on 05-Dec-2021 (Sun)

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

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) [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).

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].

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.

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.

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)

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) [1]

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 [1]:

● 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.

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.

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 [18].

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.

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

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

If 40 mEq of KCl is added to isotonic saline, the final osmolality 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.

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.

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, given its 25-hour half-life and 42-hour duration of effect, as it will take at least three to four days to reach steady state [23]

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.

Insulin therapy lowers the serum glucose concentration (by decreasing hepatic glucose production, the major effect, and enhancing peripheral utilization, a less important effect [24]), 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].

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 [30]. The insulin dosing is the same in DKA and HHS (algorithm 1 and algorithm 2).

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 [26].

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]

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.

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

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 [ 32]:

● 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.

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 [39].

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

The indications for bicarbonate therapy in DKA are controversial [40], and evidence of benefit is lacking [41-43].

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 [35]

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 [41]

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.

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

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

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]

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 [57], 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 [13]. Beta-hydroxybutyrate can then be measured every two hours depending on the clinical response [58]. When bedside meters are not available, monitoring venous pH and/or the venous bicarbonate and anion gap is sufficient

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

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

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, 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 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)

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 [63]. Hyperglycemia may recur from interruption or discontinuation of IV insulin without adequate coverage with subcutaneous insulin

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 [64]. 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

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 [1]. 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 [1]:

● 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) [64]. These interventions raise the plasma osmolality (Posm) and generate an osmotic movement of water out of brain cells and a reduction in cerebral 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 [11]. 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.

It is important to assess for potentially dangerous organic causes of agitation as soon as this can be done safely (table 1). In the emergency department (ED), drug and alcohol intoxication or withdrawal are the most common diagnoses in combative patients [22,23]. A rapid serum glucose measurement (eg, fingerstick glucose), pulse oximetry, and a complete set of vital signs should be obtained in all patients.

The mnemonic FIND ME (functional [ie, psychiatric], infectious, neurologic, drugs, metabolic, endocrine) may be helpful to organize a diagnostic search for the etiology of delirium and violence (table 2).