show that patients generally have a water deficit of around 100 ml/kg of body weight.

First 2 hours: isotonic saline (0.9% NaCL) at a rate of 15-20 mL/kg/hour, although patients with hypovolemic shock may require several additional liters.
2-24 hours: reduce the rate of isotonic saline to 250 mL/h or change to 0.45% saline (250–500 mL/h) depending on the serum sodium concentration (use isotonic saline if corrected serum sodium is low) and state of hydration. The goal is to replace half of the estimated water deficit over a period of 12-24 hours. The goal is to replace half of the estimated water deficit over a period of 12-24 hours; and also change IV fluids to 5% glucose (dextrose) 0.45% saline @150-200 mL/hr when plasma glucose reaches ~250 mg/dL.

Potassium

Patients with DKA generally have large total body potassium deficits (mainly due to urinary losses related to glucose osmotic diuresis & secondary hyperaldosteronism). Potassium should be addressed as follows:

If initial serum K+ is below 3.3 mEq/L, hold insulin and give K+ 40 mEq/hour intravenously (IV) until K+ concentration is above 3.3 mEq/L.

If initial serum K+ is between 3.3 mEq/L and 5.3 mEq/L, give K+ 20-30 mEq/L IV fluid; maintain K+ between 4 mEq/L to 5 mEq/L.

If initial serum K+ is above 5.3 mEq/L do not give K+; check K+ every 2 hours.

Insulin therapy

In addition to fluids, the other cornerstone of the management of DKA is insulin therapy. In critically ill patients, regular insulin should be given intravenously by continuous infusion. Although newer, faster acting insulins (lispro and aspart) can be given intravenously, these are more expensive and do not work more quickly than regular insulin when given intravenously.

Give an initial intravenous bolus of 0.1unit/kg of body weight followed (within 5 minutes) by a continuous infusion of regular insulin of 0.1 unit/kg/hour (roughly equivalent to 7 units/hr in a 70 kg patient). This generally results in a decrease of plasma glucose concentration at a rate of 65-125mg/h. If serum glucose does not decrease by at least 10% in the first hour, give an insulin bolus of 0.14 units/kg, then continue previous infusion.
Check blood glucose every hour during continuous infusion of insulin.

For patients who are admitted to a general hospital ward, the use of regular insulin every 1-2 hours by subcutaneous or intramuscular routes has been shown to be as effective as intravenous insulin. These patients should receive the recommended hydrating solution and an initial “priming” dose of regular insulin of 0.4 unit/kg of body weight, given half as intravenous bolus and half as a subcutaneous or intramuscular injection This approach should only be attempted when adequate staffing is available to carefully & closely monitor the patient & blood glucose can be checked every hour.

Bicarbonate

Bicarbonate administration in patients with DKA remains controversial. Severe metabolic acidosis can lead to impaired myocardial contractility, cerebral vasodilatation and coma, and several gastrointestinal complications. However, rapid alkalinization may result in hypokalemia, paradoxical central nervous system acidosis, and worsened intracellular acidosis. Controlled studies have failed to show any benefit from bicarbonate therapy in patients with DKA with an arterial pH between 6.9 and 7.1. However, bicarbonate replacement is commonly used in patients with a pH below 7.0 as follows.

If the arterial pH is between 6.90 and 7.00, give 50 meq of sodium bicarbonate plus 10 meq of potassium chloride in 200 mL of sterile water over two hours.
If the arterial pH is below 6.90, give 100 meq of sodium bicarbonate plus 20 meq of potassium chloride in 400 mL sterile water over two hours.

Phosphate

Total body phosphate deficiency is also universally present in patients with DKA. The clinical relevance of this is not well understood and aggressive replacement may be harmful. As a result, careful phosphate repletion (in the form of a potassium salt) is generally restricted to patients whose serum phosphate concentration is lower than 1.0-1.5 mg/dL. It is important to monitor serum calcium levels during phosphate infusion to minimize associated risks.

B. Physical Examination Tips to Guide Management.

The most common complications of the treatment of DKA are metabolic—hypoglycemia and hypokalemia—and these require careful laboratory monitoring as detailed above. However, it is important to assess volume status and ensure resolution of abdominal symptoms. In addition, patients are also at risk for cerebral edema and non-cardiogenic pulmonary edema.

General: check orthostatic vital signs every hour until stable if patient not overtly hypotensive.
Abdominal examination: expect resolution of abdominal tenderness in 1-2 hours after treatment. If it does not resolve, consider the possibility of another abdominal process and further testing including diagnostic imaging.
Heart/lung examination: monitor for signs of pulmonary edema, which is the result of decreased colloid osmotic pressure leading to increased lung water content.
Neurologic examination: although cerebral edema generally occurs in children with DKA it can also occur in adults. The pathophysiology of cerebral edema is not well understood. Patients with evidence of cerebral edema should be transferred to the ICU if not already there. Mannitol, reduction in fluid rate, and hyperventilation (via mechanical ventilation) are often used to treat the condition with minimal supporting evidence.

C. Laboratory Tests to Monitor Response to, and Adjustments in, Management.

Potassium

Check potassium every 2-4 hours until the anion gap is closed and the potassium has stabilized.

Insulin therapy

When plasma glucose reaches 200 mg/dL, the insulin infusion rate should be reduced to 0.05 unit/kg/hour and dextrose (5-10%) should be added to the intravenous fluid. The rate of the insulin may need to be further adjusted downward to maintain blood glucose values greater than 200 mg/dL until the ketoacidosis has resolved. (DKA is considered resolved when the blood glucose is around 200 mg/dL, the anion gap has closed (less than 12 mEq/L), and pH is greater than 7.3.) Check blood glucose every 1-2 hours during continuous infusion of insulin.

Fluid therapy

Once the patient’s serum glucose reaches 250 mg/dL dextrose (5%) should be added to the saline solution and continued until the anion gap has closed.

D. Long-term Management.

Once the DKA has resolved (as defined above) and patients are able to eat, the transition to subcutaneous insulin can begin. It is critical to allow a 2-4 hour overlap of intravenous insulin and subcutaneous insulin to avoid recurrence of DKA.

In patients with known diabetes, the home dose of insulin can be restarted.
In patients newly diagnosed with diabetes, an insulin dose of 0.6 unit/kg/day is generally given using split-dose therapy (both regular/short-acting and intermediate-acting, for example with a 50/50 or, less commonly, a 70/30 split, etc.). Give 1/2 (or less commonly 2/3) of this total daily dose in the morning; and 1/2 (or less commonly 1/3) of this total daily dose in the evening.

In patients who are unable to eat, intravenous insulin should be continued with an infusion of 5% dextrose in half-normal saline at a rate of 100-200 mL/h.

E. Common Pitfalls and Side-Effects of Management.

The treatment of DKA is generally protocol driven. The use of an order set and detailed flowsheets have been shown to improve the quality of care delivered. A sample order set is provided below. Other common pitfalls include hypoglycemia and hypokalemia, the risk of which can be minimized through the use of flowsheets and frequent monitoring. The management of glucose and potassium has been described above. Symptomatic hypoglycemia should be treated with 50 ml D50W intravenously once while the rate of dextrose containing fluid is increased. In addition, the frequency of blood glucose monitoring should be increased until glucose levels stabilize.

Sample order set

1. Diet:

NPO.

2. Initial laboratory work:

CBC, Na, K, Cl, CO2, Glucose, BUN, Creatinine, Ca, PO4, Mg, Serum beta-hydroxybutyrate, Serum Osmolality, urinalysis, ABG.

Other__________________________________________________________

3. Subsequent statistical laboratory orders:

A. Check blood glucose (BG) q1 hour with glucose meter. If BG >500 send to lab.Do not use fingertip for blood sample if patient is hypotensive or in shock.

B. Na, K, Cl, CO2 q2h x 3, then q4 hour.

C. Other ________________________________________

4. IV Fluids:

Monitor I/O’s q2 hour.

Bolus: ___________________ NS at __________ cc/hour Additive: KCl _________ meq/liter 1/2 NS at _________ cc/hour Other: ______________________

5. Initial insulin dose:

A. IV Insulin Bolus: give 0.1 units/kg IV push (if not done in ED).

B. Insulin Infusion: Mix Standard Insulin Solution (Mix 25 units of regular human insulin in 250 ccNS; Standard Concentration is 1 unit/10 cc). Flush first 50 cc through tubing before connecting to patient.

C. Begin Insulin Infusion at 0.1 units/kg/hour (equivalent to 7 units/hr in a 70 kg patient).

6. Adjustment of insulin infusion rate:

A. When BG >200 mg/dL, adjust Insulin Infusion rate as follows:

1. If BG has decreased by 50-200 mg/dL in a one hour period keep the insulin drip rate the same.2. Call physician if BG has decreased by <50 mg/dL or >200 mg/dL in a one hour.

B. When BG <200 mg/dL, call physician and:

1. Change IV solution to: D5 1/2 NS at _______ cc/hour + KCl _____ meq/liter.2. Change insulin infusion to _______ units/hour (See General Guidelines on back).3. Check BS q1 hour.4. Adjust Insulin Infusion rate as follows:

BG <80 mg/dL STOP insulin infusion and Call House Officer (see #7 below).*Do not restart insulin infusion until BG ≥100 mg/dL.*BG 80-120 mg/dL. Decrease drip by 0.5 units/hour.BG 121-180 mg/dL. No change in drip rate.BG 181-250 mg/dL. Increase drip by 0.5 units/hour.BG >250 mg/dL. Bolus 5 units regular insulin and increase drip by 0.5 units/hour.

7. For a BG <80 mg/dL or >400 mg/dL, call physician:

BG <80 mg/dL but >60mg/dL. Stop insulin infusion. Check BG q15 minutes.BG ≤60 mg/dL. Stop insulin infusion; give 50 cc D50 IV push; check BG q15 minutes and repeat treatment until BG >100 mg/dL.When BG ≥100 mg/dL. Call physician or new insulin infusion rate.BG >400 mg/dL. Call physician to reassess insulin infusion rate.

8. Call physician for urine output <30 cc/hour.

9. When converting to subcutaneous (SQ) insulin, give prescribed SQ dose 2-4 hours prior to discontinuing insulin infusion.

IV. Management with Co-Morbidities.

The management of DKA is affected by several comorbidities. These are described in detail below.

A. Renal Insufficiency.

The management of DKA in patients with end stage renal disease (ESRD) or chronic kidney disease (CKD) is challenging. Patients generally have limited volume deficits secondary to the absence of glucosuria and may even be volume overloaded. As a result, instead of aggressive fluid replacement (rate of fluid administration will be dependent on volume status), management is principally focused on the administration of low doses of intravenous insulin adjusted as follows:

No dose adjustment if glomerular filtration rate (GFR) greater than 50 mL/min.

Reduce to approximately 75% if GFR is between 10mL/min and 50 mL/min.

Reduce to approximately 50% if GFR < 10 mL/min.

In hemodialysis (HD) patients use 2 units/hour.

Patients with ESRD often have severe hyperkalemia secondary to the combination of acidosis and extracellular fluid hypertonicity and will need to be followed closely. Consult nephrology early in the management of these patients as the metabolic and volume abnormalities may be severe enough to necessitate urgent or emergent dialysis.