What is hyperosmolar hyperglycemic state

Hyperosmolar hyperglycemic state also known as hyperosmolar hyperglycemic nonketotic syndrome is a dangerous condition resulting from very high blood glucose levels. Hyperosmolar hyperglycemic state can affect both type 1 and type 2 diabetes, yet it usually occurs amongst people with type 2 diabetes. The exact incidence of hyperosmolar hyperglycemic state is not known, but it is estimated to account for <1% of hospital admissions in patients with diabetes ¹. Mortality due to hyperosmolar hyperglycemic state has been reported as high as 10% to 20%, and a recent cohort study reported 30-day mortality of 16% ². Hyperosmolar hyperglycemic state usually causes 10 time greater morbidity and mortality than DKA (diabetic ketoacidosis), depending on the severity of dehydration, hyper-osmolality, and patient age ³. The prognosis of hyperosmolar hyperglycemic state is determined by the severity of dehydration, presence of comorbidities, and advanced age ⁴.

When hyperosmolar hyperglycemic state affects a person with diabetes, usually in people with type 2 diabetes who experience very high blood glucose levels (often over 40mmol/l or 720 mg/dL), blood sugar levels rise and the body passes excess sugar into the urine. This causes regular frequent urination and over time this affects the color of the urine because of severe dehydration. Dehydration can occur if you do not drink liquid regularly, and this can become severe and lead to coma, seizures and even death.

• Current diagnostic hyperosmolar hyperglycemic state criteria include a plasma glucose level >600 mg/dL (>33.3 mmol/L) and increased effective plasma osmolality >320 mOsm/kg in the absence of ketoacidosis ⁵.
• Hyperosmolar hyperglycemic state is a syndrome characterized by severe hyperglycemia, hyperosmolality, and dehydration in the absence of ketoacidosis ⁵.

Usually, hyperosmolar hyperglycemic state is brought on by an illness or infection.

Hyperosmolar hyperglycaemic state can develop over a course of weeks through a combination of illness (e.g. infection) and dehydration.

Stopping diabetes medication during illness (e.g. because of swallowing difficulties or nausea) can contribute, but blood glucose often rises despite the usual diabetes medication due to the effect of other hormones the body produces during illness.

Symptoms of hyperosmolar hyperglycemic state can frequently include:

• urination,
• thirst
• nausea
• dry skin
• disorientation and, in later stages, drowsiness and a gradual loss of consciousness.

Hyperosmolar hyperglycemic state does not usually lead to the presence of ketones in the urine, as occurs in diabetic ketoacidosis (DKA), which is why it was previously referred to as hyperglycemic hyperosmolar non-ketotic state. Ketones develop when the blood glucose level is high due to lack of insulin which is needed to allow glucose to enter the cells for energy. Because people with Type 2 diabetes may still be producing some insulin, ketones may not be created.

Who is at risk of Hyperosmolar Hyperglycaemic State?

Periods of illness can significantly raise blood glucose levels, which could lead to hyperosmolar hyperglycemic state if medication is not sufficient to lower sugar levels.

Having blood glucose levels above 33 mmol/l (594 mg/dl) for extended periods of time presents a risk of hyperosmolar hyperglycemic state occurring.

Serious complications of diabetes, such as hyperosmolar hyperglycemic state, usually manifest themselves amongst older people, who may be less aware of high blood glucose levels and how to treat them.

Hyperosmolar hyperglycemic state complications

Diabetic hyperosmolar syndrome can lead to:

• Seizures
• Heart attack
• Stroke
• Coma

Without prompt treatment, diabetic hyperosmolar syndrome can be fatal.

Hyperosmolar hyperglycemic state vs DKA

DKA also known as diabetic ketoacidosis is a life-threatening emergency in which extreme hyperglycemia (high blood sugar level), along with a severe lack of insulin. Although most common in people with type 1 diabetes, anyone who depends on insulin could develop DKA (diabetic ketoacidosis). In exceptionally rare cases, people controlling their diabetes with diet or tablets have been known to develop DKA when severely ill.

DKA (diabetic ketoacidosis) starts with a lack of the hormone insulin. When things are working normally, insulin ushers glucose (a kind of sugar from food) into cells, where it can be converted into energy. But without enough insulin in the body, glucose accumulates in the blood, where it is of little use. Even though there is plenty of glucose around, it can’t get into the cells to feed them. The body’s response is to drive up blood glucose even more by spurring the liver to break down its glucose stores and to make additional glucose from scratch.

This insulin deficiency stimulates the elevation of the counter regulatory hormones (glucagon, catecholamines, cortisol, and growth hormone). Without the ability to use glucose, the body needs alternative energy sources. Lipase activity increases, causing a breakdown of adipose tissue that yields free fatty acids. These components are converted to acetyl coenzyme A, some of which enter the Krebs cycle for energy production; the remainder are broken down into ketones (acetone, acetoacetate, and β-hydroxybutyrate). Ketones can be used for energy, but accumulate rapidly. Glycogen and proteins are catabolized to form glucose. Together, these factors promote hyperglycemia, which leads to an osmotic diuresis resulting in dehydration, metabolic acidosis, and a hyperosmolar state.

An accumulation of ketones in the blood and urine in diabetic ketoacidosis can lead to dehydration and confusion. Signs of diabetic ketoacidosis are nausea, vomiting, stomach pain, fruity odor on the breath, and rapid (Kussmaul) breathing. If not treated, people with DKA can become unconscious and can die.

• Diabetic ketoacidosis is characterized by a serum glucose level greater than 250 mg per dL (13.9 mmol/L), a pH less than 7.3, a serum bicarbonate level less than 18 mEq per L, an elevated serum ketone level, and dehydration.

Diabetic ketoacidosis usually occurs in people with type 1 diabetes. It is rare in type 2 diabetes – a third of diabetic ketoacidosis cases occur in those with type 2 diabetes. Although most cases of diabetic ketoacidosis affect people over the age of 20 and the great majority of diabetic ketoacidosis cases in kids aren’t fatal, this condition is still the No. 1 killer of children and adolescents with type 1 diabetes. And in some instances, people discover that they have diabetes after they land in the hospital with diabetic ketoacidosis. So it’s important to know the signs of diabetic ketoacidosis—and how to avoid it.

Diabetic ketoacidosis can occur in persons of all ages, with 14 percent of cases occurring in persons older than 70 years, 23 percent in persons 51 to 70 years of age, 27 percent in persons 30 to 50 years of age, and 36 percent in persons younger than 30 years ⁶. The case fatality rate is 1 to 5 percent ⁷. About one-third of all cases are in persons without a history of diabetes mellitus.

The symptoms of DKA include high blood glucose, high levels of ketones in the urine, and:

• quick breathing (Kussmaul)
• flushed cheeks
• abdominal pain
• breath that smells like sweet acetone (similar nail polish remover)
• vomiting
• dehydration.

Ketone testing is a key part of type 1 diabetes management as it helps to prevent a dangerous short term complication, DKA (diabetic ketoacidosis), from occurring.

If you have type 1 diabetes, it is recommended that you have ketone testing supplies on your prescription.

Ketone testing may also be useful in people with other types of diabetes that are dependent upon insulin.

Check your blood sugar level if you have symptoms of DKA (diabetic ketoacidosis).

You can detect ketones with a simple urine test using a test strip, similar to a blood testing strip. Ask your health care provider when and how you should test for ketones. If your blood sugar is 11 mmol/L (198 mg/dL) or over and you have a blood or urine ketone testing kit, check your ketone level. Many experts advise to check your urine for ketones when your blood glucose is more than 250 mg/dL (13.9 mmol/L).

When you are ill (when you have a cold or the flu, for example), check for ketones every 4 to 6 hours. And check every 4 to 6 hours when your blood glucose is more than 250 mg/dL (13.9 mmol/L).

The presence of high levels of ketones in the bloodstream is a common complication of diabetes, which if left untreated can lead to ketoacidosis.

Ketones build up when there is insufficient insulin to help fuel the body’s cells.

High levels of ketones are therefore more common in people with type 1 diabetes or people with advanced type 2 diabetes.

DKA prevention

DKA is usually avoidable. Making sure you always take your insulin in the right amounts for your food and activity patterns, keeping a good check on your blood glucose levels and consulting your healthcare team appropriately will help you to avoid episodes which are both life-disrupting and life-threatening.

DKA treatment

Diabetic ketoacidosis is typically treated in the hospital using a three-pronged approach.

Diabetic ketoacidosis treatments include:

• insulin, usually given into a vein
• fluids given into a vein to rehydrate your body
• nutrients given into a vein to replace any you’ve lost

Intravenous fluid replacement is necessary to combat dehydration. Electrolytes—which affect the heart, muscles, and nerve cells—are reduced in diabetic ketoacidosis, so treatment also focuses on bringing them back to healthy levels. Finally, since a lack of insulin brings on diabetic ketoacidosis, insulin treatment reverses the process. Insulin will bring down blood glucose and halt the acidification of blood by ketones.

You’ll also be closely monitored for any life-threatening problems that can occur, such as problems with the brain, kidneys or lungs.

You can leave hospital when you’re well enough to eat and drink and tests show a safe level of ketones in your body. It’s normal to stay in hospital for a couple of days.

Before leaving hospital, ask to speak to a diabetes nurse about why diabetic ketoacidosis occurred and what you can do to stop it happening again.

Hyperosmolar hyperglycemic state causes

Diabetic hyperosmolar syndrome may be triggered by:

• Illness or infection
• Not following a diabetes treatment plan or having an inadequate treatment plan
• Certain medications, such as water pills (diuretics)

Sometimes undiagnosed diabetes results in diabetic hyperosmolar syndrome.

Risk factors for hyperosmolar hyperglycemic state

Your risk of developing diabetic hyperosmolar syndrome might be higher if you:

• Have type 2 diabetes. If you don’t monitor your blood sugar or you don’t yet know you have type 2 diabetes, your risk is higher.
• Are older than age 65.
• Have another chronic health condition, such as congestive heart failure or kidney disease.
• Have an infection, such as pneumonia, a urinary tract infection or a virus, which causes your blood sugar levels to rise.
• Take certain medications. Some drugs — such as corticosteroids (prednisone), diuretics (hydrochlorothiazide and chlorthalidone) and the anti-seizure medication phenytoin (Dilantin).

Hyperosmolar hyperglycemic state prevention

Good daily control of your diabetes can help you prevent diabetic hyperosmolar syndrome.

• Know the symptoms of high blood sugar. Be alert for the warning symptoms of high blood sugar, as well as the situations that put you at risk of developing hyperosmolar syndrome, such as illness or infections.
• Monitor your blood sugar level. Monitoring will help you stay in your target range and alert you to dangerous highs. Ask your doctor how often you should test your blood sugar. Monitor more often when you’re sick.
• When you’re sick, drink plenty of liquids. Drink a glass of nonalcoholic, caffeine-free beverage hourly until you can ask your doctor for advice.
• Follow your diabetes management plan. Eat nutritious meals, take medications as directed and exercise regularly.
• Educate your loved ones, friends and co-workers. Teach people you spend time with to recognize early signs and symptoms of blood sugar extremes — and to summon emergency help if you pass out.
• Wear a medical ID bracelet or necklace. If you’re unconscious, the ID can provide valuable information to others, including emergency personnel.
• Stay current on vaccinations. Get an annual flu shot and ask your doctor if you need the pneumococcal vaccine, which protects against some forms of pneumonia.

Recommended target blood glucose level ranges

The National Institute for Health and Care Excellence (NICE) recommended target blood glucose levels are stated below for adults with type 1 diabetes, type 2 diabetes and children with type 1 diabetes.

For people with diabetes, blood sugar level targets are as follows:

• Before meals: 4 to 7 mmol/L (72 to 126 mg/dL) for people with type 1 or type 2 diabetes
• After meals: under 9 mmol/L (under 162 mg/dL) for people with type 1 diabetes and under 8.5mmol/L (under 153 mg/dL) for people with type 2 diabetes

In addition, the International Diabetes Federation’s target ranges for people without diabetes is stated ⁸.

The table provides general guidance. An individual target set by your healthcare team is the one you should aim for.

Table 1. The National Institute for Health and Care Excellence recommended target blood glucose level ranges

*The non-diabetic figures are provided for information but are not part of NICE guidelines.

Hyperosmolar hyperglycemic state symptoms

Diabetic hyperosmolar syndrome can take days or weeks to develop. Possible signs and symptoms include:

• Blood sugar level of 600 mg/dL or 33.3 mmol/L or higher
• Excessive thirst
• Dry mouth
• Increased urination
• Warm, dry skin
• Fever
• Drowsiness, confusion
• Hallucinations
• Vision loss
• Convulsions
• Coma

Major warning signs of hyperosmolar hyperglycemic state for people with diabetes:

• Dry mouth
• Elevated blood sugar levels
• Extreme thirst
• Warm skin without sweat
• Fever
• Confusion or feeling sleepy
• Vision loss
• Hallucinations
• Nausea
• Weakness down one side of the body

Hyperosmolar hyperglycemic state diagnosis

For diabetic hyperosmolar syndrome, prompt diagnosis is critical. The emergency medical team will do a physical and mental status exam and may ask those who are with you about your medical history.

Lab tests

You’ll likely have blood and urine tests to measure your blood sugar level and kidney function and to detect infection, among other conditions.

Hyperosmolar hyperglycemic state treatment

Hospital treatment for hyperosmolar hyperglycemic state aims to correct dehydration and bring blood glucose down to an acceptable level by giving replacement fluid and insulin by an intravenous drip.

Emergency treatment can correct diabetic hyperosmolar syndrome within hours includes:

• Intravenous fluids to counter dehydration
• Intravenous insulin to lower your blood sugar levels
• Intravenous potassium, and occasionally sodium phosphate replacement to help your cells function correctly

If you have an infection, or an underlying health condition, such as congestive heart failure or kidney disease, these conditions will be treated, as well.

The importance of hydration and electrolyte replacement has been recognized in the management of patients with hyperosmolar hyperglycemic state ¹⁰. Isotonic saline (0.9% NaCl) is recommended at 15–20 mL/kg during the first 1–2 hours, followed by 250–500 mL/h until resolution of the hyperglycemic crisis. Fluid replacement alone has been shown to reduce glucose concentration by 75–100 mg/h, due to a reduction in counterregulatory hormones and improvement of renal perfusion ¹¹. In addition, many patients with hyperosmolar hyperglycemic state have high serum potassium despite total body potassium deficit due to insulin deficiency and hyperosmolality, which cause a shift of potassium from the intracellular compartment into plasma ¹². During insulin treatment and hydration, serum potassium levels rapidly fall; therefore, it is recommended that potassium replacement should be initiated when serum levels fall <5.5 mEq/L, with the goal to maintain a serum potassium concentration in the range of 4–5 mEq/L.

Arieff and colleagues ¹³ first reported the development of brain edema, a feared complication of treatment after rapid correction of hyperglycemia and hyperosmolality. They reported that cerebral edema developed during diabetic coma treatment after a rapid lowering of plasma glucose levels in nondiabetic animals. Hyperglycemia was induced by infusing 50% glucose to maintain the plasma glucose level at ~60 mmol/L (1,080 mg/dL) for periods of 1–4 h. After 4 h of hyperglycemia, brain osmolality (343 mOsm/kg H20) was similar to that of cerebrospinal fluid (340 mOsm/kg). The authors proposed that during glucose infusion and the development of extracellular hyperosmolality, the brain protects against changes in volume by increasing osmolality, largely through a gain in unidentified solutes (idiogenic osmoles). They also observed that rapid normalization of plasma glucose due to insulin and hypotonic fluid administration resulted in gross brain edema as a result of an osmotic gradient between brain and plasma ¹⁴. Although such observations have not been demonstrated in humans, it is believed that rapid changes in plasma and brain osmolality after the administration of hypotonic fluids could result in brain edema. Thus, it is recommended that glucose levels be kept at ∼300 mg/dL when managing patients with hyperosmolar hyperglycemic state in order to prevent brain edema ¹⁴.

Several unresolved questions regarding the pathogenesis and treatment of hyperosmolar hyperglycemic state in adults and children need to be addressed in prospective clinical trials. The frequency and pathogenesis of cerebral edema in adults and children with hyperosmolar hyperglycemic state needs to be determined in well-designed prospective studies. Similarly, prospective studies are needed to settle the long-term controversy regarding the use of anticoagulant therapy in patients with hyperglycemic crises. Several case reports have indicated an increased risk of thrombosis, which is greater in hyperosmolar hyperglycemic state than in ketoacidosis ¹⁵. Severe dehydration and hypertonicity may result in osmotic disruption of endothelial cells, leading to a release of tissue thromboplastins and elevated vasopressin caused by the fluid status, which may contribute to enhanced coagulation ¹⁶. However, uncomplicated diabetes has never been shown to be an independent risk factor for venous thromboembolism ¹⁷. In a retrospective review of 426,831 cases of venous thromboembolism, the overall incidence among patients with hyperosmolarity was 1.7%, which is only modestly lower than the incidence in patients undergoing orthopedic surgery ¹⁸. The risk benefit of anticoagulation therapy in patients with hyperosmolar hyperglycemic state and DKA has not been evaluated prospectively.

The most recent American Diabetes Association Position Statement on the management of hyperglycemic crises in adult patients proposed a single treatment algorithm for the management of DKA and hyperosmolar hyperglycemic state. Low-dose insulin infusion protocols for treating DKA appear to be effective, but the mortality rate is about 10 times higher in hyperosmolar hyperglycemic state patients than in DKA patients ¹⁹. Thus, prospective studies are needed to determine effective and safe insulin and hydration strategies, as well as to determine glucose targets during intravenous insulin infusion and during the transition to subcutaneous insulin therapy in patients with hyperosmolar hyperglycemic state.

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