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HYPEROSMOLAR HYPERGLYCEMIC NONKETOTIC SYNDROME (HHNS)
Hyperosmolar: In biochemistry, pertaining to an osmolar concentration of the body fluids that is abnormally increased. As, for examples, in hyperglycemic hyperosmolar syndrome and hyperosmolar coma.

Nonketotic hyperglycinemia (NKH) is an inherited condition in which the body is unable to breakdown and process some of the building blocks of protein (amino acids). It is considered an amino acid condition because it can lead to high levels of the amino acidglycine in the body. There are several forms of NKH, which differ in regards to disease severity and age of onset. The symptoms and long term outcome of each form vary widely. In some forms of NKH, detecting the condition early and beginning proper treatment may help prevent or delay some of the severe health outcomes associated with the condition. It is important to remember that every child diagnosed with NKH is affected differently.

IN TERMS OF MEDICAL DEFINITION
Hyperosmolar hyperglycemic state (HHS) is 1 of 2 serious metabolic derangements that occurs in patients with diabetes mellitus (DM) and can be a life-threatening emergency. [1] It is less common than the other acute complication of diabetes, diabetic ketoacidosis (DKA). HHS was previously termed hyperosmolar hyperglycemic nonketotic coma (HHNC); however, the terminology was changed because coma is found in fewer than 20% of patients with HHS. HHS most commonly occurs in patients with type 2 DM who have some concomitant illness that leads to reduced fluid intake. Infection is the most common preceding illness, but many other conditions can cause altered mentation, dehydration, or both. Once HHS has developed, it may be difficult to differentiate it from the antecedent illness. The concomitant illness may not be identifiable. ( Etiology.) HHS has also been reported in patients with type 1 DM, in whom DKA is more common. HHS usually presents in older patients with type 2 DM and carries a higher mortality than DKA, estimated at approximately 10-20%. (See Epidemiology.) HHS is characterized by hyperglycemia, hyperosmolarity, and dehydration without significant ketoacidosis. Most patients present with severe dehydration and focal or global neurologic deficits. In as many as one third of cases, the clinical features of HHS and DKA overlap and are observed simultaneously ; this suggests that these 2 states of uncontrolled DM differ only with respect to the magnitude of dehydration and the severity of acidosis. According to the consensus statement published by the American Diabetes Association, diagnostic features of HHS may include the following: Plasma glucose level of 600 mg/dL or greater Effective serum osmolality of 320 mOsm/kg or greater Profound dehydration, up to an average of 9L Serum pH greater than 7.30 Bicarbonate concentration greater than 15 mEq/L Small ketonuria and absent-to-low ketonemia Some alteration in consciousness Detection and treatment of an underlying illness are critical. Standard care for dehydration and altered mental status is appropriate, including airway management, intravenous (IV) access, crystalloid administration, and any medications routinely given to coma patients. Although many patients with HHS respond to fluids alone, IV insulin in dosages similar to those used in DKA can facilitate correction of hyperglycemia. Insulin used without concomitant vigorous fluid replacement increases the risk of shock.

IN TERMS OF METABOLIC PATHWAY
HHS is characterized by extreme elevations in serum glucose concentrations and hyperosmolality without significant ketosis. These metabolic derangements result from synergistic factors including insulin deficiency and increased levels of counterregulatory hormones (glucagon, catecholamines, cortisol, and growth hormone). Hyperglycemia develops because of an increased gluconeogenesis and accelerated conversion of glycogen to glucose (glycogenolysis) and by inadequate use of glucose by peripheral tissues, primarily muscle. From the quantitative standpoint, increased hepatic glucose production represents the major pathogenic disturbance responsible for hyperglycemia in DKA. As the glucose concentration and osmolality of extracellular fluid increase, an osmolar gradient is created that draws water out of the cells. Glomerular filtration is initially increased, which leads to glucosuria and osmotic diuresis. The initial glucosuria prevents the development of severe hyperglycemia as long as the glomerular filtration rate is normal. However, with continued osmotic diuresis, hypovolemia eventually occurs, which leads to a progressive decline in glomerular filtration rate and worsening hyperglycemia.

Pathogenesis of HHS. Higher hepatic and circulating insulin concentration as well as lower glucagon are present in HHS compared with patients with ketoacidosis. The higher circulating ratio of insulin/glucagon in patients with HHS prevents ketogenesis and the development of ketoacidosis. This concept is supported by clinical studies both in animals and in humans, which have shown that the half-maximal concentration of insulin for antilipolysis is lower than for glucose use by peripheral tissues. Finally, a direct role of hyperosmolarity by inhibiting lipolysis and free fatty acid release from adipose tissue has been shown in experimental animals.

Severe hyperglycemia is associated with a severe inflammatory state characterized by an elevation of proinflammatory cytokines (tumor necrosis factor-α, interleukin (IL)β, IL6, and IL8) and reactive oxygen species, with insulin secretion and action. Hyperglycemia causes an increase in oxidative stress markers such as membrane lipid peroxidation. The degree of lipid peroxidation is directly proportional to the glucose concentrations in diabetic patients. This is thought to occur via several well-studied mechanisms, including increased polyol pathway flux, increased intracellular formation of advanced glycation end products, activation of protein kinase C, or overproduction of superoxide by the mitochondrial electron transport chain. By interest, elevations of circulating proinflammatory cytokines are reduced to normal levels promptly in response to insulin therapy and normalization of blood glucose concentration.

Warning Signs
Blood sugar level over 600 mg/dl Dry, parched mouth Extreme thirst (although this may gradually disappear) Warm, dry skin that does not sweat High fever (over 101 degrees Fahrenheit, for example) Sleepiness or confusion Loss of vision Hallucinations (seeing or hearing things that are not there) Weakness on one side of the body

How to Avoid It
HHNS only occurs when diabetes is uncontrolled. The best way to avoid HHNS is to check your blood sugar regularly. Many people check their blood sugar several times a day, such as before or after meals. Talk with your health care team about when to check and what the numbers mean. You should also talk with your health care team about your target blood sugar range and when to call if your blood sugars are too high, or too low and not in your target range. When you are sick, you will check your blood sugar more often, and drink a glass of liquid (alcohol-free and caffeine-free) every hour. Work with your team to develop your own sick day plan.

Diagnosis
The major differential diagnosis is diabetic ketoacidosis (DKA). In contrast to DKA, serum glucose levels in HHS are extremely high, usually greater than 40-50 mmol/L, but an anion-gap metabolic acidosis is absent or mild. Delirium is also more common in HHS than DKA. Although traditionally DKA has been associated with Type I Diabetes, whereas HHS has been associated with Type II, HHS can be seen in patients of both types. HHS also tends to have an elderly preponderance.

Cranial imaging is not used for diagnosis of this condition. However, if MRI is performed, it may show cortical restricted diffusion with unusual characteristics of reversible T2 hypointensity in the subcortical white matter.[4]

Pathophysiology
Nonketotic coma is usually precipitated by an infection,[5] myocardial infarction, stroke or another acute illness. A relative insulin deficiency leads to a serum glucose that is usually higher than 33 mmol/L (600 mg/dL), and a resulting serum osmolarity that is greater than 320 mOsm. This leads to excessive urination (more specifically an osmotic diuresis), which, in turn, leads to volume depletion and hemoconcentration that causes a further increase in blood glucose level. Ketosis is absent because the presence of some insulin inhibits hormone-sensitive lipase mediated fat tissue breakdown.

Intravenous fluids
Treatment of HHS begins with reestablishing tissue perfusion using intravenous fluids. People with HHS can be dehydrated by 8 to 12 liters. Attempts to correct this usually take place over 24 hours with initial rates of normal saline often in the range of 1 L/h for the first few hours or until the condition stabilizes.[6]

Electrolyte replacement
Severe potassium deficits often occur in HHS. They usually range around 350 mEq in a 70 kg person. This is generally replaced at a rate 10 mEq per hour as long as there is urinary output.[7]

Insulin
Insulin is given to reduce blood glucose concentration; however, as it also causes the movement of potassium into cells, serum potassium levels must be sufficiently high or dangerously low blood potassium levels may result. Once potassium levels have been verified to be greater than 3.3 mEq/l, then an insulin infusion of 0.1 units/kg/hr is started.[8]