Most commonly associated with diabetes mellitus but also occurs in patients with renal insufficiency, liver disease, malnutrition, congestive heart failure, sepsis or cancer.

National Institute of Health statistics show that 2% to 4% of all deaths in diabetics are from hypoglycemia.

In addition to the deaths, diabetic hypoglycemic periods of severe low blood sugar can also cause permanent brain damage.

Can be seen with  several systemic diseases: sepsis, malnourished state, anorexia nervosa, liver failure, kidney failure, congestive heart failure, adrenal insufficiency or disorders of carbohydrate metabolism.

Symptoms are nonspecific and low glucose levels can be found in asymptomatic patients.

Glucose use in the brain is primarily insulin independent.

The brain cannot synthesize or store glucose.

Hypoglycemia is associated with significant morbidity including impaired cognition function, higher risk of dementia, stroke, and death.

Hypoglycemia can impair concentration ability, and reaction time, placing an individual and others at risk in situations where these abilities are important.

Severe hypoglycemia can cause seizures, may be life-threatening, or cause death. 

Hypoglycemia can impair concentration ability and reaction time, or can cause seizures, be life-threatening, or cause death. 

The body has several mechanisms to prevent hypoglycemia including: hormonal and neural signaling pathways that ensure glucose availability from intake, hepatic and renal gluconeogenesis, and hepatic glycogenolysis.

In the context of systemic diseases, some of the above pathways may be dysfunctional or impaired such that normal competent processes are overwhelmed and hypoglycemia occurs.

Patients with complex health problems, limited life expectancy, advanced age are unlikely to benefit from tight glycemic control and are more likely to be harmed by it compared with younger, healthier individuals.

Measurement of beta-cell polypeptide levels at the time of hypoglycemia is the best test to diagnose the cause of .hypoglycemia.

The brain accounts for approximately 60% of the total basal glucose consumption, and because of it’s limited glycogen reserves the symptoms of hypoglycemia are primarily neurologic in origin.

Whipple’s triad include symptoms of hypoglycemia, low blood glucose level at the time of symptoms, and resolution of symptoms at the correction of hypoglycemia is the first step in the diagnosis of significant hypoglycemia.

Uncommonly, cancer can be complicated by non- islet cell tumor hypoglycemia as a paraneoplastic syndrome resulting in overproduction of insulin like growth factor II which stimulates the insulin receptor: this complication is seen with large, clinically obvious tumors such as mesenchymal tumors, fibromas, adenocarcinomas or hepatocellular carcinomas.

Hypoglycemia can be due to ingestion of drugs or toxins, and in heavy alcohol use in persons with poor nutritional status or impaired liver function due to hepatic glycogen depletion.

Factors which may increase the risk of hypoglycemia include changes in meal pattern,  changes in level of physical activity, or changes to co-administered medication.

Black patients with diabetes, have a 1.7 higher rate of severe hypoglycemia versus white patients.

Patients with renal or hepatic impairment may be at higher risk of hypoglycemia

Medications associated with hypoglycemia include: fluoroquinolones, quinine, beta blockers, angiotensin converting enzyme inhibitors, herbal products contaminated with sulfonylureas and glyburide, sulfonylureas, insulin and insulin secretagogues.

Hypoglycemic symptoms are described as autonomic or neuroglycopenic.

Accidental hypoglycemia can be induced with an unintentional use of a diabetic medicine or medication errors or contamination.

Hypoglycemia can happen suddenly and symptoms may differ across individuals and change over time in the same individual.

Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using certain medications,  or in patients who experience recurrent hypoglycemia. 

Patients may have factitious hypoglycemia or an underlying psychiatric disorder, or may have a malicious hypoglycemia.

Causes of hypoglycemia includes increased endogenous insulin production with noninsulinoms pancreatogenous hypoglycemia syndrome, insulin autoimmune hypoglycemia and insulinomas.

Autonomic symptoms include paresthesias, dizziness, anxiety, sweating, and tremulousness.

Most hypoglycemic symptoms reported occur in the fasting state. accounting for 73 % of such episodes, while 21% are reported in the fasting or postprandial state, and 6% occur in the postprandial period only.

Neuroglycopenic symptoms include drowsiness, fatigue, impaired concentration ability, confusion, amnesia, difficulty speaking, abnormal behavior, and unresponsiveness.

Patients with hypoglycemia are generally more aware of the autonomic symptoms than neuroglycopenic processes.

The annual mortality rate of patients with insulin induced hypoglycemia, estimated between three and six percent.

Hypoglycemia in elderly patients with diabetes increases the risk of cardiovascular and cerebrovascular event, is associated and progression of dementia,increases the risk for falls, emergency department visits and hospitalization.

Of all medications, insulin and oral hypoglycemic agents are the second most common cause of the emergency department visits and hospitalization.

Sulfonylureas associated with hypoglycemia, and this problem is enhanced by the use of concomitant amntibiotics such as clarithromycin levofloxacin, sulfamethoxazole-trimethoprim, metronidazole, and ciprofloxacin.

Adding sulfonylureas to metformin greatly increases the risk of hypoglycemia in type II diabetes.

Insulin the second most common medication associated with adverse drug events reported to the FDA.

Glucagon, cortisol, epinephrine, and growth hormone are key hormones that are normally secreted to increase serum glucose levels as a protective mechanism against hypoglycemia.

The prevalence and trends of severe hypoglycemia are unknown in the US, but comorbid medical and mental health conditions are highly prevalent among persons older than 65 yearsand could affect the risk of hypoglycemia.

Episodes are common in older adults with poor glycemic control (Munshi MN et al).

A 72 hour fast re-creates the environment in which symptomatic hypoglycemia is likely to occur and is a test of choice to investigate hypoglycemia if Whipple Triad has not been demonstrable or there is uncertainty regarding the cause of hypoglycemia.

Hypoglycemia unawareness and the risk of subsequent hypoglycemia are highest among those who have had hypoglycemia most frequently in the past.

Long acting insulin analogues cannot be modulated following injection to provide greater insulin delivery in the pre-breakfast hours, in order to counter the increase in blood glucose levels at that time of day ( dawn phenomenon).

Errors in estimating the size and composition of meals, and the timing and magnitude of preprandial insulin dose may cause excessive hyperglycemia or late hypoglycemia.

The mortality rate associated with hypoglycemia events in type one diabetes is estimated to be as high as 10%(Skrivarhuag T et al).

In the above study 65% patients with a hemoglobin A1c of 8% or greater experienced one or more hypoglycemic episodes in a 3 day period, and 12 of the 26 patients with hypoglycemia experienced at least one episode of severe hypoglycemia with blood sugar levels less than 50 mg/dL.

Fingerstick glucose testing 4 times a day does not coincide with continuous glucose monitoring detected hypoglycemia (Munshi MN et al).

Continuous glucose monitoring systems often used by diabetics for monitoring are imprecise, particularly at levels lower than 70 mg/dL, and have limited usefulness in the diagnosis of hypoglycemic disorders.

Continuous glucose monitoring devices measure glucose levels in the interstitial fluid, and there is a time lag between decreases in venous blood glucose levels and a change in interstitial fluid glucose values limiting the utility of such monitoring for hypoglycemia.

Erratic absorption and action of subcutaneous injected insulin leads to unpredictable swings in glucose levels and is associated with hypoglycemia.

Occurs in about 25% of patients with type I diabetes, characterized by loss of autonomic warning symptoms before development of neuroglycopenia.

Unawareness of hypoglycemia associated with a sevenfold increase in the frequency of severe hypoglycemia.

Episodes are difficult to diagnose in the elderly and are easily missed by intermittent finger stick measurements.

Large studies have shown lack of benefit and sometimes higher risk of morbidity and mortality with tight glycemic control, especially in the elderly (Skyler JS et al).

Glycemic targets should be relaxed for patients with advanced age, high risk of hypoglycemia and short life expectancy.

Patients with type I diabetes experience progressive reduction in the plasma catecholamine response to hypoglycemia.

Cases of postgastric bypass hypoglycemia due the excess formation of new beta cells from pancreatic duct stem cells have been reported.

In a study of 1604 patients (Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation) admitted to an ICU for critical illness undergoing randomization to intensive glucose control vs. conventional glucose control (target of 180 mg or less per deciliter) with a primary endpoint of death from any cause within 90 days of randomization: severe hypoglycemia occurred in the intensive group 6.8% of cases and in 0.5% of cases in the conventional group, no significant difference in the groups in median days in the ICU, or hospital, or median number of days on mechanical ventilation or renal replacement therapy, 27.5% in the intensive group died and 24.9% in the conventional group died (NICE-SUGAR study).

Conclusion of the NICE-SUGAR study is that intensive glucose control increased mortality among adult patients in the ICU-hypoglycemia presumably the cause.

A low beta hydroxybutyrate level and glucose response of more than 25 mg/dL following the administration of 1 mg of glucagon at the time of hypoglycemia supports an insulin mediated process with adequate glycogen reserve.

Insulin related hypoglycemia and errors are highest in patients 80 years of age or older.

The risks of hypoglycemic sequelae in the elderly should be considered in treatment decisions and intensity of insulin therapy.

There is an estimated 97648 emergency department visits for insulin related hypoglycemic events annually (Geller Ai et al).

About one third of the emergency department visits for insulin related hypoglycemic events result in hospitalization.

American Geriatrics Society Choosing Wisely initiative advises against diabetic medications other than Metformin to achieve a hemoglobin A-1 C level of 7.5% in most older patients because of the risk of hypoglycemia and other harms, including mortality.

Intensive glucose lowering therapy particularly among vulnerable complex adults, especially the elderly, should be discouraged because it may lead to hypoglycemic episodes.

Glucose tablets, glucagon auto-injectors, and devices for intranasal administration or available for management.

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