Diabetic Ketoacidosis, Type 1 Diabetes Case File

Diabetic Ketoacidosis, Type 1 Diabetes Case File

Eugene C. Toy, MD, Gabriel M. Aisenberg, MD

Case 52

An 18-year-old woman is brought to the emergency department by her mother because the daughter seems confused and is behaving strangely. The mother reports the patient has always been healthy and has no significant medical history, but she has lost 20 lb recently without trying and has been complaining of fatigue for 2 or 3 weeks. The patient had attributed the fatigue to sleep disturbance, as recently she has been getting up several times at night to urinate. This morning, the mother found the patient in her room, complaining of abdominal pain and vomiting. She appeared confused and did not know that today was a school day.

On examination, the patient is slender and lying on a stretcher with her eyes closed, but she is responsive to questions. She is afebrile and has a heart rate (HR) of 118 beats per minute (bpm), blood pressure (BP) of 125/84 mm Hg, and deep and rapid respirations at the rate of 24 breaths per minute. Upon standing, her HR rises to 145 bpm, and her BP falls to 110/80 mm Hg. Her fundoscopic examination is normal, her oral mucosa is dry, and her neck veins are flat. Her chest is clear to auscultation, and her heart is tachycardic with a regular rhythm and no murmur. Her abdomen is soft with active bowel sounds and mild diffuse tenderness, but no guarding or rebound. Her neurologic examination reveals no focal deficits.

Laboratory study results include serum Na+ 131 mEq/L, K+ 5.3 mEq/L, Cl– 95 mEq/L, HCO3 9 mEq/L, blood urea nitrogen (BUN) 35 mg/dL, creatinine 1.3 mg/dL, and glucose 475 mg/dL. Arterial blood gas (ABG) reveals pH 7.12 with PCO2 24 mm Hg and PO2 95 mm Hg. Urine drug screen and urine pregnancy test are negative, and urinalysis shows no hematuria or pyuria, but 3+ glucose and 3+ ketones. A chest radiograph is normal, and plain film of the abdomen has a nonspecific gas pattern but no signs of obstruction.

▶ What is the most likely diagnosis?

▶ What is the underlying pathophysiology of this diagnosis?

▶ What are some known precipitating factors associated with this diagnosis?

▶ What is your next step in medical management?

ANSWERS TO CASE 52:

Diabetic Ketoacidosis, Type 1 Diabetes

Summary: An 18-year-old woman presents with

• A few weeks of unintentional weight loss, nocturia, and polyuria
• Hyperglycemia that likely represents new-onset diabetes mellitus, probably type 1
• Hypovolemia due to osmotic diuresis
• An anion gap metabolic acidosis due to an increase in ketoacid production
• Acute altered mental status (confusion)
• Abdominal pain, vomiting, and labored breathing

Most likely diagnosis: Diabetic ketoacidosis (DKA).

Underlying pathophysiology: Absolute insulin deficiency favors glycogenolysis, gluconeogenesis, and ketosis, resulting in hyperglycemia, osmotic diuresis, and an anion gap metabolic acidosis.

Known precipitating factors: New-onset diabetes mellitus (typically type 1), inadequate insulin treatment or nonadherence, poor socioeconomic status, infection, pancreatitis, volume depletion, cocaine use, pregnancy, myocardial infarction, or cerebrovascular accident.

Next step in medical management: Aggressive hydration to improve her volume status and insulin therapy to resolve the ketoacidosis.

ANALYSIS

Objectives

1. Differentiate causes of anion gap metabolic acidosis. (EPA 2)
2. Differentiate DKA from nonketotic hyperosmolar hyperglycemia and alcoholic ketoacidosis. (EPA 2, 3)
3. Manage DKA by restoring volume, replacing electrolyte, and treating ketosis and hyperglycemia. (EPA 4, 10)
4. List the complications of DKA and of improper management. (EPA 12)

Considerations

DKA occurs as a result of severe insulin deficiency and may be the initial presentation of diabetes mellitus, as in this patient. In all patients with DKA, one must be alert for precipitating factors, such as infection, pregnancy, or severe physiologic stressors, such as myocardial infarction. The diagnostic criteria include arterial pH < 7.3, low serum bicarbonate with an anion gap, glucose > 250 mg/dL, elevated serum ketones (> 5 mEq/L), and elevated beta-hydroxybutyrate (> 3 mmol/L). The patient in this scenario has significant DKA based on the pH of 7.11. The bicarbonate of 9 mEq/L and anion gap of 27 mEq/L confirm metabolic acidosis from accumulation of organic acids. This patient needs immediate fluid repletion with normal saline (NS) and insulin infusion. Initial testing should include serum glucose, serum electrolytes, magnesium, phosphorus, amylase and lipase, urine dipstick, serum ketones, ABG, complete blood count (CBC), BUN and creatinine, urine and/or blood cultures, and an electrocardiogram (ECG).

APPROACH TO:

Diabetic Ketoacidosis

DEFINITIONS

DIABETIC KETOACIDOSIS: A syndrome of hyperglycemia, anion gap metabolic acidosis, and ketone bodies in the serum, caused by insufficient insulin levels.

KUSSMAUL RESPIRATIONS: Deep and rapid breathing that represents hyperventilation in an attempt to generate a respiratory alkalosis to compensate for the metabolic acidosis.

CLINICAL APPROACH

Pathophysiology

DKA is a hyperglycemic complication of diabetes mellitus caused by a significant insulin deficiency and characterized by anion gap metabolic acidosis, hyperglycemia, and ketosis. It is a medical emergency, with an overall mortality rate less than 5% if patients receive prompt and appropriate medical treatment. Most episodes are preventable, and many deaths are avoidable with proper attention to detail during management.

Normal Physiology. In the normal physiologic state, there is a fine balance between anabolic and catabolic hormones. In the fed state, anabolic actions of insulin predominate. Glycogenesis, lipogenesis, and protein synthesis all are increased. This results in storage of energy reserves in the form of triglycerides and glycogen.

In the fasting state, insulin serves to inhibit lipolysis, ketogenesis, gluconeogenesis, glycogenolysis, and proteolysis. These effects are critical in controlling the rate of breakdown of energy stores under the influence of catabolic hormones. Glucagon is the most important catabolic hormone. In the fasting state, it maintains normal glucose levels by stimulating hepatic gluconeogenesis and glycogenolysis.

Diabetic Ketoacidosis. Diabetes mellitus is the condition of relative or absolute insulin deficiency. When there is a severe insulin deficiency and a relative excess of glucagon, lipolysis is enhanced, causing release of free fatty acids. Oxidation of the fatty acids produces ketones, such as acetoacetate and beta-hydroxybutyrate, which are organic acids often referred to as ketoacids. The excess of these ketoacids can produce a life-threatening metabolic acidosis. In addition, hyperglycemia produces an osmotic diuresis, which causes severe volume depletion and electrolyte deficiencies by washing extracellular sodium, potassium, magnesium, phosphate, and water out of the body. The combination of acidosis, hypovolemia, and electrolyte deficiencies can lead to cardiovascular collapse, the most common cause of death in DKA.

Patients with diabetes have an underlying impairment in glucose metabolism and, when challenged by a stressor, an increase in insulin requirements. If they are unable to meet these insulin requirements, DKA may result. It is important to correct precipitating factors in order to restore metabolic balance. Identifiable sources of infection should be treated aggressively. Possible presence of ischemia and infarction should be evaluated and treated appropriately with help from specialists as needed. The most common precipitating events are infections such as pneumonia or urinary tract infection, vascular disorders such as myocardial infarction, or other stressors such as trauma.

DKA may be the presentation of new-onset diabetes; it may also occur in patients with established diabetes because of failure to use insulin or because of the use of other medications (eg, glucocorticoids) that interfere with insulin action.

Clinical Presentation

An episode of DKA evolves over a short period of time, typically in less than 24 hours. The patient with DKA has the signs and symptoms of hyperglycemia, acidosis, and dehydration. Polyuria, polydipsia, weight loss, visual blurring, and alteration in mental status are related to hyperglycemia and osmotic diuresis. Nausea, vomiting, abdominal pain, fatigue, malaise, and shortness of breath may be related to the acidosis.

Typical signs include decreased skin turgor, dry mucous membranes, hypotension, and tachycardia related to volume depletion. Kussmaul respirations, deep and rapid breathing, represent hyperventilation in an attempt to generate a respiratory alkalosis to compensate for the metabolic acidosis. One may also note the fruity breath odor typical of ketosis.

Laboratory Values. Laboratory values show hyperglycemia (usually > 250 mg/dL), acidosis (pH < 7.3), anion gap (usually > 15 mmol/L), and ketonemia. The most important laboratory parameters are the degree of acidosis, the anion gap, and the serum potassium level. Beta-hydroxybutyrate assay may be obtained in order to quantify the severity of the ketonemia present. Patients with a very low pH (< 7.0) are severely acidotic and have a worse prognosis. The lower pH is a result of the higher concentration of ketoacids, which are estimated using the anion gap.

Anion Gap. The first step in evaluating any patient with metabolic acidosis should be calculation of the anion gap. This concept is based on the principle of electrical neutrality, that is, all the cations must equal all the anions. The anion gap estimates those negatively charged particles that are not routinely measured and can be calculated using the following calculation:

Anion Gap = [Na] – [Cl + HCO3]

The normal anion gap is 10 to 12 mmol/L. When it is elevated, there is an excess of unmeasured anions, which typically occurs because of one of the four causes (Table 52–1).

Reproduced with permission, from Braunwald E, Fauci AS, Kasper KL, et al. Harrison’s Principles of Internal Medicine. 16th ed. 2005. Copyright © McGraw Hill LLC. All rights reserved.

Lactic acidosis results from severe tissue hypoxia, as in septic shock or carbon monoxide poisoning, or from hepatic failure and subsequent inability to metabolize lactate. Ketoacidosis most commonly occurs as an acute complication of uncontrolled diabetes, but it also can be seen in starvation and alcoholism. The ingested toxins may be organic acids themselves, such as salicylic acid, or have acidic metabolites, such as formic acid from methanol. Renal failure leads to an inability to excrete organic acids as well as inorganic acids such as phosphates (often without an anion gap).

In patients with DKA, total body potassium stores are depleted because of urinary losses, and potassium replacement will always be necessary. Initially, the measured serum potassium levels may be high despite the total body potassium deficit because of acidosis resulting in movement of potassium from the intracellular to the extracellular compartment. With the correction of the acidosis and the administration of insulin, which drives potassium intracellularly, serum potassium levels will fall rapidly.

The serum sodium level can be variable. Hyperglycemia causes water to move extracellularly, which can lead to hyponatremia. Similarly, phosphate levels can be variable in the presence of body store deficits, with the extracellular movement of phosphate caused by catabolic state. BUN and creatinine levels are elevated, reflecting hypovolemia. Serum acetoacetate may cause a false elevation in the serum creatinine level because of interference with the assay.

Treatment

The goal of treatment is restoration of metabolic homeostasis with correction of precipitating events and biochemical deficits, which consists of the following:

1. Replacement of fluid losses with improvement of circulatory volume
2. Correction of hyperglycemia and, in turn, plasma osmolality
3. Replacement of electrolyte losses
4. Clearance of serum ketones
5. Identification and treatment of precipitating cause and complications

Close monitoring of the patient is important. A flow sheet recording vital signs, fluid input and output, insulin dosage, and metabolic progress is important. Serum glucose concentration should be measured every 1 hour, and levels of serum electrolytes and phosphate must be assessed every 3 to 5 hours. Common ketone assays, blood, urine, and/or sputum cultures should be obtained if urine analysis or chest radiography indicates infection. Electrocardiography (ECG) should be checked to look for evidence of a cardiovascular event or arrhythmias due to metabolic derangement. Other investigations should be pursued as symptoms and signs warrant.

Fluids. All patients with DKA are volume depleted as a consequence of osmotic diuresis as well as from other ongoing losses, such as vomiting. Hydration improves renal perfusion and cardiac output, facilitating glucose excretion. Rehydration may also diminish insulin resistance by decreasing levels of counterregulatory hormones and hyperglycemia. Sudden reduction in hyperglycemia can lead to vascular collapse with a shift of water intracellularly. To avoid this, initial replacement fluid should be isotonic NS to correct circulatory volume deficit. Over the first hour, 1 to 2 L of NS should be infused. Following this, total body water deficit is corrected at the rate of 250 to 500 mL/h, depending on the state of hydration. The composition of fluid should be tailored according to serum sodium and chloride measurements. Hydration should be gentler in patients with heart failure or end-stage renal disease because such patients can easily be affected by fluid overload.

Insulin. The goal of therapy is a glucose reduction of 80 to 100 mg/dL/h. Use of continuous low-dose intravenous infusion of insulin is recommended because it reduces episodes of hypoglycemia and hypokalemia, and it allows for a more controlled reduction of serum glucose and osmolality. Intramuscular and subcutaneous routes can be used if tissue perfusion is adequate.

Insulin treatment may be initiated as an intravenous bolus of 0.1 to 0.15 U/kg. This should be followed by a continuous infusion of 0.1 U/kg/h with hourly serum glucose determinations. If blood glucose fails to decline at the desired rate, volume status should be reassessed, and the insulin infusion should be titrated accordingly. The rate of infusion should be decreased to 0.05 U/kg/h when the blood glucose level decreases to 250 to 300 mg/dL (if the acidosis is corrected). Glucose levels fall more quickly than ketosis resolves. Insulin is necessary for resolution of the ketoacidosis and can be coadministered with a glucose infusion until the anion gap is resolved. A 5% to 10% dextrose solution should be added to the hydrating solution when plasma glucose is less than 300 mg/dL.

One can judge the resolution of ketoacidosis when the bicarbonate is more than 18 mEq/L, the anion gap is less than 12, the patient feels better, and the vital signs are stabilized. Serial determination of serum ketone levels is not clinically useful in measuring response to therapy. Common ketone assays utilize nitroprusside, measuring acetoacetate and acetone, but not beta-hydroxybutyrate. Administration of insulin will induce oxidation of beta-hydroxybutyrate to acetoacetate, resulting in an increase in ketone levels despite effective therapy. When available, beta-hydroxybutyrate assay can be helpful, as a level greater than 3 mmol/L is shown to be highly sensitive and specific for DKA.

In the event serum ketone measurements are not available, one should be guided by normalizing the anion gap when making decisions about the rate of insulin infusion. Subcutaneous insulin should be given approximately 30 minutes before stopping insulin infusion to avoid rebound acidosis.

Bicarbonate. Bicarbonate therapy is controversial and should not be given to ketoacidotic patients unless their arterial pH is less than 7.00 or other indications, such as cardiac instability or severe hyperkalemia, are present. Bicarbonate therapy can cause worsening hypokalemia, paradoxical central nervous system acidosis, and delay in ketone clearance.

Electrolytes. In DKA, there is a deficit of total body potassium, phosphate, and magnesium. Patients frequently have hyperkalemia as a result of acidosis, insulin deficiency, and hypertonicity that cause a shift of potassium extracellularly. During treatment, the plasma potassium concentration will fall as the metabolic abnormalities are corrected. Potassium should be added to initial intravenous fluids once the concentration is less than 5 mEq/L. Once adequate urine output is established, 20 to 40 mEq of potassium should be added to each liter of fluid. The goal is to maintain potassium in the range of 4 to 5 mEq/L. Cardiac monitoring is recommended in the presence of hypokalemia or hyperkalemia.

Other Electrolytes. Phosphate replacement should be given to patients with serum phosphate concentrations less than 1 mg/dL and to patients with moderate hypophosphatemia with concomitant hypoxia, anemia, or cardiorespiratory compromise. Careful monitoring of the serum calcium level is necessary with phosphate administration. Magnesium and calcium can be supplemented as needed.

Prevention. The major precipitating factors in the development of DKA are inadequate insulin treatment and infection. These events can be prevented by patient education and effective communication with a health care team. Sick-day management regarding dosing of insulin, blood glucose monitoring, avoiding prolonged fasting, and preventing dehydration should be addressed. Socioeconomic barriers contribute to the high rates of admission for DKA. Appropriate allocation of health care resources toward preventive strategies is needed.

Complications

Cerebral edema secondary to hyperglycemia and osmotic diuresis, acute respiratory distress syndrome, thromboembolism secondary to coagulation cascade and fibrinolysis derangement, fluid overload, and acute gastric dilation are rare, but serious, complications of DKA.

Other metabolic complications of deranged carbohydrate metabolism deserve mention at this point. The first is hyperosmolar nonketotic diabetic coma. This condition occurs mainly in patients with type 2 diabetes who become profoundly dehydrated because of osmotic diuresis. However, these patients have sufficient insulin action to prevent the development of ketoacidosis. They may present with glucose levels more than 1000 mg/dL, serum osmolarity more than 320 to 370 Osm/L, and neurologic symptoms ranging from confusion to seizures to coma. Compared to patients with DKA, they have a much larger fluid deficit, and therapy is primarily volume resuscitation with NS. Insulin is also used to reverse hyperglycemia but usually is given in lesser doses than is required for clearance of ketosis in DKA.

Alcoholic ketoacidosis develops in chronic alcoholics who are malnourished and have depleted glycogen stores. It is often seen in the setting of binge drinking, which may shift the ratio of the reduced form of nicotinamide adenine dinucleotide (NADH) to nicotinamide adenine dinucleotide (NAD), inhibiting gluconeogenesis. These patients develop an anion gap metabolic acidosis as a result of ketoacidosis and lactic acidosis. They present with the same symptoms of acidosis as do DKA patients, for example, abdominal pain, nausea, and vomiting, but with low, normal, or slightly elevated glucose levels (in contrast to DKA, in which the glucose level usually is markedly elevated). Treatment is administration of volume in the form of NS and glucose solution. Insulin administration is typically unnecessary. Thiamine may need to be coadministered.

CASE CORRELATION

• See also Case 41 (Urinary Tract Infection With Sepsis in the Elderly), Case 53 (Thyrotoxicosis/Graves Disease), and Case 59 (Delirium/Alcohol Withdrawal).

COMPREHENSION QUESTIONS

52.1 A 36-year-old woman is brought into the emergency department for lethargy. She is unable to respond to commands but does open her eyes to painful stimuli. On examination, her HR is 110 bpm, BP is 90/60 mm Hg, and respiratory rate (RR) is 24 breaths/min. An arterial blood gas reveals a pH of 7.28, pco2 of 28 mm Hg, po2 of 90 mm Hg, and HCO3 of 22 mEq/L. Serum electrolytes reveal Na+ 138 mEq/L, K+ 3.8 mEq/L, Cl- 105 mEq/L, and HCO3 of 23 mEq/L. Which of the following is the most likely diagnosis that led to this patient’s condition?

A. Diarrhea

B. Lactic acidosis

C. Diabetic ketoacidosis

D. Ethylene glycol ingestion

52.2 An 18-year-old man is being seen the emergency center for nausea, vomiting, lightheadedness, and fatigue. He is a known type 1 diabetic and states that he has been taking his insulin as scheduled. On examination, his BP is 80/40 mm Hg, temperature is 101 °F, HR is 120 bpm, and RR is 30 breaths/min. He has some adenopathy of the cervical area. Laboratory test values show an arterial pH of 7.20, po2 of 100 mm Hg, pco2 of 28 mm Hg, and HCO3 of 12 mEq/L. His serum glucose level is 400 mg/dL. Which of the following is the most accurate statement regarding this patient’s likely potassium status?

A. Likely to have a serum potassium level less than 3 mEq/L.

B. Likely to have a serum potassium level more than 7 mEq/L.

C. Likely to have a total body potassium deficit regardless of the serum level.

D. Serum level is likely to increase with correction of the acidosis.

52.3 An 11-year-old girl is being seen in the pediatric emergency department for near syncope. She is being followed for type 1 diabetes and is not very adherent to her medications or diet. Her current BP is 90/60 mm Hg, HR is 120 bpm, RR is 26 breaths/min, and temperature is afebrile. Based on an arterial blood gas with a pH of 7.23 and a serum glucose level of 550 mg/dL, she is diagnosed with DKA. Which of the following is the most important first step in the treatment of this patient?

A. Replacement of potassium

B. Intravenous fluid replacement

C. Replacement of phosphorus

D. Antibiotic therapy

52.4 A 59-year-old man with a long history of diabetes with chronic renal insufficiency due to diabetic nephropathy is seen in clinic for routine laboratory work. He is asymptomatic, but his glucose is elevated at 258 mg/dL. His other chemistries are as follows: sodium 135 mEq/L, potassium 5.4 mEq/L, chloride 108 mEq/L, and bicarbonate 18 mEq/L. His creatinine is stable at 2.1 mg/dL. Which of the following is the most likely cause of this patient’s acidemia?

A. Diabetic ketoacidosis

B. Lactic acidosis

C. Type 4 renal tubular acidosis (RTA)

D. Accidental salicylate overdose

ANSWERS

52.1 A. This patient has a metabolic acidosis based on the low pH and the low pco2 (partial respiratory compensation). The anion gap is calculated by the following formula: Anion Gap = [Na+] – [Cl-+ HCO3]. In this case, the patient’s anion gap = 138 – (105 + 23) = 10, which is normal (recall normal anion gap is 10-12). Diarrhea leads to bicarbonate loss and usually does not affect the anion gap. All other choices (answer B, lactic acidosis; answer C, DKA; and answer D, ethylene glycol ingestion) are causes of a high anion gap metabolic acidosis. Common causes can be remembered with the MUDPILES mnemonic (methanol, uremia, DKA, propylene glycol, iron/isoniazid/infection, lactic acidosis, ethylene glycol, salicylates).

52.2 C. Total body potassium usually is depleted regardless of the serum level due to urinary loss; an extracellular shift of potassium in the setting of acidosis may explain high serum potassium levels (answer B) upon diagnosis of DKA. Answer A (serum potassium < 3 mEq/L) would be unusual in light of the acidosis; the typical level would be normal. Answer D (serum potassium > 7 mEq/L) would be highly unusual, since this level of elevation would often lead to cardiac arrhythmias and possibly death; a mildly elevated or normal serum potassium level would be more commonly encountered.

52.3 B. The basic tenets of treating DKA include intravenous fluid, insulin to control the glucose level, correction of metabolic disturbances (eg, repletion of potassium), and identification of the underlying etiology. Intravenous fluids to support the circulatory status (BP) are the most important first step in this patient. Lowering the blood sugar would be the next important step. Correction of metabolic abnormalities such as of potassium (answer A) and phosphorus (answer C) are next considered, although the potassium level is more dangerous and a higher priority. Answer D (antibiotics) should be given if a patient is thought to have an infection leading to the DKA; in this patient, there is no fever or symptom suggestive of infection. Even with the presence of infection, intravenous fluids would be the first priority.

52.4 C. The patient likely has type 4 RTA. RTA leads to electrolyte abnormalities due to abnormal renal tubular transport.

• Type 1 = impaired renal hydrogen ion excretion in the distal tubule
• Type 2 = impaired bicarbonate resorption in the proximal tubule
• Type 4 = abnormal aldosterone production or response (usually hyperkalemia and non–anion gap acidosis)

NOTE: Type 3 RTA is combined proximal and distal tubule and very rare.

The laboratories are consistent with a non–anion gap metabolic acidosis. The anion gap = 135 – (108 + 18) = 9 (normal is 10-12). Patients with chronic kidney disease due to diabetes are prone to subtle volume expansion and low plasma renin activity, leading to hypoaldosteronism. Since aldosterone is the major hormone that promotes potassium excretion, hyperkalemia is the primary electrolyte abnormality. The disorder is typically associated with a type 4 RTA and a mild metabolic acidosis (bicarbonate usually > 17 mEq/L). The other illnesses (answer A, DKA; answer B, lactic acidosis; and answer D, accidental salicylate overdose) cause anion gap acidosis.

CLINICAL PEARLS

▶ All patients with DKA are volume depleted and require significant replacement of salt solution and, later, free water in the form of glucose solutions.

▶ Despite sometimes elevated initial potassium concentrations, all patients with DKA have a total body potassium deficit and will require substantial potassium replacement.

▶ Patients with DKA develop an anion gap metabolic acidosis. This acidemia prompts respiratory compensation, resulting in deep and rapid breathing to ventilate carbon dioxide. This is known as Kussmaul breathing.

▶ Glucose levels fall more quickly than ketones resolve. Continuous insulin therapy is necessary for resolution of the ketoacidosis and can be coadministered with a glucose infusion until the anion gap is resolved.

▶ Cerebral edema can result from overly rapid correction of hyperglycemia or possibly from rapid administration of hypotonic fluids.

▶ DKA can be precipitated by either insulin deficiency or a physiologic stressor such as infection.

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