Treatment of diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults Authors Abbas E Kitabchi, PhD, MD, FACP, FACE Burton D Rose, MD Section Editor David M Nathan, MD Deputy Editor Jean E Mulder, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Dec 2012. | This topic last updated: jun 26, 2012. INTRODUCTION Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS, also called nonketotic hyperglycemia) are two of the most serious acute complications of diabetes. They are part of the spectrum of hyperglycemia and each represents an extreme in the spectrum. The treatment of DKA and HHS in adults will be reviewed here. The epidemiology, pathogenesis, clinical features, and diagnosis of these disorders are discussed separately. (See "Epidemiology and pathogenesis of diabetic ketoacidosis and hyperosmolar hyperglycemic state" and "Clinical features and diagnosis of diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults".) DEFINITIONS DKA and HHS differ clinically according to the presence of ketoacidosis and the degree of hyperglycemia [1-3]. The definitions proposed by the American Diabetes Association for DKA and HHS are shown in the table (table 1) [1]. In DKA, metabolic acidosis is often the major finding, while the serum glucose concentration is generally below 800 mg/dL (44 mmol/L) [1-3]. However, serum glucose concentrations may exceed 900 mg/dL (50 mmol/L) in patients with DKA who are comatose [3,4]. In HHS, there is little or no ketoacid accumulation, the serum glucose concentration frequently exceeds 1000 mg/dL (56 mmol/L), the serum osmolality may reach 380 mosmol/kg, and neurologic abnormalities are frequently present (including coma in 25 to 50 percent of cases) [1,2,5,6].

Significant overlap between DKA and HHS occurs in more than one-third of patients [7]. The typical total body deficits of water and electrolytes in DKA and HHS are compared in the table (table 2). (See "Clinical features and diagnosis of diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults", section on 'Definitions'.) TREATMENT Treatment overview and protocols The treatment of DKA and HHS is similar, including the administration of insulin and correction of the fluid and electrolyte abnormalities that are typically present, including hyperglycemia and hyperosmolality, hypovolemia, metabolic acidosis (in DKA), and potassium depletion (table 3) [1,8-10]. The factors responsible for these metabolic abnormalities are discussed separately. (See "Clinical features and diagnosis of diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults".) Therapy also requires frequent patient monitoring and identification and treatment of precipitating events. Infection (most commonly pneumonia and urinary tract infection) is a common precipitating

event. Thus, cultures should be obtained if there are suggestive clinical findings, recognizing that infection may be present in the absence of fever [1,9,10]. An algorithmic approach developed for the ADA is shown in the flow diagrams for treating DKA (algorithm 1) and HHS (algorithm 2) [1,3]. Initial evaluation Both DKA and HHS are medical emergencies that require prompt recognition and management. An initial history and rapid but careful physical examination should focus on: Airway, breathing, and circulation (ABC) status Mental status Possible precipitating events (eg, source of infection, myocardial infarction) Volume status

The initial laboratory evaluation of a patient with suspected DKA or HHS should include determination of: Serum glucose Serum electrolytes (with calculation of the anion gap), BUN, and plasma creatinine Complete blood count with differential Urinalysis and urine ketones by dipstick Plasma osmolality Serum ketones (if urine ketones are present) Arterial blood gas if the serum bicarbonate is substantially reduced Electrocardiogram

Additional testing, such as cultures of urine, sputum, and blood, serum lipase and amylase, and chest x-ray, should be performed on a case-by-case basis. Monitoring The serum glucose should initially be measured every hour until stable, while serum electrolytes, blood urea nitrogen, creatinine, osmolality, and venous pH (for DKA) should be measured every two to four hours, depending upon disease severity and the clinical response [1,10]. Repeat arterial blood gases are unnecessary during the treatment of DKA; venous pH, which is about 0.03 units lower than arterial pH [11], is adequate to assess the response to therapy and avoids the pain and potential complications associated with repeated arterial punctures (figure 1). Monitoring serum bicarbonate is another alternative if blood chemistries can be returned in a timely fashion. Acidosis in DKA Direct measurement of beta-hydroxybutyrate in the blood is the preferred method for monitoring the degree of ketonemia and has become more convenient with the development of bedside meters capable of measuring whole blood beta-hydroxybutyrate [12]. However, this approach is not available in many hospitals. Nitroprusside tablets or reagent sticks react with acetoacetate and acetone (produced by the decarboxylation of acetoacetic acid), but do not identify beta-hydroxybutyrate. (See "Clinical features and diagnosis of diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults", section on 'Serum ketones'.)

During insulin therapy, beta-hydroxybutyrate is converted to acetoacetate. Thus, if the nitroprusside method is used for monitoring of ketones in the blood or urine, an increasingly positive test due to this conversion may erroneously lead the clinician to believe that ketosis has worsened (figure 2) [13]. As a result, assessments of urinary or serum ketone levels by the nitroprusside method should not be used as an indicator of response to therapy. If the results of blood chemistries can be returned in a timely fashion, an alternative to monitoring venous pH and serum beta-hydroxybutyrate is monitoring the serum bicarbonate concentration (to assess correction of the metabolic acidosis) and the serum anion gap (to assess correction of the ketoacidemia). The serum anion gap provides an estimate of the quantity of unmeasured anions in the plasma, such as albumin and, in DKA, ketoacid anions. It is calculated by subtracting the major measured anions (chloride and bicarbonate) from the major measured cation (sodium): Serum anion gap = Serum sodium - (serum chloride + bicarbonate) (See "Approach to the adult with metabolic acidosis", section on 'Serum anion gap and differential diagnosis'.) Monitoring the anion gap will give a good estimate of serum ketoacid anion levels in DKA. Normalization of the anion gap reflects disappearance of ketoacid anions in the serum and correction of the ketoacidosis. However, ketonemia and ketonuria may persist for more than 36 hours due to the slower removal of acetone, in part via the lungs [14,15]. Since acetone is biochemically neutral, such patients do not have persistent ketoacidosis. The factors that can affect the anion gap during the treatment of DKA are reviewed below. (See 'Anion gap' below.) Fluid replacement Initial fluid therapy in DKA and HHS is directed toward expansion of the intravascular volume and restoration of renal perfusion [16]. Adequate rehydration with subsequent correction of the hyperosmolar state may result in a more robust response to low dose insulin therapy [17,18]. The average fluid loss is 3 to 6 liters in DKA and up to 8 to 10 liters in HHS, due largely to the glucose osmotic diuresis (table 2) [1,2,8,10]. In addition to inducing water loss, glucosuria results in the loss of approximately 70 meq of sodium and potassium for each liter of fluid lost. The aim of therapy is to replete the extracellular fluid volume without inducing cerebral edema due to too rapid reduction in the plasma osmolality. (See 'Cerebral edema' below and "Treatment and complications of diabetic ketoacidosis in children", section on 'Cerebral edema'.) Fluid repletion is usually initiated with isotonic saline (0.9 percent sodium chloride). This solution will replace the fluid deficit, correct the extracellular volume depletion more rapidly than one-half isotonic saline, lower the plasma osmolality (since it is still hypoosmotic to the patient), and reduce the serum glucose concentration both by dilution and by increasing urinary losses as renal perfusion is increased [16,19]. The optimal rate at which isotonic saline is given is dependent upon the clinical state of the patient. Isotonic saline should be infused as quickly as possible in patients who are in shock. In the absence of cardiac compromise, isotonic saline is infused at a rate of 10 to 15 mL/kg lean body weight per hour (about 1000 mL/hour in an average-sized person) during the first few hours, with a maximum of 50 mL/hour). If the patient is hemodynamically stable, one-half isotonic saline is preferred since the addition of potassium to isotonic saline will result in a hypertonic solution that will delay correction of the hyperosmolality. The serum potassium should be maintained between 4.0 and 5.0 meq/L. (See'Effect of potassium supplementation' above.) Potassium repletion is more urgent in patients with massive potassium deficits who are hypokalemic prior to therapy [34,35]. Such patients require aggressive potassium replacement (20 to 30 meq/hour), which usually requires 40 to 60 meq/L added to one-half isotonic saline. Since insulin will worsen the hypokalemia, insulin therapy should be delayed until the serum potassium is above 3.3 meq/L to avoid possible arrhythmias, cardiac arrest, and respiratory muscle weakness [1,34,35].

Serum sodium Hyperglycemia in uncontrolled diabetes mellitus has a variable effect on the serum sodium concentration, as factors are present that can both lower and raise the measured value [36]: By raising the serum osmolality, hyperglycemia results in osmotic water movement out of the cells, thereby lowering the serum sodium concentration by dilution. The direct effect of hyperglycemia is counteracted by the glucosuria-induced osmotic diuresis. The diuresis results in water loss in excess of sodium and potassium, which will tend to raise the serum sodium concentration and plasma osmolality unless there is a comparable increase in water intake.

The serum sodium concentration at presentation varies with the balance of these mechanisms. (See "Clinical features and diagnosis of diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults", section on 'Serum sodium'.) Reversing the hyperglycemia with insulin will lower the plasma osmolality, which will cause water to move from the extracellular fluid into the cells, thereby raising the serum sodium concentration [1,5,10,36,37]. Thus, a patient with a normal initial serum sodium concentration will usually become hypernatremic during therapy with insulin and isotonic saline. The degree to which this is likely to occur can be estimated at presentation by calculation of the "corrected" serum sodium concentration, that is, the serum sodium concentration that should be present if the serum glucose concentration were lowered to normal with insulin alone [36]: Corrected serum Na = Measured serum Na + [SG 42] Where SG is the increment above normal in the serum glucose concentration (in mg/dL). The SG should be divided by 2.3 if measured in mmol/L. Bicarbonate and metabolic acidosis The indications for bicarbonate therapy in DKA are controversial [38] and evidence of benefit is lacking [39-41]. In a randomized trial of 21 DKA patients with an admission arterial pH between 6.90 and 7.14 (mean 7.01), bicarbonate therapy did not change morbidity or mortality [39]. However, the study was small, limited to patients with an arterial pH 6.90 and above, and there was no difference in the rate of rise in the arterial pH and serum bicarbonate between the bicarbonate and placebo groups. No prospective randomized trials have been performed concerning the use of bicarbonate in DKA with pH values less than 6.90. The specific indications for bicarbonate administration are important because there are three potential concerns with such therapy: Overzealous use of alkali can lead to a rise in pCO2 (since there is less of an acidemic stimulus to hyperventilation), resulting in a paradoxical fall in cerebral pH as the lipidsoluble CO2 rapidly crosses the blood-brain barrier. Neurologic deterioration has been reported in this setting, but is probably a rare event [42]. The administration of alkali may slow the rate of recovery of the ketosis [43,44]. In a study of seven patients, the three patients who were treated with bicarbonate had a rise in serum ketoacid levels during bicarbonate infusion, resulting in a six-hour delay in improvement of ketosis [43]. Animal studies suggest that bicarbonate therapy increases hepatic ketogenesis. However, in the randomized trial cited above, bicarbonate therapy had no effect on the rate of decline in serum ketone levels [39].

Alkali administration can lead to a posttreatment metabolic alkalosis, since metabolism of ketoacid anions with insulin results in the generation of bicarbonate and spontaneous correction of most of the metabolic acidosis. (See 'Anion gap' below.)

There are, however, selected patients who may benefit from cautious alkali therapy [42]. These include: Patients with an arterial pH less than 7.00 in whom decreased cardiac contractility and vasodilatation can further impair tissue perfusion. At an arterial pH above 7.00, most experts agree that bicarbonate therapy is not necessary, since insulin therapy alone will result in resolution of most of the metabolic acidosis [45]. Patients with potentially life-threatening hyperkalemia, since bicarbonate administration in acidemic patients drives potassium into cells, thereby lowering the serum potassium concentration [46]. (See "Treatment and prevention of hyperkalemia in adults".)

We recommend administering bicarbonate if the arterial pH is less than 6.90. We give 100 meq of sodium bicarbonate in 400 mL sterile water with 20 meq of potassium chloride, if the serum potassium is less than 5.3 meq/L, administered over two hours. The venous pH should be monitored every two hours, and bicarbonate dosed as above, until the pH rises above 7.00. Anion gap There is a variable relationship between the elevation in serum anion gap and the fall in serum bicarbonate concentration because of the excretion of ketoacid anions in the urine [47,48]. (See "The anion gap/HCO3 ratio in patients with a high anion gap metabolic acidosis".) Ketoacid anions have been called "potential bicarbonate," since their metabolism following the administration of insulin results in the generation of bicarbonate and reversal of the acidosis. The effect of ketoacid anion excretion on the course of ketoacidosis varies with the accompanying cation: The excretion of ketoacid anions with hydrogen or ammonium is associated with an equivalent loss of protons, correcting both the anion gap and the acidemia. It has been estimated that approximately 30 percent of the ketoacids produced in DKA are excreted in the urine in patients with relatively normal renal function; the conversion of acetoacetic acid to acetone can neutralize another 15 to 25 percent of the acid load [49]. The excretion of ketoacid anions with sodium or potassium represents the loss of bicarbonate precursors (ie, "potential bicarbonate") and is therefore equivalent to bicarbonate loss. The net effect is that the anion gap is reduced but the acidosis persists.

As a result of the urinary loss of "potential bicarbonate," almost all patients with DKA (except those with advanced renal failure) develop a normal anion gap acidosis (also known as a "non-gap acidosis") during treatment [47,50,51]. Suppose, for example, that a patient has a serum bicarbonate of 8 meq/L and an anion gap of 24 meq/L (approximately 16 meq/L above normal). Insulin therapy promotes correction of the ketoacidosis by inhibiting lipolysis, which decreases the supply of free fatty acids to the liver for ketogenesis, by inhibiting ketogenesis in the liver, and by promoting peripheral ketone metabolism. (See "Insulin action", section on 'Insulin and ketone body metabolism'.)

The net effect is that the 16 meq/L of ketoacid anion will be metabolized, which will regenerate some of the HCO3 lost in the initial buffering reaction. However, the plasma HCO3 may only rise by about 8 meq/L (to 16 meq/L), with the rest of the HCO3 replenishing the cell and bone buffer stores. At this point, the patient will have metabolic acidosis with a normal AG, due to the combination of the previous production of the intact ketoacid and the subsequent loss of the ketoacid anion in the urine. If no ketoacid anions had been excreted in the urine (as in a dialysis patient), then insulin therapy would have returned both the anion gap and serum bicarbonate concentration to baseline. (See "The anion gap/HCO3 ratio in patients with a high anion gap metabolic acidosis", section on 'Ketoacidosis'.) Phosphate depletion Whole body phosphate depletion is common in uncontrolled diabetes mellitus, although the serum phosphate concentration may initially be normal or elevated due to movement of phosphate out of the cells [8,52]. As with potassium balance, phosphate depletion is rapidly unmasked following the institution of insulin therapy, frequently leading to hypophosphatemia that is usually asymptomatic. The fall in serum phosphate concentration during the treatment of DKA is acute, self-limited, and usually not associated with marked phosphate depletion or adverse effects. Clinically evident hemolysis as well as rhabdomyolysis with myoglobinuria are rare complications of the hypophosphatemia [53-55]. (See "Signs and symptoms of hypophosphatemia".) Prospective randomized trials of patients with DKA have failed to show a beneficial effect of phosphate replacement on the duration of ketoacidosis, dose of insulin required, rate of fall of serum glucose, or morbidity and mortality [56-58]. In addition, phosphate replacement may have adverse effects such as hypocalcemia and hypomagnesemia [56,59-61]. Based upon these observations, we do NOT recommend the routine use of phosphate in the treatment of DKA or HHS. However, to avoid cardiac and skeletal muscle weakness and respiratory depression due to hypophosphatemia, careful phosphate replacement may be indicated in patients who develop cardiac dysfunction, hemolytic anemia, or respiratory depression, and in those with a serum phosphate concentration below 1.0 mg/dL (0.32 mmol/L) [62]. When needed, 20 to 30 meq/L of potassium phosphate can be added to replacement fluids. COMPLICATIONS The most common complications of the treatment of DKA and HHS, hypoglycemia and hypokalemia, have been reduced significantly since the administration of low dose insulin and careful monitoring of serum potassium [63]. Hyperglycemia may result from interruption or discontinuation of intravenous insulin without prior coverage with subcutaneous insulin. Cerebral edema Cerebral edema in uncontrolled diabetes mellitus (usually DKA, with occasional reports in HHS) is primarily a disease of children and almost all affected patients are below the age of 20 years [64]. Symptoms typically emerge with 12 to 24 hours of the initiation of treatment for DKA, but may be present prior to the onset of therapy. Issues related to cerebral edema in DKA, including pathogenesis, are discussed in detail separately in the pediatric section but will be briefly reviewed here. (See "Cerebral edema in children with diabetic ketoacidosis".) Headache is the earliest clinical manifestation, followed by lethargy, and decreased arousal. Neurologic deterioration may be rapid, with seizures, incontinence, pupillary changes, bradycardia, and respiratory arrest. These symptoms progress if brainstem herniation occurs, and the rate of progression may be so rapid that papilledema is not seen.

Cerebral edema is associated with a mortality rate of 20 to 40 percent [1]. Thus, an essential part of therapy in DKA is careful monitoring for changes in mental or neurologic status that would permit early identification and therapy of cerebral edema. The 2009 ADA guidelines on hyperglycemic crises in diabetes in adults suggested that the following preventive measures may reduce the risk of cerebral edema in high-risk patients [1]: Gradual replacement of sodium and water deficits in patients who are hyperosmolar. The usual regimen for the first few hours is isotonic saline at a rate of 10 to 15 mL/kg lean body weight per hour (about 1000 mL/hour in an average-sized person) with a maximum of 7.3, serum bicarbonate >15 mEq/l, and minimal ketonuria and ketonemia. Normal laboratory values vary; check local lab normal ranges for all electrolytes.IV: intravenous; SC: subcutaneous. * After history and physical exam, obtain capillary glucose and serum or urine ketones (nitroprusside method). Begin one liter of 0.9 percent NaCl over one hour and draw arterial blood gases, complete blood count with differential, urinalysis, serum glucose, BUN, electrolytes, chemistry profile and creatinine levels STAT. Obtain electrocardiogram, chest X-ray, and specimens for bacterial cultures, as needed. Serum Na+ should be corrected for hyperglycemia (for each 100 mg/dl glucose >100 mg/dl, add 1.6 mEq to sodium value for corrected serum sodium value). An alternative IV insulin regimen is to give a continuous intravenous infusion of regular insulin at 0.14 units/kg per hour; at this dose, an initial intravenous bolus is not necessary.

Copyright 2006 American Diabetes Association From Diabetes Care Vol 29, Issue 12, 2006. Modifications from Diabetes Care Vol 32, Issue 7, 2009. Reprinted with permission from the American Diabetes Association.