Diabetic ketoacidosis and Hyperosmolar Hyperglycemic State (DKA and HHS)

Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are the most life threatening acute complications of diabetes mellitus. DKA is more common in younger patients with type 1 diabetes, but can also occur in type 2 diabetes. In DKA, the lack of leads to lipolysis and ketogenesis with the formation of ketone bodies (mainly acetoacetate, beta-hydroxybutyrate and acetone). In HHS, on the other hand, ketogenesis is absent or minimal since there is still some circulating insulin.

SITUATIONS THAT CAN TRIGGER DKA OR HHS:

Acute diseases that can lead to an excess of counter regulatory hormones (infections, cardiac ischemia, stroke, pancreatitis, trauma, surgery)
Medications (glucocorticoids, thiazide diuretics, beta-agonists, antipsychotics, SGLT2 inhibitors)
Illegal drugs (cocaine)
Psychogenic disorders, negligence or failure of subcutaneous insulin device (lack of proper treatment with insulin)

CLINICAL FEATURES:

DKA: Acute onset, with signs and symptoms cause by anion gap metabolic acidosis such as tachypnea, nausea, vomiting and abdominal pain. Patient can also present with polydipsia, polyuria and dehydration. Neurologic symptoms may be present but are less common in DKA and more common in HHS. Patients may also have a fruity breath odor due to exhaled acetone. Glucose levels are usually around 350-500mg/dL (19-28mmol/L) and are very unlikely to go under 800mg/dL. Some patients (not eating well, using SGLT2 inhibitors) may even develop euglycemic DKA.

HHS: Symptoms are usually more insidious and can take longer to develop. Polydipsia, polyuria and dehydration are frequent. Neurological symptoms are the main feature of HHS and may vary from lightheadedness and altered mental status to focal signs and deep coma. Due to the lack of acidosis, hyperventalation and GI symptoms are often not present in HHS. The serum glucose can be higher than 1000mg/dL (56mmol/L).

TESTS TO ORDER:

CBC w/diff (leukocytosis may be present due to cortisol and catecholamines. However, very high number of WBCs or left shift should increase suspicion for infection)
Urinalysis and Ketones (dipstick)
Serum glucose and electrolytes (to calculate anion gap) or CMP (include items mentioned)
Serum beta-hydroxybutyrate (since some patients can have false-negative readings in the urine dipstick even with severe acidosis).
Arterial Blood Gas
ECG (electrolytes and acidosis can affect conduction)
Hemoglobin A1C (can provide information about the previous control of DM)
Other tests may be needed if the provider suspects that there is an active pathology causing the DKA. If infection is suspected, urine and blood cultures and a chest X-Ray may be necessary. If a cardiac event is suspected, EKG, chest X-Ray, echo or CT scan may be needed.

Useful formulas:
Anion gap = Sodium – [Chloride + Bicarbonate], normal lower than 10.

Effective Plama Osm = [2 x Na (mEq/L)] + [glucose (mg/dL) ÷ 18]
OR
Effective Plasma Osm = [2 x Na (mmol/L)] + glucose (mmol/L)

Sodium correction: The sodium should be corrected for hyperglycemia, since it can be reduced by 1.6mEq/L to 2mEq/L for every 100mg/dL increase in glucose concentration above normal levels.

TREATMENT:

Management of DKA and HHS is similar. The patient should have his mental status and hemodynamic status assessed before anything else. After that, five main factors should be taken into consideration: IV fluids, potassium replacement, insulin therapy, need for bicarbonate and need for phosphate.

After ruling out life threatening neurological or hemodynamic events and securing airway, breathing, and circulation, and obtaining large IV access and monitoring the patient with a cardiac monitor, capnography and pulse oximetry, IV replacement fluid therapy should be started to expand ECF volume.

IV fluids:
For replacement fluid therapy, IV isotonic saline at 15-20 mL/kg/hour (~1000mL/h) should be given for the first few hours. After that, half-isotonic (0.45%) saline at 4-14mL/kg/hr (~500mL/h) should be given if the corrected sodium is normal or elevated (if it is reduced, continue isotonic saline). When glucose is reduced to under 200mg/dL (for DKA) or 250-300mg/dL ( for HHS) dextrose 5% should be added to the saline solution (0.45%) at 150-250mL/h. The glucose should be maintained around 150-200mg/dL (DKA) or 250-300 (HHS) until resolution of the DKA/HHS AND the patient is able to eat.

Potassium replacement:
Potassium replacement should be started immediately if or when serum potassium is <5.3mEq/L and EVEN BEFORE insulin if it is <3.3mEq/L at the beginning of treatment. Potassium chloride can be used at 20-40mEq/hour until K+ > 3.3mEq/L. After that, the rate can be reduced to 20-30mEq per liter of IV fluid until potassium is between 4-5 mEq/L. Potassium should not be used if K+ >5.3mEq/L.

Insulin therapy:
Insulin should be always given, except for those patients that present with hypokalemia <3.3mEq/L (in these cases, correct the potassium and fluids first). Two regimens of regular insulin are possible for IV infusion: 0.1U/kg IV bolus, then continuous IV infusion of 0.1U/kg/h; OR continuous IV infusion at 0.14U/kg/h without bolus. Glucose should fall by 50-70mg/dL/h. If not, double the rate of infusion. When glucose is below 200mg/dL (DKA) or 250-300 (HHS) insulin dose can be reduced to 0.02-0.05U/kg/hr IV OR replaced by SC rapid-acting insulin (0.1U/kg SC every two hours). This regimen of insulin (and dextrose to maintain glucose between 150-200 for DKA or 250-300 for HHS) should be maintained at least until DKA/HHS is resolved AND the patient is able to eat. It is important to maintain the IV insulin for the first couple hours after starting the multi-dose SC insulin regimen.

The subcutaneous multi-dose insulin regimen should be started when acidosis is absent* and serum glucose <200 for DKA or <250-300 for HHS. The SC insulin regimen can be started with a total daily dosage of 0.5 to 0.8U/kg/day, including basal insulin and bolus insulin. During the first two hours of the SC insulin treatment, the patient should continue to receive IV insulin to guarantee good insulin levels, as mentioned before.

*Absence of acidosis should be confirmed by at least two of three: Anion gap <12 mEq/L, Bicarbonate ≥15 mEq/L and Venous pH >7.30.

Need for bicarbonate?
Only severe acidosis with pH <6.9 may need administration of bicarbonate. Sodium bicarbonate can be used (100mEq in 400mL of sterile water with 20mEq of potassium if needed as mentioned above, over 2 hours). It may be repeated until pH >7.0

Need for phosphate?
Phosphate replacement should be considered ONLY if there is hypophosphatemia (<1.0mg/dL or 0.32mmol/L), in which case sodium phosphate or potassium phosphate can be added to the IV fluids (20-30mEq/1L).

MONITORING:
Serum glucose should be monitored hourly.
Serum electrolytes and venous pH or bicarbonate should be monitored q2-4hr.

RESOLUTION CRITERIA:
DKA has resolved (normal AG and/or levels of beta-hydroxybutyrate) OR, for HHS, patient is mentally alert and plasma osmolality is under 315mOsmol/kg.
Patient is able to eat.

The protocol below can be useful as a quick guideline:

Image from: Umpierrez GE. et al. Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar Syndrome. Diabetes Spectrum 2002 Jan; 15(1): 28-36.

REFERENCES & FURTHER READING: