CC

A 17-year-old female with diabetes presents to the oral and maxillofacial surgery clinic 5 days after extraction of her four third molars. She complains of “nausea and vomiting.”

HPI

The patient reports a history of poor oral intake and frequent emesis (vomiting) for the past 3 days. She has been feeling progressively more fatigued, with general malaise (secondary to dehydration). Because she has not been able to eat or drink regularly, she decided to discontinue all her insulin injections. (Lack of insulin is the key cause of diabetic ketoacidosis [DKA].)

She also complains of blurry vision (secondary to volume depletion), vague abdominal pain (metabolic acidosis results in gastric distension and blockage, and β-hydroxybutyrate induces vomiting), cramping in her extremities (secondary to hypokalemia and dehydration commonly associated with DKA), an elevated temperature (secondary to development of infection and dehydration), and swelling of the left mandible that has progressively exacerbated over the past 48 hours. She reported an increase in the frequency of urination (polyuria) in the first few postoperative days but has not voided for the past day (initial osmotic diuresis causing dehydration). At first, her mother was not concerned about a developing infection because the patient’s breath actually smelled “fruity” (acetone breath odor secondary to elevated plasma ketones). However, she became anxious when her daughter appeared progressively less responsive. (Stupor and coma can be caused by rapid increases in blood osmolarity, which cause water to be drawn out of the central nervous system, resulting in cellular dehydration and changes in consciousness.) The on-call surgeon was contacted the night before and attributed the nausea and vomiting to excessive narcotic intake. The swelling was assessed via telephone to appropriately correspond to postsurgical edema. The patient was prescribed promethazine and advised to see the treating surgeon the next day. (Any suspicion of DKA should prompt evaluation in the emergency department as soon as possible. Unrecognized DKA can be deleterious.)

PMHX/PDHX/medications/allergies/SH/FH

The patient was diagnosed with diabetes mellitus type 1 at age 14 years. She takes regular insulin (short-acting insulin) and NPH (intermediate-acting insulin) twice a day under the care of an endocrinologist. (A clogged tubing in patients on an insulin pump can result in similar presentation.) She denies the use of alcohol, tobacco, and recreational drugs.

Examination

General. The patient is an intermittently nonresponsive female who does not follow commands (altered mental status). She is breathing without obstruction, but it is deep and slow (Kussmaul breathing, partial respiratory compensation for metabolic acidosis).

Vital signs. Blood pressure is 101/50 mm Hg (hypotension), heart rate is 114 bpm (tachycardia), respirations are 20 per minute (hyperventilation illustrates respiratory compensation of metabolic acidosis), and temperature is 38.8°C (febrile).

Orthostatic. When the patient rises from a supine to a standing position, the heart rate increases to 140 bpm, and the blood pressure decreases to 80/40 mm Hg. (An increase in heart rate >30 bpm or a decrease in systolic blood pressure by >20 mg/dL or in diastolic blood pressure by >10 mg/dL is an indication of severe volume depletion.)

Maxillofacial. The patient has significant tenderness (dolor), edema (tumor), and erythema (rubor) of the left lower face, and her face is warm (calor) to the touch. (These are the cardinal signs of inflammation.) Fluctuance is palpated over the angle of the mandible. She is unable to open her mouth more than 10 mm (trismus, suggestive of masticator space infection). The patient is able to maintain her secretions. (Drooling would be indicative of significant oropharyngeal swelling or dysphagia.)

Intraoral. Purulence is noted around the extraction socket of the left mandibular third molar, with surrounding gingival edema and erythema. The floor of the mouth is soft and is not raised. There is moderate swelling of the left lateral pharyngeal wall, with slight deviation of the uvula (indicative of left lateral pharyngeal spread of infection). Dry mouth (xerostomia) and difficulty swallowing (dysphagia) can develop secondary to dehydration.

Cardiovascular. The patient has sinus tachycardia with intermittent pause, which correlates with premature ventricular contractions. (Electrolyte abnormalities, such as hyperkalemia, result in abnormal heart rhythms.)

Pulmonary. The patient’s chest is bilaterally clear on auscultation with deep breathing.

Abdominal. Generalized pain on palpation but otherwise nontender and nondistended.

Imaging

A panoramic radiograph and a computed tomography (CT) scan of the head and neck may be indicated to evaluate the spread of infection in the parapharyngeal and masticator spaces and for evaluation of the airway. In patients with compromised renal function, as determined by an elevated creatinine level, contrast CT is contraindicated. Noncontrast CT, although less useful for demonstrating soft tissue spread of infection, can still be of value.

There should be a low threshold for ordering CT or magnetic resonance imaging scans to search for brain edema, particularly in pediatric patients with altered mental status.

Labs

A full set of laboratory studies (complete blood count, electrolytes, and urinalysis) is essential in the management of DKA. DKA patients have a serum ketone concentration greater than 5 mEq/L. Ketones consist of acetoacetate, β-hydroxybutyrate, and acetone. The following laboratory study results also were obtained for the current patient:

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  Hemogram: White blood cell count of 18.2 cells/μL with a differential of 70% neutrophils, 20% bands, 8% lymphocytes, 1% monocytes, and 1% eosinophils (elevated neutrophil count is indicative of acute inflammation); hemoglobin and hematocrit of 15 mg/dL and 45%, respectively (volume depletion results in overestimation of the hemoglobin and hematocrit); and platelet count within normal limits.

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  Basic metabolic panel: Na ⁺ 130 is mEq/dL (hyperglycemia induces an intracellular movement of sodium); K ⁺ is 6.5 mEq/dL (elevated secondary to acidosis causing transcellular shift of K ⁺ into the extracellular space in exchange for H ⁺ ions); Cl ⁻ is 95 mEq/dL (normal chloride is consistent with an anion gap metabolic acidosis [most common causes of anion gap metabolic acidosis are ketoacidosis, lactic acidosis, drugs and kidney failure), bicarbonate is 10 mEq/dL (a low bicarbonate level is indicative of metabolic acidosis), blood urea nitrogen is 60 mEq/dL, creatinine is 3 mEq/dL (blood urea nitrogen and creatinine are both elevated secondary to decreased intravascular volume [prerenal azotemia]), and glucose is 550 mg/dL (primarily secondary to the lack of insulin).

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  Arterial blood gas (venous blood gas is sufficient) analysis: pH is 7.1, P co ₂ is 25 mm Hg, and PO ₂ is 90 mm Hg on F i o ₂ of 40%. (A pH of 7.1 is a strong acidemia. These findings, along with a low P co ₂ , are indicative of metabolic acidosis with respiratory compensation.)

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  Urine analysis: Positive ketones, +3 glucosuria (the proximal convoluted tubules’ ability to reabsorb glucose is maximized at a blood glucose of 180–200 mg/dL, after which glucose is spilled into the urine, causing osmotic diuresis); +2 proteinuria. (Glomeruli damage in diabetic nephropathy results in protein wasting and nephrotic syndrome; microproteinuria is indicative of diabetic nephropathy and may be avoided or delayed by daily intake of angiotensin-converting enzyme inhibitors.)

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  Urine dipstick test: +4 for nitroprusside (indicative of acetoacetate and acetone [ketones] in the urine). Rarely, urine ketone is negative. Although the predominant ketone in severe DKA is β-hydroxybutyrate, a urine dip stick cannot test for it. As the clinical condition improves, the urine dip stick may change from negative to positive as acetoacetate predominates.

Electrocardiogram

The electrocardiogram shows widened QRS complexes and peaked T waves (secondary to hyperkalemia) and occasional premature ventricular contractions.

Assessment

Diabetic ketoacidosis secondary to parapharyngeal and masticator space infection. (Infection is the leading cause of DKA.)

Treatment

Treatment begins with assessment of the ABCs—airway, breathing, and circulation. Intravenous (IV) fluid is the first line of treatment; start with normal saline and subsequently switch to D ₁₀ 1/2 normal saline (NS; 10% dextrose in 0.45% normal saline when glucose is <14 mmol/L) to eliminate ketones. This addresses dehydration and decreases the plasma glucose level by dilution. Any indication of cardiac instability (peaked T waves, wide QRS complexes, and premature ventricular contractions) caused by hyperkalemia should be treated first with calcium gluconate. This is followed by an IV insulin drip (0.1 units/kg/hr, also known as a fixed-rate IV insulin infusion) to gradually decrease serum glucose and osmolarity (osmoles of solute per liter of solution). The difference between the measured osmolarity and calculated osmolarity (2Na + Glucose/18 + Blood urea nitrogen/2.8 + Ethanol/4.6) is called the osmolal gap; this would be elevated because of the high ketones or other anions (which are unmeasured anions and therefore the cause of an anion gap metabolic acidosis). A rapid reduction in osmolarity results in cerebral edema and should be avoided.

Diabetic ketoacidosis can result in cerebral edema in small children and result in pupillary light reflex and death. Glucose is decreased at about 100 mg/dL/hr. A rapid reduction in glucose stimulates the counterregulatory hormones and hence ketone production. The combination of hydration and insulin decreases potassium. Urine output is carefully monitored for evaluation of fluid status. With correction of acidosis, the serum potassium may precipitously decrease, requiring careful monitoring and supplementation. (Insulin causes transfer of hydrogen ions from the extracellular space to the intracellular space.) Other electrolytes to consider are magnesium and phosphate; both may need to be replenished. Patients commonly have deficiencies of the B-complex vitamins (caused by malnutrition), particularly thiamine, which should be corrected. Bicarbonate is rarely recommended for the treatment of acidosis (high risk for development of cerebral edema). It is generally reserved for patients with a pH below 7.0.

The current patient was admitted to the hospital and started on IV normal saline. Calcium gluconate was administered to maintain cardiac stability. The patient was started on a regular insulin drip, with frequent blood glucose checks to adjust the dose. The potassium level was evaluated intermittently and supplemented as needed. When the blood glucose level dropped below 200 mg/dL, dextrose supplementation was used to prevent dangerous hypoglycemia. The insulin drip was continued until resolution of the metabolic acidosis. Diagnostically, venous blood gas analysis may be just as valuable as arterial blood gas analysis and may be used to reduce arterial complications. The patient was empirically started on ampicillin–sulbactam (combination of β-lactam and β-lactamase inhibitor) and was taken to the operating room for surgical drainage of the lesion. The IV fluid was changed to D ₁₀ 1/2 NS when the patient was deemed hemodynamically stable and a there was a decrease in serum glucose. Urine output improved, metabolic acidosis and pseudohyperkalemia (elevated plasma potassium despite total body depletion secondary to shift of potassium from the intracellular space caused by high H+ concentration) resolved, and the patient was transferred to the ward. An American Diabetic Association 1800-kcal diet was initiated (patient education is critical in preventing reoccurrence). The patient remained afebrile, with normalization of her white blood cell count, electrolytes, and urinalysis. She was subsequently discharged to home care on a 10-day regimen of amoxicillin with clavulanic acid. DKA resolution occurs when pH is less than 7.3 units, bicarbonate is above 15 mmol/L, and blood ketone level is less than 0.6 mmol/L.

Complications

Complications of diabetes can be divided into acute and chronic. The acute complications include hypoglycemia (see Chapter 109), DKA, and hyperosmolar hyperglycemic syndrome. Chronic complications include microvascular and macrovascular disease (see Chapter 109). Patients with DKA generally present with metabolic acidosis and a blood glucose level below 500 mg/dL, whereas patients with nonketotic hyperglycemia coma present with a blood glucose level above 1000 mg/dL with no acidosis. The pathophysiology of both disorders is related to the physiologic response to stress. Acute insulin deficiency (caused by lack of compliance, pump blockage, brittle diabetes), infection (the most common cause of DKA), trauma, ischemia (cerebrovascular accident, myocardial infarction), or volume depletion can induce signals to increase catecholamines, cortisol, growth hormone, and glucagon (insulin counterregulatory hormones that increase gluconeogenesis), resulting in an imbalance of glucose metabolism. These stress hormones increase blood glucose and osmolarity while decreasing cellular insulin. The lack of insulin results in ketone production by the liver and the development of an anion gap metabolic acidosis. DKA also presents with nausea, vomiting, abdominal pain, polyuria, polydipsia, weight loss, diplopia, delirium, or coma. Objective laboratory studies reveal a metabolic acidosis, pseudohyperkalemia, glucosuria, and both serum and urine β-hydroxybutyrate and acetoacetate (ketones). Because of the rapid onset of acidosis and good renal clearance in younger patients with type 1 diabetes, the blood glucose level rarely exceeds 800 mg/dL.

Diabetic ketoacidosis is the most commonly observed acute complication of type 1 diabetes. Patients with type 2 diabetes may also develop DKA, but it is not common. Ketose-prone type 2 diabetics are more often of Afro-Caribbean or Hispanic descent. Patients with type 2 diabetes taking sodium-glucose cotransporter-2 (SGLT2) inhibitors such as empagliflozin may present with euglycemia or slightly elevated glucose DKA. Euglycemic ketoacidosis described more recently develop with anionic gap acidosis, ketonemia, or ketonuria. Patients on ketogenic (low-carbohydrate diet) should not be placed on SGLT2 inhibitors. The most common cause of DKA is patient noncompliance with insulin. Other causes are infection, acute vascular event, new diagnosis of type 1 diabetes, inadequate insulin therapy in the hospital, and medications such as steroids.

Discussion

The diagnosis of DKA is based on the history, clinical examination, and laboratory findings. This disease arises from a relative or an absolute deficiency of insulin and an increase in the counterregulatory hormones, resulting in gluconeogenesis, glycogenolysis, and lipolysis. It is a triad of ketonemia (3.0 mmol/L or ketonuria >2+), hyperglycemia (11.0 mmol/L) and acidemia (pH <7.3 or bicarbonate concentration <15.0 mmol/L). The work-up should include the serum glucose and electrolyte levels; anion gap; blood urea nitrogen; creatinine; urinalysis, including ketones; electrocardiogram; complete blood count; arterial blood gas analysis; HbA _1c levels; and any tests required to determine the underlying cause.

The differential diagnosis of a patient with ketosis also includes alcoholism and starvation, but only DKA presents with hyperglycemia. The excess anions (ketones) in DKA cause an anion gap metabolic acidosis (gap acidosis) (see Chapter 109). The differential diagnosis includes methanol toxicity, uremia, DKA, paraldehyde ingestion, isoniazid toxicity, isopropyl alcohol toxicity, lactic acidosis, ethylene glycol toxicity, and salicylate toxicity. However, only DKA produces hyperglycemia. The symptoms of DKA can arise rapidly (within 24 hours), manifesting as polyuria, polyphagia, polydipsia, weakness, and fatigue in addition to nausea, vomiting, and vague abdominal pain. Mental status may range from normal to profound coma. As dehydration becomes pronounced, the hypovolemic polyuria is not as prominent.

The differential diagnosis for hyperglycemia should include dawn and Somogyi phenomena. Dawn phenomenon results from a natural nocturnal increase in counterregulatory hormones (cortisol and growth hormone). The Somogyi effect results from an increase in nocturnal counterregulatory hormones caused by midsleep hypoglycemia. Therefore, both the dawn and Somogyi phenomena result in hyperglycemia caused by an increase in counterregulatory hormones. The difference is that the dawn phenomenon is a natural nocturnal rise in hormones, whereas the Somogyi effect is caused by a rebound from hypoglycemia.

Acidosis results in a shift of potassium ions from the intracellular to the extracellular compartments. This causes elevation of the plasma potassium concentration. However, with glucose-driven osmotic diuresis, potassium is excreted by the kidneys, causing depletion of total body potassium despite elevated plasma levels, hence the term pseudohyperkalemia (seen in more than one-third of patients with DKA). With the correction of acidosis, the extracellular potassium shifts back to the intracellular space, causing significant lowering of plasma potassium. The plasma potassium needs to be replaced as the acidosis is corrected to avoid life-threatening hypokalemia.

The severity of DKA is measured by presence of blood ketone of over 6 mmol/L, bicarbonate level below 5 mmol/L, venous or arterial pH below 7, hypokalemia on admission, Glasgow Coma Scale score below 12, oxygen saturation below 92%, systolic blood pressure below 90 bpm, pulse above 100 or below 60 beats per minute and anion gap above 16.

Another acute complication of diabetes is hyperosmolar hyperglycemic syndrome, which has a less insidious onset than DKA. It generally begins with mild hyperglycemia, which is compensated for by glycosuria. As hyperglycemia worsens, osmotic diuresis wastes more glucose through urine. If the patient maintains adequate hydration, the kidneys continue to excrete the excess glucose. As the patient becomes confused or incapacitated, oral hydration decreases, and the kidneys’ ability to excrete glucose is diminished, exacerbating the hyperglycemia and causing mental status changes. During treatment, the plasma glucose level should be reduced no faster than 75 to 100 mg/dL/hr. A more rapid decline could cause brain edema.