INTRODUCTION — Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS, also known as hyperosmotic hyperglycemic nonketotic state [HHNK]) 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, evaluation, and diagnosis of these disorders are discussed separately. DKA in children is also reviewed separately.
DEFINITIONS — DKA and HHS differ clinically according to the presence of ketoacidosis and, usually, the degree of hyperglycemia [1-3]. The definitions proposed by the American Diabetes Association (ADA) for DKA and HHS are shown in the table (table 1) .
●In DKA, metabolic acidosis is often the major finding, while the serum glucose concentration is generally below 800 mg/dL (44.4 mmol/L) and often in the 350 to 500 mg/dL (19.4 to 27.8 mmol/L) range [1-3]. However, serum glucose concentrations may exceed 900 mg/dL (50 mmol/L) in patients with DKA, most of whom are comatose [3,4], or may be normal or minimally elevated (<250 mg/dL [13.9 mmol/L]) in patients with euglycemic DKA (which occurs more often in patients with poor oral intake, those treated with insulin prior to arrival in the emergency department, pregnant women, and those who use sodium-glucose co-transporter 2 [SGLT2] inhibitors).
●In HHS, there is little or no ketoacid accumulation, the serum glucose concentration frequently exceeds 1000 mg/dL (56 mmol/L), the plasma osmolality (Posm) may reach 380 mOsmol/kg, and neurologic abnormalities are frequently present (including coma in 25 to 50 percent of cases) [1,2,5,6].
The typical total body deficits of water and electrolytes in DKA and HHS are compared in the table (table 2). (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis", section on 'Serum glucose' and "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis", section on 'Diagnostic criteria'.)
Overview and protocols — The treatment of DKA (algorithm 1) and HHS (algorithm 2) is similar, including correction of the fluid and electrolyte abnormalities that are typically present (hyperosmolality, hypovolemia, metabolic acidosis [in DKA], and potassium depletion) and the administration of insulin [1,7-9].
●Correction of fluid and electrolyte abnormalities – The first step in the treatment of DKA or HHS is infusion of isotonic saline to expand extracellular volume and stabilize cardiovascular status (table 3). This also increases insulin responsiveness by lowering the plasma osmolality (Posm), reducing vasoconstriction and improving perfusion, and reducing stress hormone levels [10,11]. The next step is correction of the potassium deficit (if present). The choice of fluid replacement should be influenced by the potassium deficit. The osmotic effect of potassium repletion must be considered since potassium is as osmotically active as sodium. (See 'Fluid replacement' below and 'Potassium replacement' below.)
●Administration of insulin – Low-dose intravenous (IV) insulin should be administered to all patients with moderate to severe DKA who have a serum potassium ≥3.3 mEq/L. If the serum potassium is less than 3.3 mEq/L, insulin therapy should be delayed until potassium replacement has begun and the serum potassium concentration has increased. The delay is necessary because insulin will worsen the hypokalemia by driving potassium into the cells, and this could trigger cardiac arrhythmias. IV regular insulin and rapid-acting insulin analogs are equally effective in treating DKA. (See 'Insulin' below.)
Therapy requires frequent clinical and laboratory monitoring and the identification and treatment of any precipitating events, including infection. Sodium-glucose co-transporter 2 (SGLT2) inhibitors, which can precipitate DKA, should be discontinued. (See 'Monitoring' below and "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis", section on 'Precipitating factors'.)
Our approach outlined below is based upon clinical experience and is largely in agreement with the American Diabetes Association (ADA) consensus algorithms for the treatment of DKA (algorithm 1) and HHS (algorithm 2) and the Joint British Diabetes Societies guideline for the management of DKA [1,12,13].
Fluid replacement — In patients with DKA or HHS, we recommend IV electrolyte and fluid replacement to correct both hypovolemia and hyperosmolality. Fluid repletion is usually initiated with isotonic saline (0.9 percent sodium chloride [NaCl]). Patients with euglycemic DKA generally require both insulin and glucose to treat the ketoacidosis and prevent hypoglycemia, respectively, and in such patients, dextrose is added to IV fluids at the initiation of therapy. For patients with a more classic presentation of hyperglycemic DKA, we add dextrose to the saline solution when the serum glucose declines to 200 mg/dL (11.1 mmol/L) in DKA (algorithm 1) or 250 to 300 mg/dL (13.9 to 16.7 mmol/L) in HHS (algorithm 2).
The optimal rate of initial isotonic saline infusion is dependent upon the clinical state of the patient:
●In patients with hypovolemic shock, isotonic saline should be infused as quickly as possible. (See "Treatment of severe hypovolemia or hypovolemic shock in adults".)
●In hypovolemic patients without shock (and without heart failure), isotonic saline is infused at a rate of 15 to 20 mL/kg lean body weight per hour (approximately 1000 mL/hour in an average-sized person) for the first couple of hours, with a maximum of <50 mL/kg in the first four hours (algorithm 1 and algorithm 2) .
●In euvolemic patients, isotonic saline is infused at a lower rate, guided by clinical assessment.
After the second or third hour, optimal fluid replacement depends upon the state of hydration, serum electrolyte levels, and the urine output. The most appropriate IV fluid composition is determined by the sodium concentration "corrected" for the degree of hyperglycemia. The "corrected" sodium concentration can be approximated by adding 2 mEq/L to the plasma sodium concentration for each 100 mg/100 mL (5.5 mmol/L) increase above normal in glucose concentration (calculator 1).
If the "corrected" serum sodium concentration is :
●Less than 135 mEq/L, isotonic saline should be continued at a rate of approximately 250 to 500 mL/hour
●Normal or elevated, the IV fluid is generally switched to one-half isotonic saline at a rate of 250 to 500 mL/hour in order to provide electrolyte-free water
The timing of one-half isotonic saline therapy may also be influenced by potassium balance. Potassium repletion affects the saline solution that is given since potassium is as osmotically active as sodium. Thus, concurrent potassium replacement may be another indication for the use of one-half isotonic saline. (See 'Potassium replacement' below.)
Adequate rehydration with correction of the hyperosmolar state may enhance the response to low-dose insulin therapy [10,11]. Adequacy of fluid replacement is judged by frequent hemodynamic and laboratory monitoring (see 'Monitoring' below). In patients with abnormal renal or cardiac function, more frequent monitoring must be performed to avoid iatrogenic fluid overload [8,9,11,14-17]. The goal is to correct estimated deficits (table 2) within the first 24 hours. However, osmolality should not be reduced too rapidly, because this may generate cerebral edema. (See 'Cerebral edema' below and "Diabetic ketoacidosis in children: Treatment and complications", section on 'Cerebral injury'.)
Potassium replacement — Potassium replacement is initiated immediately if the serum potassium is <5.3 mEq/L as long as there is adequate urine output (approximately >50 mL/hour) (algorithm 1). Almost all patients with DKA or HHS have a substantial potassium deficit, usually due to urinary losses generated by the glucose osmotic diuresis and secondary hyperaldosteronism. Despite the total body potassium deficit, the serum potassium concentration is usually normal or, in approximately one-third of cases, elevated at presentation. This is largely due to insulin deficiency and hyperosmolality, each of which cause potassium movement out of the cells .
●If the initial serum potassium is below 3.3 mEq/L, IV potassium chloride (KCl; 20 to 40 mEq/hour, which usually requires 20 to 40 mEq/L added to saline) should be given. The choice of replacement fluid (isotonic or one-half isotonic saline) depends upon the state of hydration, corrected sodium concentration, dose of KCl, blood pressure, and a clinical assessment of overall volume status. Patients with marked hypokalemia require aggressive potassium replacement (40 mEq/hour, with additional supplementation based upon hourly serum potassium measurements) to raise the serum potassium concentration above 3.3 mEq/L [19-21].
●If the initial serum potassium is between 3.3 and 5.3 mEq/L, IV KCl (20 to 30 mEq) is added to each liter of IV replacement fluid. Adjust potassium replacement to maintain the serum potassium concentration in the range of 4 to 5 mEq/L.
●If the initial serum potassium concentration is greater than 5.3 mEq/L, then potassium replacement should be delayed until its concentration has fallen below this level.
Potassium salts added to IV fluids have the same osmotic effect as sodium salts, and this should be considered when determining the potential impact of IV fluid infusion on osmolality. As an example, 40 mEq of KCl added to 1 L of fluid generates 80 mOsmol/L of electrolyte osmolarity. The addition of 40 mEq of potassium to 1 L of one-half isotonic saline creates a solution with an osmolarity of 234 mOsmol/L (77 mEq NaCl and 40 mEq KCl), which is osmotically equal to three-quarters isotonic saline. (The osmolarity of isotonic saline is 308 mOsmol/L.) If 40 mEq of KCl is added to isotonic saline, the final osmolarity will be approximately 388 mOsmol/L. However, KCl will not have the same extracellular fluid (ECF) expansion effect as NaCl, because most of the potassium will shift into cells very rapidly. (See "Maintenance and replacement fluid therapy in adults", section on 'Choice of replacement fluid'.)
The altered potassium distribution is rapidly reversed with the administration of insulin and can result in an often dramatic fall in the serum potassium concentration, despite potassium replacement [19,20]. However, potassium replacement must be done cautiously if renal function remains depressed and/or urine output does not increase to a level >50 mL/hour. Careful monitoring of the serum potassium is essential for the management of both DKA and HHS. (See 'Monitoring' below and "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Epidemiology and pathogenesis", section on 'Potassium'.)
Insulin — We recommend initiating treatment with low-dose IV insulin in all patients with moderate to severe DKA or HHS who have a serum potassium ≥3.3 mEq/L. The only indication for delaying the initiation of insulin therapy is if the serum potassium is below 3.3 mEq/L since insulin will worsen the hypokalemia by driving potassium into the cells. Patients with an initial serum potassium below 3.3 mEq/L should receive fluid and potassium replacement prior to treatment with insulin. Insulin therapy should be delayed until the serum potassium is above 3.3 mEq/L to avoid complications such as cardiac arrhythmias, cardiac arrest, and respiratory muscle weakness [1,19,20]. (See 'Fluid replacement' above and 'Potassium replacement' above.)
IV regular insulin and rapid-acting insulin analogs are equally effective in treating DKA . The choice of IV insulin is based upon institutional preferences, clinician experience, and cost concerns. We generally prefer regular insulin, rather than rapid-acting insulin analogs, due to its much lower cost. For acute management of DKA or HHS, there is no role for long- or intermediate-acting insulin; however, long-acting (glargine, detemir) or intermediate-acting (NPH) insulin is administered after recovery from ketoacidosis, prior to discontinuation of IV insulin, to ensure adequate insulin is available when IV insulin is discontinued. In this setting, we do not use degludec or ultra-long-acting U-300 insulin glargine (given their long half-life) as it will take at least three to four days to reach steady state . In patients with mild DKA (particularly in patients with mild DKA due to rationed or missed doses of basal insulin), intermediate- or long-acting insulin can be administered at the initiation of treatment, along with rapid-acting insulin. (See 'Intravenous regular insulin' below and 'Converting to subcutaneous insulin' below and 'Intravenous insulin analogs' below and 'Subcutaneous insulin regimens' below.)
Insulin therapy lowers the serum glucose concentration (by decreasing hepatic glucose production, the major effect, and enhancing peripheral utilization, a less important effect ), diminishes ketone production (by reducing both lipolysis and glucagon secretion), and may augment ketone utilization. Inhibition of lipolysis requires a much lower level of insulin than that required to reduce the serum glucose concentration. Therefore, if the administered dose of insulin is reducing the glucose concentration, it should be more than enough to stop ketone generation [8,24,25]. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Epidemiology and pathogenesis", section on 'Pathogenesis'.)
Intravenous regular insulin — In HHS or moderate to severe DKA, treatment can be initiated with an IV bolus of regular insulin (0.1 units/kg body weight) followed within five minutes by a continuous infusion of regular insulin of 0.1 units/kg per hour (equivalent to 7 units/hour in a 70-kg patient) [8,26-29]. Alternatively, the bolus dose can be omitted if a higher dose of continuous IV regular insulin (0.14 units/kg per hour, equivalent to 10 units/hour in a 70-kg patient) is initiated . The insulin dosing is the same in DKA and HHS (algorithm 1 and algorithm 2). The possible role of other insulin preparations is discussed below. (See 'Intravenous insulin analogs' below and 'Subcutaneous insulin regimens' below.)
These doses of IV regular insulin usually decrease the serum glucose concentration by approximately 50 to 70 mg/dL (2.8 to 3.9 mmol/L) per hour [24,27-29]. Higher doses do not generally produce a more prominent glucose-lowering effect, probably because the insulin receptors are fully saturated and activated by the lower doses . However, if the serum glucose does not fall by at least 50 to 70 mg/dL (2.8 to 3.9 mmol/L) from the initial value in the first hour, check the IV access to be certain that the insulin is being delivered and that no IV line filters that may bind insulin have been inserted into the line. After these possibilities are eliminated, the insulin infusion rate should be doubled every hour until a steady decline in serum glucose of this magnitude is achieved.
The fall in serum glucose is the result of both insulin activity and the beneficial effects of volume repletion. Volume repletion alone can initially reduce the serum glucose by 35 to 70 mg/dL (1.9 to 3.9 mmol/L) per hour due to the combination of ECF expansion; reduction of plasma osmolality; increased urinary losses resulting from improved renal perfusion and glomerular filtration; and a reduction in the levels of "stress hormones," which oppose the effects of insulin [15,28]. The serum glucose levels often fall more rapidly in patients with HHS who are typically more volume depleted.
When the serum glucose approaches 200 mg/dL (11.1 mmol/L) in DKA or 250 to 300 mg/dL (13.9 to 16.7 mmol/L) in HHS, switch the IV saline solution to dextrose in saline and attempt to decrease the insulin infusion rate to 0.02 to 0.05 units/kg per hour [9,11,26]. If possible, do not allow the serum glucose at this time to fall below 200 mg/dL (11.1 mmol/L) in DKA or 250 to 300 mg/dL (13.9 to 16.7 mmol/L) in HHS, because this may promote the development of cerebral edema. (See 'Cerebral edema' below and "Diabetic ketoacidosis in children: Cerebral injury (cerebral edema)".)
Intravenous insulin analogs — There is no advantage of rapid-acting or ultra-rapid-acting insulin analogs over regular insulin. Intravenous regular insulin and glulisine insulin are equally effective and equipotent for the treatment of DKA . (See "General principles of insulin therapy in diabetes mellitus", section on 'Human insulins'.)
Subcutaneous insulin regimens — Patients with mild DKA (table 1) can be safely treated with subcutaneous, rapid-acting insulin analogs on a general medical floor or in the emergency department but only when adequate staffing is available to carefully monitor the patient and check capillary blood glucose with a reliable glucose meter, typically every hour. We do not recommend the use of continuous glucose monitoring (CGM) in this situation, as it has not been studied.
Subcutaneous insulin protocols are being used with increasing frequency to treat selected patients with mild to moderate DKA during the COVID-19 pandemic, when intravenous insulin may not be practical owing to the need to limit frequency of contact of staff with patients. In this setting, dosing and monitoring is being performed every two to four hours. (See "COVID-19: Issues related to diabetes mellitus in adults", section on 'DKA/HHS'.)
Treatment of DKA with subcutaneous insulin has not been evaluated in severely ill patients. In mild DKA, direct comparison of intramuscular, subcutaneous, and IV insulin therapy for hemodynamically stable DKA patients shows similar efficacy and safety [31-34]. In addition, subcutaneous administration of rapid-acting insulin analogs (eg, insulin lispro, aspart) given every one or two hours has been demonstrated to be safe in two randomized trials in adults with uncomplicated DKA (algorithm 1) [32,33]. In one trial, for example, 40 patients with DKA were assigned to one of two regimens :
●Subcutaneous, rapid-acting insulin lispro as an initial injection of 0.3 units/kg, followed by 0.1 units/kg every hour until the serum glucose was less than 250 mg/dL (13.9 mmol/L). The insulin lispro dose was then decreased to 0.05 to 0.1 units/kg and administered every one or two hours until resolution of the ketoacidosis. These patients were treated on a regular internal medicine floor or in an intermediate care unit.
●IV regular insulin as an initial bolus of 0.1 units/kg, followed by an infusion of 0.1 units/kg per hour until the serum glucose was less than 250 mg/dL (13.9 mmol/L). The insulin dose was then decreased to 0.05 to 0.1 units/kg per hour until resolution of the ketoacidosis. These patients were treated in the intensive care unit.
The duration of therapy until correction of hyperglycemia and resolution of ketoacidosis was the same with both regimens (7 and 10 to 11 hours, respectively), but there was a 39 percent reduction in cost with insulin lispro, mainly related to the higher cost of treatment in the intensive care unit.
Bicarbonate and metabolic acidosis — Although the indications for sodium bicarbonate therapy to help correct metabolic acidosis are controversial, there are selected patients who may benefit from cautious alkali therapy . They include:
●Patients with an arterial pH ≤6.9 in whom decreased cardiac contractility and vasodilatation can impair tissue perfusion [36,37]. At an arterial pH above 7.0, most experts agree that bicarbonate therapy is not necessary since therapy with insulin and volume expansion will largely reverse the metabolic acidosis .
For patients with pH ≤6.9, we give 100 mEq of sodium bicarbonate in 400 mL sterile water administered over two hours. If the serum potassium is less than 5.3 mEq/L, we add 20 mEq of KCl. When the bicarbonate concentration increases, the serum potassium may fall and more aggressive KCl replacement may be required.
●Patients with potentially life-threatening hyperkalemia, since bicarbonate administration in acidemic patients may drive potassium into cells, thereby lowering the serum potassium concentration. The exact potassium level that should trigger this intervention has not been defined; we administer sodium bicarbonate if the potassium level is >6.4 mEq/L . (See "Treatment and prevention of hyperkalemia in adults".)
The venous pH and bicarbonate concentration should be monitored every two hours, and bicarbonate doses can be repeated until the pH rises above 7.0. (See 'Monitoring' below.)
The indications for bicarbonate therapy in DKA are controversial , and evidence of benefit is lacking [41-43]. 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 . 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.
Bicarbonate administration is also controversial because, in addition to lack of evidence for benefit, there are several potential harmful effects:
●If bicarbonate infusion successfully increases the blood bicarbonate concentration, this can reduce the hyperventilatory drive, which will raise the blood partial pressure of carbon dioxide (pCO2). Increased blood carbon dioxide (CO2) tension is more quickly reflected across the blood brain barrier than the increased arterial bicarbonate. This may cause a paradoxical fall in cerebral pH. Although neurologic deterioration has been attributed to this mechanism, it remains a very controversial effect and, if it occurs, is rare .
●The administration of alkali may slow the rate of recovery of the ketosis [44,45]. In a study of seven patients, the three patients treated with bicarbonate had a rise in serum ketoacid anion levels and a six-hour delay in resolution of ketosis . Animal studies indicate that bicarbonate infusion can accelerate ketogenesis. This is thought to be related to the fact that acidemia has a "braking effect" on organic acid generation. This brake is lessened by any maneuver that increases systemic pH .
●Alkali administration can lead to a post-treatment 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 "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Epidemiology and pathogenesis", section on 'Anion gap metabolic acidosis'.)
Phosphate depletion — Based upon the observations described below, we do not recommend the routine use of phosphate replacement in the treatment of DKA or HHS. However, phosphate replacement should be strongly considered if severe hypophosphatemia occurs (serum phosphate concentration below 1 mg/dL or 0.32 mmol/L), especially if cardiac dysfunction, hemolytic anemia, and/or respiratory depression develop [46-50]. When needed, potassium or sodium phosphate 20 to 30 mEq can be added to 1 L of IV fluid.
Although whole-body phosphate depletion is common in uncontrolled diabetes mellitus, the serum phosphate concentration may initially be normal or elevated due to movement of phosphate out of the cells [7,47]. Similar to potassium, phosphate depletion and hypophosphatemia may be rapidly unmasked following the institution of insulin therapy and IV volume expansion. This frequently leads to asymptomatic hypophosphatemia, which gradually resolves. (See "Hypophosphatemia: Clinical manifestations of phosphate depletion".)
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; or the rate of fall of serum glucose, morbidity, or mortality [51-53]. In addition, phosphate replacement may have adverse effects, such as hypocalcemia and hypomagnesemia [51,54-56]. Consequently, routine replacement is not indicated. When the patient stabilizes, phosphate-rich food such as dairy products and almonds may be recommended.
General — The serum glucose should initially be measured every hour until stable, while serum electrolytes, blood urea nitrogen (BUN), creatinine, and venous pH (for DKA) should be measured every two to four hours, depending upon disease severity and the clinical response [1,9]. In-patient serum glucose measurement should be done with hospital-approved bedside devices or in the chemistry laboratory and not with continuous glucose monitoring (CGM) devices.
The effective plasma osmolality (effective Posm) or tonicity can be estimated from the sodium and glucose concentrations using the following equations, depending upon the units for sodium (Na) and glucose:
Effective Posm = [2 x Na (mEq/L)] + [glucose (mg/dL) ÷ 18]
Effective Posm = [2 x Na (mmol/L)] + glucose (mmol/L)
The Na in these equations is the actual measured plasma sodium concentration and not the "corrected" sodium concentration.
It is strongly suggested that a flow sheet of laboratory values and clinical parameters be utilized because it allows better visualization and evaluation of the clinical picture throughout treatment of DKA (form 1).
Monitoring with arterial blood gases is unnecessary during the treatment of DKA; venous pH, which is approximately 0.03 units lower than arterial pH , is adequate to assess the response to therapy and avoids the pain and potential complications associated with repeated arterial punctures. If blood chemistry results are promptly available, an alternative to monitoring venous pH is to monitor the serum bicarbonate concentration (to assess correction of the metabolic acidosis) and the serum anion gap (to assess correction of the ketoacidemia).
Where available, bedside ketone meters that measure capillary blood beta-hydroxybutyrate are an alternative to the measurement of electrolytes and anion gap for monitoring the response to treatment. These devices are increasingly available, reliable, and convenient . Beta-hydroxybutyrate can then be measured every two hours depending on the clinical response . When bedside meters are not available, monitoring venous pH and/or the venous bicarbonate and anion gap is sufficient.
Resolution of DKA/HHS — The hyperglycemic crisis is considered to be resolved when the following goals are reached:
●The ketoacidosis has resolved, as evidenced by normalization of the serum anion gap (less than 12 mEq/L) and, when available, blood beta-hydroxybutyrate levels
●Patients with HHS are mentally alert and the effective plasma osmolality has fallen below 315 mOsmol/kg
●The patient is able to eat
The disappearance of ketoacid anions in the serum and correction of the ketoacidosis can be monitored by measuring venous pH, beta-hydroxybutyrate directly, and/or serum electrolytes and bicarbonate concentrations with calculation of the serum anion gap. The serum anion gap provides an estimate of the quantity of unmeasured anions in the plasma. It is calculated by subtracting the major measured anions (chloride and bicarbonate) from the major measured cation (sodium). The sodium concentration used for this calculation is the concentration reported by the laboratory not the "corrected" sodium concentration.
Accumulation of ketoacid anions (the sum of beta-hydroxybutyrate and acetoacetate) increases the anion gap above its baseline, and the increment reflects the sum of their concentrations in serum. Monitoring the anion gap will provide a reasonable estimate of changes in these serum ketoacid anion concentrations. The anion gap returns to the normal range when ketoacid anions have disappeared from the serum.
Correction of the ketoacidosis can also be monitored by direct measurement of serum or capillary beta-hydroxybutyrate. Although assessments of urinary or serum ketone levels by the nitroprusside method can be used for the initial diagnosis of ketoacidosis, it should not be used for monitoring resolution of DKA. Nitroprusside reacts mainly with acetoacetate, to a much lesser degree with acetone (which is not an acid), and not with beta-hydroxybutyrate. These characteristics of this test can generate clinical confusion. For example, a positive nitroprusside test may persist for up to 36 hours after resolution of the ketoacidosis due to a positive reaction with acetone, which is slowly eliminated, mainly via the lungs [59,60]. Since acetone is not an acid, a persistent nitroprusside reaction due to acetone does not indicate ketoacidosis. In addition, active treatment of ketoacidosis shifts the reaction between beta-hydroxybutyrate and acetoacetate toward acetoacetate. This may result in an increasingly positive nitroprusside test (due to higher acetoacetate concentrations) despite an overall improvement of the ketoacidosis (figure 1) .
In the absence of severe kidney disease, almost all patients develop a normal anion gap acidosis ("non-gap" or "hyperchloremic acidosis") during the resolution phase of the ketoacidosis. This occurs because aggressive intravenous (IV) volume expansion reverses volume contraction and improves renal function, which accelerates the loss of ketoacid anions with sodium and potassium [61,62]. The loss of these ketoacid anion salts into the urine represent "potential" bicarbonate loss from the body. Insulin therapy will have no further effect on the acidosis when this stage evolves. The hyperchloremic acidosis will slowly resolve as the kidneys excrete ammonium chloride (NH4Cl) and regenerate bicarbonate.
Converting to subcutaneous insulin — For patients with DKA, we initiate a multiple-dose (basal-bolus), subcutaneous insulin schedule when the ketoacidosis has resolved and the patient is able to eat (see 'Resolution of DKA/HHS' above). If the patient is unable to eat, it is preferable to continue the IV insulin infusion. For patients with HHS, IV insulin infusion can be tapered and a multiple-dose (basal-bolus), subcutaneous insulin schedule started when the serum glucose falls below 250 to 300 mg/dL (13.9 to 16.7 mmol/L).
The most convenient time to transition to subcutaneous insulin is before a meal. The IV insulin infusion should be continued for two to four hours after initiating the short- or rapid-acting subcutaneous insulin because abrupt discontinuation of IV insulin acutely reduces insulin levels and may result in recurrence of hyperglycemia and/or ketoacidosis. Basal insulin (NPH, U-100 glargine, or detemir) can be administered either (a) at the same time as the first injection of rapid-acting insulin, or (b) earlier (for example, the previous evening), along with a decrease in the rate of IV insulin infusion. We typically do not administer degludec or U-300 glargine as the basal insulin when transitioning from IV insulin due to its very long half-life, and subsequently, the time it takes to reach steady state (two to three days).
For patients with known diabetes who were previously being treated with insulin, their pre-DKA or pre-HHS insulin regimen may be restarted. For patients who are treated with continuous subcutaneous insulin infusion (insulin pump), the previous basal rate can be resumed. However, if the IV insulin requirements are significantly higher than their usual insulin requirements, it is reasonable to increase the basal rate temporarily.
In patients with new-onset type 1 diabetes who have presented with DKA, an initial total daily dose (TDD) of 0.5 to 0.8 units/kg units of insulin per day is reasonable, until an optimal dose is established. Approximately 40 to 50 percent of the TDD should be given as a basal insulin, either as once- or twice-daily U-100 glargine or detemir, or as twice-daily intermediate-acting insulin (NPH). The long-acting insulin can be given either at bedtime or in the morning; the NPH is usually given as approximately two-thirds of the dose in the morning and one-third at bedtime. The remainder of the TDD is given as short-acting or rapid-acting insulin, divided before meals. The pre-meal dosing is determined by the pre-meal glucose level, meal size, and content, glucose trends (when available from CGM), as well as activity and exercise pattern. If NPH is the basal insulin used, a mid-day (pre-lunch) rapid-acting insulin may not be necessary. Good clinical judgment and frequent glucose assessment are vital in initiating a new insulin regimen in insulin-naive patients. Most importantly, the regimen needs to be adjusted based on empiric results provided by glucose monitoring and responsive to individual lifestyle patterns including eating and activity and exercise patterns. (See "General principles of insulin therapy in diabetes mellitus" and "Management of blood glucose in adults with type 1 diabetes mellitus", section on 'Designing an MDI insulin regimen' and "Insulin therapy in type 2 diabetes mellitus".)
COMPLICATIONS — Hypoglycemia and hypokalemia are the most common complications of the treatment of DKA and HHS. These complications have become much less common since low-dose intravenous (IV) insulin treatment and careful monitoring of serum potassium have been implemented . Hyperglycemia may recur from interruption or discontinuation of IV insulin without adequate coverage with subcutaneous insulin.
Cerebral edema — Cerebral edema in uncontrolled diabetes mellitus (usually DKA, with only occasional reports in HHS) is primarily a disease of children, and almost all affected patients are younger than 20 years old . Symptoms typically emerge within 12 to 24 hours of the initiation of treatment for DKA but may exist 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 "Diabetic ketoacidosis in children: Cerebral injury (cerebral edema)".)
Headache is the earliest clinical manifestation, followed by lethargy and decreased arousal. Neurologic deterioration may be rapid. Seizures, incontinence, pupillary changes, bradycardia, and respiratory arrest can develop. Symptoms progress if brainstem herniation occurs, and the rate of progression may be so rapid that clinically recognizable papilledema does not develop.
DKA-associated cerebral edema has a mortality rate of 20 to 40 percent . Thus, careful monitoring for changes in mental or neurologic status that would permit early identification and therapy of cerebral edema is essential.
The 2009 American Diabetes Association (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 :
●Gradual replacement of sodium and water deficits in patients who are hyperosmolar. The usual IV fluid regimen during the first few hours of treatment is isotonic saline at a rate of 15 to 20 mL/kg lean body weight per hour (approximately 1000 mL/hour in an average-sized person) with a maximum of <50 mL/kg in the first two to three hours (algorithm 1 and algorithm 2).
●Dextrose should be added to the saline solution once the serum glucose levels have fallen to 200 mg/dL (11.1 mmol/L) in DKA or 250 to 300 mg/dL (13.9 to 16.7 mmol/L) in HHS. In patients with HHS, the serum glucose should be maintained at 250 to 300 mg/dL (13.9 to 16.7 mmol/L) until the hyperosmolality and mental status improve and the patient is clinically stable.
Data evaluating the outcome and treatment of cerebral edema in adults are not available. Recommendations for treatment are based upon clinical judgment in the absence of scientific evidence. Case reports and small series in children suggest benefit from prompt administration of mannitol (0.25 to 1 g/kg) and perhaps from hypertonic (3 percent) saline (5 to 10 mL/kg over 30 min) . These interventions raise the plasma osmolality (Posm) and generate an osmotic movement of water out of brain cells and a reduction in cerebral edema.
Noncardiogenic pulmonary edema — Hypoxemia and rarely noncardiogenic pulmonary edema can complicate the treatment of DKA [65-68]. Hypoxemia is attributed to a reduction in colloid osmotic pressure that results in increased lung water content and decreased lung compliance . Patients with DKA who are found to have a wide alveolar-arterial oxygen gradient and/or rales may be at higher risk for the development of pulmonary edema.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyperglycemic emergencies".)
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SUMMARY AND RECOMMENDATIONS
●General principles – The treatment of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are similar and involves correction of the fluid and electrolyte abnormalities that are typically present, including hyperosmolality, hypovolemia, metabolic acidosis (in DKA), and potassium depletion, and the administration of insulin (table 3 and algorithm 1 and algorithm 2). Frequent monitoring is essential, and underlying precipitating events should be identified and corrected. (See 'Overview and protocols' above.)
●Fluid replacement – We recommend intravenous (IV) fluid replacement to correct both hypovolemia and hyperosmolality (Grade 1A). Fluid replacement should correct estimated deficits within the first 24 hours, with care to avoid an overly rapid reduction in the serum osmolality. The optimal rate of initial isotonic saline infusion is dependent upon the clinical state of the patient. (See 'Fluid replacement' above.)
•Hypovolemia with shock – Isotonic saline should be infused as quickly as possible in patients with hypovolemic shock.
•Hypovolemia without shock – In hypovolemic patients without shock (and without heart failure), we begin with isotonic (0.9 percent) saline infused at a rate of 15 to 20 mL/kg per hour (approximately 1000 mL/hour in an average-sized person) for the first couple of hours. This is followed by one-half isotonic (0.45 percent) saline at a rate of approximately 250 to 500 mL/hour if the serum sodium (corrected for hyperglycemia) is normal or elevated; isotonic saline is continued at a rate of approximately 250 to 500 mL/hour if the serum sodium (corrected for hyperglycemia) is low. We add dextrose to the saline solution when the serum glucose reaches 200 mg/dL (11.1 mmol/L) in DKA or 250 to 300 mg/dL (13.9 to 16.7 mmol/L) in HHS. (See 'Fluid replacement' above.)
The need for potassium repletion may influence the timing of one-half isotonic saline therapy since the addition of potassium to isotonic saline creates a hypertonic solution that can worsen the underlying hyperosmolality. (See 'Potassium replacement' above.)
•Euvolemia – Isotonic saline is infused at a lower rate than in hypovolemic patients without shock, guided by clinical assessment.
●Potassium replacement – We recommend that replacement with IV potassium chloride (KCl) (Grade 1A) be initiated when the serum potassium concentration is ≤5.3 mEq/L. Patients with an initial serum potassium below 3.3 mEq/L should receive fluid and potassium replacement prior to treatment with insulin to prevent initial worsening of the hypokalemia. (See 'Fluid replacement' above and 'Potassium replacement' above.)
Patients with DKA or HHS typically have a marked degree of potassium depletion due to both renal and, in some patients, gastrointestinal losses. However, because of potassium redistribution from the cells into the extracellular fluid (ECF), the initial serum potassium concentration is often normal or elevated, an effect that will be reversed by insulin therapy.
•Moderate to severe DKA – We recommend initial treatment with low-dose IV insulin in all patients with moderate to severe DKA or HHS who have a serum potassium ≥3.3 mEq/L (Grade 1B). Patients with an initial serum potassium below 3.3 mEq/L should receive aggressive fluid and potassium replacement prior to treatment with insulin. (See 'Potassium replacement' above.)
The insulin regimen is the same in DKA and HHS (algorithm 1 and algorithm 2). If the serum potassium is ≥3.3 mEq/L, we give a continuous IV infusion of regular insulin at 0.14 units/kg per hour; at this dose, an initial IV bolus is not necessary. An alternative option is to administer an IV bolus (0.1 units/kg body weight) of regular insulin, followed by a continuous infusion at a dose of 0.1 units/kg per hour. The dose is doubled if the glucose does not fall by 50 to 70 mg/dL (2.8 to 3.9 mmol/L) in the first hour. (See 'Insulin' above.)
•Mild DKA – A cost-effective alternative to IV insulin in the initial treatment of mild DKA (table 1) is the use of subcutaneous, rapid-acting insulin analogs (insulin lispro, aspart, and glulisine) in selected patients in settings in which adequate monitoring can be assured. (See 'Subcutaneous insulin regimens' above.)
●Indications for bicarbonate – Indications for sodium bicarbonate therapy to help correct the metabolic acidosis are controversial. We suggest treatment with IV sodium bicarbonate in patients with an arterial pH less than 6.9 (Grade 2B). (See 'Bicarbonate and metabolic acidosis' above.)
●Indications for phosphate – Although whole-body phosphate depletion is usually present, we recommend not administering phosphate routinely (Grade 1A). We suggest phosphate replacement for patients with severe hypophosphatemia (<1 mg/dL [0.32 mmol/L]), respiratory or cardiac failure, or hemolytic anemia (Grade 2C). (See 'Phosphate depletion' above.)
●Monitoring – Monitoring involves hourly glucose measurement until stable and basic chemistry profile and venous pH (for DKA) every two to four hours. The course of ketoacidemia can be assessed by direct measurement of beta-hydroxybutyrate, the major circulating ketoacid, and/or measurement of the serum anion gap. In contrast, nitroprusside tablets or reagent sticks should not be used, because they react with acetoacetate and acetone but not with beta-hydroxybutyrate. Acetone is not an acid and does not generate metabolic acidosis. (See 'Monitoring' above.)
●Potential complications – Cerebral edema is rare in adults but is associated with high rates of morbidity and mortality. Possible preventive measures in high-risk patients include gradual rather than rapid correction of fluid and sodium deficits (maximum reduction in plasma osmolality [Posm] of 3 mOsmol/kg per hour), and maintenance of a slightly elevated serum glucose until the patient is stable. (See 'Cerebral edema' above.)
●Converting to subcutaneous insulin – We initiate a multiple-dose (basal-bolus), subcutaneous insulin schedule when the ketoacidosis has resolved and the patient is able to eat. For patients with HHS, IV insulin infusion can be tapered and a multiple-dose, subcutaneous insulin schedule started when the serum glucose falls below 250 to 300 mg/dL (13.9 to 16.7 mmol/L). The IV insulin infusion should be continued for two to four hours after initiating the subcutaneous insulin to avoid recurrence of hyperglycemia. When converting to subcutaneous insulin, we do not use ultra-long-acting insulins (eg, degludec, U-300 glargine) as the basal insulin, given their long half-life and the time it takes to reach steady state (two to three days). (See 'Converting to subcutaneous insulin' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Abbas Kitabchi, PhD, MD, FACP, MACE, who contributed to an earlier version of this topic review.
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