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Hyperglycemic Emergencies

Sep 16, 2010

Lana Kravarusic

Doctor of Pharmacy Candidate, University of Florida 



Diabetes mellitus, if uncontrolled, may lead to serious hyperglycemic emergencies. The two most serious hyperglycemic emergencies are diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS). (Hyperglycemic hyperosmolar state is synonymous with hyperosmolar syndrome and hyperglycemic hyperosmolar nonketotic state which are both older names.) DKA most commonly occurs in patients with Type 1 diabetes mellitus or pancreatic disease, while HHS occurs more frequently with Type 2 diabetes. The presentation of the two syndromes can be distinguished by several factors. Both DKA and HHS patients present with hyperglycemia, but DKA is characterized by ketonemia, ketonuria, and metabolic acidosis while HHS involves dehydration without significant ketoacidosis. It is also possible that a patient presents with a mixture of DKA and HHS.1

The incidence of DKA is estimated to be 4-8 per 1000 diabetic patients, but is likely an underestimation. Up to 25% of cases in the United States are discovered at diagnosis, especially in younger children. The current mortality rate is 2-5% with treatment, and is usually a result of the underlying associated illnesses rather than DKA itself.2 For example elderly patients (>65 years) may have a mortality rate as high as 20% due to comorbid conditions. In some rare cases, however, mortality is a result of a DKA complication such as cerebral edema which is estimated to occur in 0.7-1% of DKA cases in young adults and children. Therefore, children less than 5 years of age and elderly over the age of 65 are considered high-risk DKA patients.1

Currently, the incidence of HHS in the United States is thought to be less than 1 per 1000-person years, making HHS much less common than DKA.4 In 33-60% of HHS cases, the patients have been newly diagnosed with diabetes.1 yHypHyIn contrast to DKA, HHS has a mortality rate ranging from 10-17%, but may also be underreported since death is often attributed to a complication instead. 1,3 Serious complications that may lead to death include cardiovascular failure or progressive shock in the first 72 hours, and thromboembolic events after 72 hours.1


Glucose Regulation in Normal States

Glucose is regulated by one of two mechanisms in the body, depending on the type of tissue involved. In insulin-insensitive tissues, such as the brain, glucose is not regulated by insulin and is therefore available in both fasting and fed states. This is essential for survival since glucose is the primary fuel source for the brain. Insulin-sensitive tissues, in contrast, only use glucose in the fed state. Once in the fasting state, these tissues obtain their fuel from sources other than glucose. Specifically, adipose tissues will undergo lipolysis while liver and muscle tissue will alter their intermediary metabolism to fat metabolism. These changes occur in the fuel deprived fasting state due to a decrease in insulin and an increase in the counter-regulatory hormones catecholamines, glucagon, and cortisol. Counter-regulatory hormones are also responsible for the increased glucose production, decreased peripheral utilization of glucose, and the production of ketones from fatty acids in the liver that takes place during the fasting state. As a net result of these hormonal changes, the body is in a state of hyperglycemia and ketones are present in the bloodstream. Normally, the presence of excess glucose and ketones in the fasting state acts as a counter-regulatory signal which promotes the production of insulin. This response is crucial because the production of insulin allows for normoglycemia to be restored in this stressful metabolic state.

Glucose Regulation in Insulin Deficient States

Normal glucose regulation and its feedback mechanisms are unable to function properly in the complete or relative absence of insulin. In DKA, there is usually a complete absence of insulin since the patients are typically Type 1. When these patients are in a fuel deprived state, there is a lack of insulin and a high amount of counter-regulatory hormones present. This causes the system to spiral out of control and leads to hyperglycemia, dehydration, ketoacidosis, and ketonuria.

Diabetic Ketoacidosis (DKA) Pathogenesis

Enhanced gluconeogensis, increased glycolysis, and lack of peripheral utilization and metabolism of glucose


Osmotic diuresis à loss of fluid and electrolytes


Increased lipolysis à increased amount of free fatty acids à free fatty acids are converted to ketones in the liver


Similar mechanisms are responsible for the development of HHS, with slight differences since these patients are only relatively insulin deficient. As a result, there is still an increase in counter-regulatory hormones but not to the same extent as in DKA. When these patients are in a fuel deprived state, just enough insulin is produced in order to counteract the lipolysis and ketone formation that would otherwise be caused by the increased counter-regulatory hormones. However, not enough insulin is present to properly regulate glucose, leading to hyperglycemia. Overall, HHS results in profound dehydration, significant hyperglycemia, and hyperosmolarity. It is important to note that the hyperglycemia is usually more severe in HHS than in DKA. This occurs since the volume depletion in HHS eventually lowers the glomerular filtration rate which leads to eliminated or diminished glycosuria.

Hyperglycemic Hyperosmolar State (HHS) Pathogenesis


Enhanced gluconeogenesis, increased glycolysis, and lack of peripheral utilization and metabolism of glucose. Lowered GFR à decreased glucose elimination in urine.

Significant hyperglycemia

Long lasting osmotic diuresis due to lack of ketonemia symptoms à extreme loss of fluid and electrolytes

Profound dehydration

Dehydration and hyperglycemia

Hyperosmolarity, hypertonicity, mental-status changes

Precipitating Events

Diabetic ketoacidosis is usually precipitated by new onset diabetes, various infections such as urinary tract infections or pneumonia, improper insulin use, poor access to medical care, or lack of education about “sick-day” rules. Occasionally, psychological factors are involved. For example, patients may be afraid of weight gain so they might fast or they are afraid of hypoglycemia so they might overeat and not use insulin. Metformin, in renally impaired patients, may also contribute to DKA.

NKH can be precipitated by infection, myocardial infarction, stroke, cocaine or alcohol abuse, and overeating. In certain instances, medications including diuretics, beta-blockers, phenytoin, or glucocorticoids may cause HHS.

Clinical Features

Dehydration and Loss of Electrolytes in DKA and HHS

Patients with DKA and HHS present with significant fluid loss. About 100ml/kg of water is lost in DKA while 100-200 ml/kg of water is lost in HHS. Interestingly, because glucose osmotically pulls water out of the intracellular compartments, patients with DKA and HHS rarely experience cardiovascular collapse even though the fluid deficits exceed the normal intravascular volume. Therefore, health professionals who are assessing these patients must be careful not to underestimate the level of dehydration in these patients since the clinical picture may look better than expected.

Sodium, chloride, potassium, and phosphorous are lost in DKA and HHS. Typically, more electrolytes are lost in HHS than in DKA. As a result of the osmotic activity of glucose, intracellular fluid rich in K+ and low in Na+ is pulled into the plasma. This leads to the dilution of Na+ in the plasma and therefore, serum Na+ may appear normal or borderline low. The following correction must be performed for serum Na+ in the setting of DKA or HHS:

For every 100 mg/dl rise in glucose above 100 mg/dl, Na+ decreases by 1.6 mEq/L.

Meanwhile, the movement of intracellular fluid to the plasma causes an increase in the serum K+ concentration. Additionally, serum K+ is increased due to a deficit of insulin which normally promotes K+ uptake into cells. In DKA, since the body is in an acidotic state, serum K+ is increased by a 3rd mechanism which involves pH related exchange of vascular H+ and cellular K+. Therefore, K+ must be corrected in DKA (but not in HHS) in the following way:

For every 0.1 decrease in pH from 7.4, serum K+ increases by 0.8 mEq/L.

Amount lost in DKA per kg
Amount lost in NKH per kg

Sodium (mEq)


Potassium (mEq)


Chloride (mEq)


Phosphorous (mM)


Metabolic Acidosis in DKA

Acetoacetate, acetone, and β-hydroxybutyrate are the ketones which are produced in DKA. Of these, acetoacetate and β-hydroxybutyrate are considered acidic. Initially, the two ketoacids are eliminated in urine or buffered by bicarbonate as well as other intravascular and intracellular ions. Glomerular filtration eventually diminishes and the buffering capacity is exceeded by the ketogenesis, leading to metabolic acidosis and an increased anion gap.

Hypertonicity in HHS

Patients with HHS present with rises in serum tonicity, also known as effective osmolarity. Rises in serum tonicity are thought to be responsible for the confusion, and in severe cases coma, that may occur with HHS. The serum tonicity incorporates Na+, K+, and glucose, but does not include BUN or other freely permeable substances which are included in similar calculation of total osmolarity. In other words, only substances that are impermeable or require transport mechanisms are included in calculating tonicity. A rise in tonicity is seen with uncontrolled diabetes, but extreme glucose elevations are required to cause hypertonicity that is severe enough to cause mental status changes. Specifically, a patient’s serum tonicity would have to be at least 340 mOsm/L in order to exhibit clinical relevant changes in brain function. This tonicity translates to a blood glucose in excess of 1000 mg/dl in the affected patient.


Stewart 2004

Diabetic Ketoacidosis

Patients with ketoacidosis usually present with polyuria, polydispia, nausea, vomiting, hyperventilation, and abdominal pain. Mental status changes are unusual, despite the use of its misnomer “diabetic coma.” The nausea, vomiting, and abdominal pain are thought to be a result of the ketonemia. Hypokalemia also contributes to the abdominal pain as it causes gastro paresis and can even cause ileus. Upon physical examination, most patients will have dehydration, overt or orthostatic hypotension, Kussmaul respirations, tachycardia, and warm skin. The Kussmaul respirations present as deep, sighing hyperventilation and are a compensatory mechanism for the metabolic acidosis when the pH drops below 7.2. The following constitute a definitive diagnosis of DKA:

  • Hyperglycemia: serum glucose >250mg/dl
  • Low serum bicarbonate: <15 mEq/L
  • Low pH: <7.3
  • Ketonemia: positive minimally at 1:2 dilution

It is important to note that pregnant women may have lower serum glucose levels at presentation. Also, patients who have been unable to eat, have been vomiting, or took insulin after starting to experience symptoms in the prodromal phase may also present with lower serum glucose levels. Additional findings that are commonly seen in DKA are an increased anion gap, high white-blood cell count, elevated serum amylase, and elevated serum BUN and creatinine. During diagnosis, DKA patients should also be assessed for signs of infection, sepsis, and shock. Additionally, an ECG should be performed to determine to rule out cardiac related precipitating factors.

Hyperglycemic Hyperosmolar State

The onset of HHS is gradual and typically presents over several days. Symptoms include polyuria, worsening glycemic control, and finally, exhaustion. The primary sign of HHS is extreme dehydration which will present as hypotension (overt or postural), lack of sweating, dry skin and mucous membranes, and poor skin turgor. Similar to DKA, gastroparesis is present due to the hypertonic state, but many other abdominal symptoms are absent due to the lack of ketonemia. Mental status changes are also frequently present in HHS. Lethargy and confusion are almost always present, and in severe cases, coma may occur. If the mental status does not improve after initial treatment, other causes should be investigated such as CNS lesions or infections. All patients should be assessed for concomitant infections which may be indicated by tachypnea, hypotension, or fever. Usually, cardiac and respiratory examinations will be normal unless pneumonia is present. In addition to mental status changes, up to 25% of HHS patients may present with seizures. These seizures can frequently be resistant to anticonvulsant therapy and the HHS must be treated instead. It is important to note that phenytoin should not be used since it may worsen hyperglycemia.

Electrolyte losses are also present in HHS, with patients most frequently presenting with hypokalemia, hyponatremia, hypochloremia, and hypophosphatemia. If patients do present with normal or elevated Na+, this indicates that they have also had massive water loss. In certain severe cases of HHS, cerebral edema may occur but it is usually a complication of rapid overcorrection of blood glucose and hypovolemia rather than HHS itself. Abnormal liver transaminases, LDH, CPK-MM, albumin, amylase, bilirubin, calcium, protein, and BUN may be seen in HHS. Leukocytosis, hypercholesterolemia, and hypertriglyceridemia, and elevated hemoglobin and hematocrit may also be present.

Differentiating Between DKA and HHS

In most cases, DKA and HHS present with enough differences to be distinguished from one another. A simple way to distinguish the patients is that DKA Hyperglycemia2patients are acidotic and have warm skin, while HHS patients have a normal skin temperature, higher glucose levels, and more severe dehydration. Occasionally, HHS patients may be incorrectly diagnosed with DKA due to the mild metabolic acidosis that HHS patients may present with. The acidosis in HHS is mild and the pH remains greater than 7.3. However, in up to 33% of cases, DKA and HHS may actually be mixed. These patients would present with a mixture of the above discussed symptoms as well as a pH 320 mOsm/L.


Treatment goals for DKA and HHS include restoration and improvement of circulatory volume, improvement in tissue perfusion, correction of electrolyte abnormalities, and reduction in serum glucose. Specifically for DKA, it is important to also eliminate excess serum ketoacids.


Hydration in DKA is accomplished by giving 1 L of 0.9% saline in the first hour. If hypotension is not corrected after 1 L or if urine flow is less than 50-100 ml/hr, this rate should be continued for another hour. After this, 0.45% NaCl at 250-500 ml/hr should be given to restore the normal tonicity of the plasma. This rate should be adjusted based on the clinical picture as well the urine output and plasma sodium.

In HHS, hydration is accomplished in a similar manner. 1L of 0.9% saline is given each hour until urine output, pulse, and blood pressure improve or normalize. After this, 0.45% NaCl at 250-500 ml/hr is given and adjusted as needed. It is important to replace at least ½ of the free water loss in the first 12 hours, and the remainder of the loss over the next 24 hours.


Insulin treatment for both DKA and HHS is the same. All patients should be given 10-20U regular insulin IV push. After that, they should be given 0.1 U/kg/hr continuous IV infusion of regular insulin. Anion gap, pH, and hyperglycemia should be monitored. If no improvement is seen within 2 hours, the dose should be doubled each hour until the desired results are seen. It is important to note that insulin should not be given without concomitant fluid infusions which will help expand the intravascular space. Otherwise, vascular collapse may occur as the osmolarity decreases and fluid flows out of the intravascular space back into the intracellular compartments. Also, while insulin therapy is being given, a transient rise in urinary ketones may be seen. However, this is simply a complication of the method used for measuring urine ketones and is not a true elevation.


A rapid decline in K+ is seen after initiation of insulin and hydration in DKA treatment. This usually occurs in the first 3 hours and is a result of the increase in pH which reverses the exchange of intracellular K+ for extracellular H+. In other words, at a higher pH, more H+ is being pumped out of the cells while the K+ is being moved back inside the cells. In addition to this, the presence of insulin promotes the uptake of K+ into the cells. Therefore, in DKA, if serum K+ is less than 3.5 mEq/L and pH is <7.3, the first liter of IV fluids should have 20-40 mEq of KCl added to it. Cardiac monitoring should also be initiated in these patients. If this is not the case, the KCl should be added to the second liter of IV fluids. Once the patient is able to tolerate oral fluids, they may be switched to oral K+ replacement. Serum K+ should be monitored every 1-2 hours. If the patient is urinating and the K+ remains less than 5.5 mEq/L, K+ should continue to be added to the IV fluids.

In HHS, serum K+ should be monitored every 1-2 hours as well. However, since acute falls in serum K+ during the first few hours of therapy are less likely in HHS than in DKA, oral replacement is frequently used in HHS. If the patient is urinating and the K+ remains less than 5.5 mEq/L after oral replacement, K+ should continue to be added to each liter of IV fluids.


Bicarbonate is only replaced in certain instances of DKA, and does usually not need to be replaced in HHS. If serum pH is <6.9 in DKA, 88 mEq of bicarbonate should be given. If the pH is between 6.9 and 7 in DKA, 44 mEq of bicarbonate should be given.


Phosphorous replacement is not indicated in without severe hypophosphatemia, and is usually only necessary in DKA. If phosphorous is <1 mg/dl, 1/3 of the potassium deficit should be replaced as potassium phosphate. Otherwise, use is at the discretion of the physician.


Both diabetic ketoacidosis and hyperglycemic hyperosmolar state are serious hyperglycemic emergencies and must be treated promptly and effectively. Optimally, these emergeny states can be avoided by proper education of the diabetic patients at the time of diagnosis and as needed at each physician visit.

  1. Nathan, MH. (2002) Hyperglycemic Emergencies: Diabetic Ketoacidosis and Nonketotic Hyperosmolar Syndrome. In Leahy JL & Cefalu WT (Eds.), Insulin Therapy (173-191). New York, NY: Marcel Dekker.
  2. Young GM. Pediatric, Diabetic Ketoacidosis. EMedicine Specialities. 2009. http://emedicine.medscape.com/article/801117-overview.
  3. Sergot PB. Hyperosmolar Hyperglycemic State. EMedicine Specialities. 2010. http://emedicine.medscape.com/article/766804-overview.
  4. Nugent BW. Hyperosmolar hyperglycemic state. Emerg Med Clin North Am. Aug 2005;23(3):629-48, vii
  5. Stewart C. Diabetic Emergencies: Diagnosis and Management of Hyperglycemic Disorders. Emergency Medicine Practice. 6(2):1-24. 2004.
  6. Kitabchi AE, Wall BM. Diabetic ketoacidosis. Med Clin North Am. 79:9-37. 1995.

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