Most Effective Hypoglycemia Treatment

Guide To Beating Hypoglycemia

Here's Just A Tiny Glimpse Of The Topics Covered: The 3 main types of hypoglycemia and which type you're most likely suffering from. How snacking on chocolate bars can actually make you Fat and worsen your condition! (If you thought those delicious dark brown bars were great energy- boosters.think again!) The No. 1 question most folks have when it comes to hypoglycemia and hyperglycemia. Why you should insist on a 6-hour Gtt and not a 5-hour one. ( Why it might not be a good idea to consult a doctor to confirm your hypoglycemia. Aside from taking a Gtt, what other methods can you use to determine whether or not you're suffering from this condition? Well, refer Chapter 4, Pgs. 23-26 to take a revealing 67-question test especially designed to find out if you've got the symptoms. An inspiring motivational exercise that will help you effectively banish all of your negative thoughts that prevent you from having peace of mind. 2 good reasons why you should keep a food journal. 3 powerful nutrients that limit the effect of glucose on your blood sugar level. This is vital to a hypoglycemic as it helps slow down the absorption of sugar in the food. The secret impulse that literally forces you to say 'yes' to a candy bar or chocolate whenever you feel the hunger pangs gnawing at you. 2 ingredients that are lethal to a hypoglycemic. 'Hidden sugars' you must know to avoid buying products that can easily worsen your condition. 8 essential rules of food planning that are crucial to your speedy recovery from hypoglycemia. Leave out one of them and it could hurt your chances of recovering. How to create a healthy food plan that's suitable for both vegetarian and non- vegetarian hypoglycemics. Most food plans only focus on non-vegetarians, but this one works great for everybody! Read more...

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Clinical hypoglycemia

Although low serum glucose can be caused by excessive glucose loss or use, hypoglycemia is most commonly the result of liver glucose production that is inadequate for the rate of glucose utilization. This may be due to regulatory, enzyme, or substrate effects. The clinical syndromes are commonly divided into postabsorptive (fasting) and postprandial (reactive) hypoglycemia. Reactive hypoglycemia is uncommon and may follow gastric surgery. Rarely, it is due to inborn enzyme defects. Idiopathic or functional hypoglycemia is a controversial syndrome. If it exists, it is certainly rare. Most patients encountered clinically have postabsorptive hypoglycemia. Drugs or organ failure are the most common causes in the hospital or emergency room patient.

Evaluate for Underlying Cause of Hypoglycemia If laboratory

The 3-year-old child has ketotic hypoglycemia. (For further discussion, see Teaching Pearl Answer, below.) VII. Teaching Pearl Question What is the most common cause of hypoglycemia in children, and how is it treated VIII. Teaching Pearl Answer Ketotic hypoglycemia is the most common cause of hypoglycemia in children. Immediate treatment consists of the administration of glucose (oral glucose if patient can be aroused and airway is intact). Children with this condition are instructed to avoid fasting, especially during times of intercurrent illness, and to have frequent carbohydrate-rich meals.

Posthypoglycemic coma

Prolonged hypoglycemia, particularly in association with hypoxemia and hypotension, leads to cerebral edema. Recovery may be delayed despite the attainment of normoglycemia, a condition historically termed 'irreversible hypoglycemic coma' but better described as 'post-hypoglycemic coma'. The delay probably reflects the severity of underlying brain damage. In addition to the measures outlined above to restore normoglycemia, additional interventions to reduce cerebral swelling are required, such as head elevation, hyperventilation, high-dose steroids (dexamethasone 8 mg every 6 h), diuretics, and mannitol (0.5-1 g kg). The prognosis for patients with this condition is varied, with outcomes ranging from complete recovery to persistent vegetative state and death (Z-16 per cent). The only prognostic factor is the duration of coma before attempts at correction.

Hypoglycemia

Since the thiazolidinediones work independently of the pancreas, and typically reduce insulin levels in patients with type 2 diabetes, there is very little, if any, clinical risk of hypoglycemia with these agents. However, when circulating insulin levels are increased, such as in patients taking a sulfonylurea or insulin, the addition or pioglitazone or rosiglitazone may result in hypo-glycemia. This is usually apparent after four or more weeks of therapy, since it takes few months for the full clinical effect of the thiazolidine-diones to be manifest in most patients. Under these circumstances, the sulfonylurea or insulin dose should be reduced and therapy with the thiazolidinedione continued.

Influence of products of the immune system on the central nervous system

The immune system affects brain and behaviour, especially via the effects of immune cytokines on the central nervous system.(42) Although cytokines are relatively large molecules, some, particularly IL-1, can cross the blood-brain barrier via active transport. IL-1 is also produced in the brain by both microglia, which are macrophages resident in the central nervous system, and astrocytes. Peripheral IL-1 can affect the brain, including its production of cytokines, via stimulation of the vagus afferent fibres. There are cytokine receptors in the brain, including those for IL-1, IL-8, and interferon, on both glial cells and neurones. Cytokines play a role in the development and regeneration of myelin-producing oligodendrocytes. Brain cytokines play a role in immune effector mechanisms as regulated by the brain, including a role in brain infection and inflammation. Cytokines are relevant to the progression of multiple sclerosis, gliomas, HIV-associated dementia, brain injury, and...

Pharmacological Actions

The glycogenolytic and lipolytic actions of endogenous catecholamines are mediated by p-receptors and are subject to blockade by p-blockers. This metabolic antagonism exerted by the p-blockers is particularly pronounced if the levels of circulating catecholamines have been increased reflexively in response to hypoglycemia. Other physiological changes induced by hy-poglycemia, such as tachycardia, may be blunted by p-blockers. These agents therefore must be used with caution in patients susceptible to hypoglycemia (e.g., diabetics treated with insulin). Because the metabolic responses to catecholamines are mediated by p2-receptors and possibly by p3-receptors, p1-selective antagonists such as metoprolol and atenolol may be better choices whenever p-blocker therapy is indicated for a patient who has hypoglycemia.

Adverse Effects and Contraindications

P-Blockers potentiate hypoglycemia by antagonizing the catecholamine-induced mobilization of glycogen. The use of p-blockers in hypoglycemic patients is therefore dangerous and must be undertaken with caution. If p-blocker therapy is required, a cardioselective p-blocker is preferred.

Clinical Effects of Low Glycemic Index Approaches

Furthermore, use of acarbose in patients with diabetes in the context of the UK Prospective Diabetes Study, improved glucose control, expressed as reduced HbAlc, to a degree similar to that achieved by current hypoglycemic therapy (e.g. metformin and sulfonylurea) 19 . Finally, in the STOP-NIDDM trial subjects with impaired glucose tolerance who received 100 mg acarbose three times daily showed a significantly reduced rate of conversion to diabetes versus the control group 20 .

With Type 1 Diabetes Mellitus

Currently, the prevalence of Type 1 diabetes in the United States is estimated to be 1,000,000 individuals, and 30,000 new cases are diagnosed each year. Presently there is no practical mechanical insulin-delivery method coupled with an effective glucose-sensory device that could replace the function of the impaired cells to administer insulin with a degree of control to produce a near constant euglycemic state without risk of hypoglycemia. Therefore, persons with Type 1 diabetes are resigned to manually regulate blood glucose levels by subcutaneous insulin injection, and as a consequence, typically exhibit wide deviations of plasma glucose levels from hour to hour and from day to day. Since hypoglycemia is intolerable, glucose control must error on the high side and patients live with relative chronic hyperglycemia as evidenced by elevated HgbA1c levels. Hyperglycemia is the most important factor in the development and progression of the secondary complications of diabetes. These...

Angiotensinconverting Enzyme Inhibitors

The benefits of the use of p-blockade appear to exceed by far the risks of bronchospasm in patients diagnosed with chronic obstructive pulmonary disease (COPD) and or suppression of hypoglycemic responses in diabetics. COPD is very different from bronchospas-tic asthma. Young people with asthma have highly reactive airways and can die within hours of a broncho-spasm in response to an exposure to an external agent. This highly reversible dynamic condition contrasts sharply with the destruction of connective tissue in lung parenchyma and dead airway sacs that are not very reactive. This is a very different phenomenon.

Drug Interactions

Unlike quinidine, disopyramide does not increase the plasma concentration of digoxin in patients receiving a maintenance dose of the cardiac glycoside. Hypoglycemia has been reported with the use of disopyramide, particularly in conjunction with moderate or excessive alcohol intake.

Human growth hormone in critical illness

Human growth hormone is stimulated by the hypoglycemic state and also by exercise, sleep, high protein intake, and increased levels of leucine and arginine. Human growth hormone secretion is inhibited by long-term glucocorticoid administration and plasma free fatty acids (plasma free fatty acids are increased by epinephrine and glucagon). It is thought to exert its effects partially by direct action on tissues and partially through stimulation of the liver to produce insulin-like growth factor I, a 70-amino-acid chain.

Urgent corrective measures

Hypoglycemia can be catastrophic to the central nervous system, with the degree of injury determined by the length of time and level of the low blood glucose ( Malouf be much lower than that estimated by fingerstick methods. However, a fingerstick glucose reading below 4.0 mmol l should prompt urgent replacement of glucose. A dose of 50 ml of 50 per cent glucose in water should be given immediately to any patient with coma of unknown etiology. This will have no detrimental effect on other causes of coma (except Wernicke's encephalopathy which is discussed below). Even in the case of coma produced by hyperglycemic states, the marginal increase in total body glucose will not adversely affect treatment or generate central nervous system damage. In the case of hypoglycemia, glucose replacement may produce rapid reversal of unconsciousness.

Chapter References

Levy, D.E., et al. (1985) Predicting outcome from hypoxic-ischemic coma. Journal of the American Medical Association, 253, 1420-6. Malouf, R. and Brust, J.C. (1985). Hypoglycemia causes, neurological manifestations and outcome. Annals of Neurology, 17, 421-30. Young, G.B., et al. (1990). The encephalopathy associated with septic illness. Clinical Investigations in Medicine, 13, 294-304.

Pharmacological agents

A number of pharmacological agents may interfere with the ability of the kidney to excrete free water. These include large numbers of sedatives, hypnotics, oral hypoglycemic agents, tranquilizers, narcotics, antidepressants, and diuretics. In most such instances, there is excessive net retention of ingested or infused free water. The diuretics most commonly asociated with hyponatremia are thiazides and loop diuretics. In patients with thiazide-associated hyponatremia, there is often an idiosyncratic reaction to the drug in addition to polydipsia and a substantial loss of sodium and potassium in the urine.

Glucoseinsulin infusions

Insulin promotes potassium entry into cells by mechanisms separate from glucose entry glucose is also required to prevent hypoglycemia. There is no general agreement on the dose to be used. Commonly used prescriptions include 15 units of soluble insulin in 50 ml of 50 per cent glucose given centrally over 20 to 30 min, and 15 to 20 units of insulin in 500 ml of 10 or 20 per cent glucose over 30 to 60 min. All methods will reduce plasma potassium by approximately 1 mmol l over a period of 30 to 60 min and will usually maintain potassium at the lower level for 3 to 6 h, after which the treatment may be repeated. This may be sufficient to maintain plasma potassium levels at acceptable levels, but is usually inadequate in hypercatabolic patients and those with established renal failure in such cases it will buy time for definitive treatment.

Laboratory Data

Basic metabolic panel, glucose, calcium. Electrolyte abnormalities (hypernatremia, hyponatremia, hypocalcemia) and hypoglycemia or hyperglycemia can present with headache. Metabolic acidosis may be seen with underlying metabolic disorder or intoxication respiratory acidosis is seen in other intoxications (alcohol, benzodiazepines, and barbiturates).

Diagnosis and clinical presentation

A blood glucose measurement is part of the initial investigation of any patient presenting with disorientation or coma. Diagnosis is made by the measurement of blood glucose using arterialized capillary blood from a fingerprick. Whole-blood glucose measured in this way will be 10 to 15 per cent lower than corresponding plasma samples. If hypoglycemia is found, blood should be drawn for plasma glucose in a fluoride or oxalate tube, together with plasma insulin, C peptide, and cortisol. To assist future diagnosis, samples should be taken before treatment is initiated. A low ratio of C peptide to insulin suggests exogenous insulin administration, whereas a normal ratio suggests an endogenous source of insulin. Given the wide range of 'normal' blood glucose values, diagnosis of pathological hypoglycemia depends on the clinical recovery from neuroglycopenic symptoms after an intravenous infusion of glucose. Patients with hypoglycemia will usually present to critical care in one of the...

Other pharmacological options

In some circumstances the hypoglycemic stimulus is so powerful that an infusion of glucose alone is insufficient to restore normoglycemia. This can occur with insulin-secreting tumors. Additional therapeutic measures in these circumstances are aimed at reducing endogenous insulin production and promoting gluconeogenesis. Somatostatin and its longer-acting analog octreotide are often used for resistant hypoglycemia caused by insulinoma. However, these drugs have variable effects on gut hormone release and can cause a fall in blood glucose in some patients. Their use should be closely monitored with serial blood glucose measurements. Glucocorticoids bind to intracellular receptors and alter protein and receptor synthesis to exert their multiple pharmacodynamic effects, of which stimulation of gluconeogenesis, muscle catabolism, and lipolysis all act to increase blood glucose. Intravenous administration of hydrocortisone 100 mg every 6 h is a useful adjunct that may help in resistant...

Thiamine and Wernickes encephalopathy

Caution should be exercised in the correction of hypoglycemia in the malnourished. Thiamine deficiency will be accelerated if circulating glucose substrate is rapidly restored, causing acute and potentially fatal Wernicke's encephalopathy. This devastating syndrome is often misdiagnosed as brainstem stroke and results from cellular necrosis in structures surrounding the fourth ventricle, with the sudden onset of symptoms which include ocular palsies, ataxia, and mental confusion. Thiamine will dramatically reverse the early symptoms of Wernicke's encephalopathy, often within a few hours, but the probability of permanent dysfunction increases with the delay in administration. For this reason, supplementary thiamine 50 mg intramuscularly is usually given prior to glucagon or glucose administration if there is any doubt concerning the nutritional status of the patient. Some emergency protocols mandate the use of thiamine as part of the initial management of coma, given its lack of...

Impaired renal water excretion

Mineralocorticoid deficiency impairs water excretion by mechanisms activated by a decrease in effective circulating volume. These include non-osmotic stimulation of ADH secretion and impaired renal free water generation owing to reduced distal fluid delivery in the kidneys. However, glucocorticoid deficiency is usually of primary importance, as cortisol replacement rapidly increases the rate of water excretion and raises the plasma sodium concentration to normal. Plasma levels of ADH are usually inappropriately elevated in glucosteroid-deficient patients and return to normal upon glucocorticoid replacement. Persistent ADH secretion in patients with glucocorticoid deficiency is probably due to a loss of hypotonic suppression of ADH release owing to glucocorticoid deficiency per se, which is aggravated secondarily by multiple non-osmotic stimuli such as nausea and hypoglycemia. Both sodium loss by mineralocorticoid deficiency and ADH-related retention of free water contribute to the...

Clinical features

Respiratory alkalosis, metabolic acidosis, ketosis, hypoglycemia, and hyperglycemia may all occur. The biochemical pattern of a respiratory alkalosis together with metabolic acidosis is characteristic of salicylate poisoning. The patient usually presents with a combined respiratory alkalosis and metabolic acidosis, with a blood pH in the range 7.40 to 7.46. Later, as metabolic compensation fails, the arterial pH may fall below 7.40. The most important clinical signs of serious toxicity are a falling plasma pH, hypoxemia, and the development of pulmonary edema. Confusion and depressed consciousness are serious signs, usually indicating that salicylate has entered the central nervous system. These symptoms may be improved by correction of metabolic acidosis. The likelihood of respiratory alkalosis increases with age until 12 years, when the adult picture of respiratory alkalosis followed by metabolic acidosis occurs. The underlying mechanisms for these age-dependent differences in...

Clinical course of acetaminophen overdose

There is often a profound metabolic disturbance with hypophosphatemia, hypoglycemia, and a metabolic acidosis. Hypoglycemia can occur within the first 24 h after overdose as a result of decreased gluconeogenesis and glycogen mobilization as well as an increased insulin concentration. The metabolic acidosis can occur early within the first 12 h owing to a derangement in hepatic lactate metabolism. Over subsequent hours, this worsens because of a further reduction in hepatic lactate clearance and an increased peripheral lactate generation due to tissue hypoxia. Hypovolemia is often profound, secondary to vomiting and vasodilatation, and worsens the tissue hypoxia and peripheral lactate generation.

Diagnosis and assessment

Consistent findings are bradycardia and hypotension. The degree of hypotension reflects the severity of toxicity bradycardia is not useful in assessing toxicity as it occurs at therapeutic levels. Tachycardia has been reported with partial agonists such as pindolol. Progressive pulmonary edema and bronchospasm are uncommon unless there is pre-existing cardiac or respiratory disease. Effects on the central nervous system are unusual with hydrophilic agents such as atenolol. When present, coma and respiratory depression are poor prognostic features and are always accompanied by severe cardiovascular depression. Coma without cardiovascular depression suggests that other substances have been ingested. Although convulsions are seen as part of the central effect, they may also be caused by hypoglycemia.

Modulation Of Excitotoxic Cell Death By Neuroactive Steroids

Regardless of endogenous levels, steroids that inhibit NMDA receptor function might provide novel therapeutic treatments for CNS trauma, stroke, and neurodegenerative diseases. Prolonged exposure of neurons to glutamate induces delayed, Ca2+ dependent cell death. Specific blockade of NMDA receptors is sufficient to attenuate most of the neuronal death that develops after in vivo ischemia, hypoglycemia, in vitro hypoxia, or exposure to NMDA or glutamate (104-108). NMDA-gated channels have been shown to be permeable to Ca2+ (109). It has, therefore, been proposed that NMDA receptors play an important role in glutamate excitotoxicity by increasing Ca2+ influx. There is a strong correlation of the effects of neuroactive steroids on NMDA-induced Ca2+ accumulation by neurons (20,21) with modulation of the NMDA induced membrane current (Fig. 4), indicating that neuroactive steroids can be expected to be effective in modulating NMDA-induced neuronal death.

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A GCS sum score of 8 or less without eye opening is coma. In patients with a history of brain injury, an impaired conscious level should not be attributed to metabolic disturbance (hypoglycemia), intoxication (alcohol, drug overdose), or hypothermia. Repetitive assessment of the GCS allows the clinician to evaluate the efficacy of management and to chart deterioration. The GCS sum score and in particular the GCS motor score have prognostic value ( Iable3).

Pancreas Transplantation

The incidence of insulin-dependent diabetes mellitus (IDDM) is approximately 0.5 , indicating that between 1 and 1.5 million people in the US have IDDM. Although subcutaneous injection of insulin is a well-established therapy, it does not result in normal glucose metabolism. Pancreas transplantation is indicated in patients with extremely labile IDDM despite complex insulin regimens and in patients with hypoglycemia unawareness, resulting in poor quality of life. In addition, patients with severe neuropathy, especially autonomic neuropathy, may benefit from pancreas transplantation. Pancreas transplantation should also be considered in patients who already require immunosuppression, most frequently because of a kidney transplant. After successful pancreas transplantation, there is total independence from exogenous insulin administration, and glucose levels should be normal although responses to oral and intravenous glucose administration may be slightly abnormal. Secondary...

Causes of hypothermia

Hypothermia can be precipitated by alteration of thermoregulatory mechanisms for example, alcoholic intoxication induces peripheral vasodilatation, decreases shivering capacity, depresses central thermoregulatory mechanisms, and impairs judgment. Alcoholics may stay outside for many hours wearing few clothes, either asleep or unconscious, in parks, on river banks, or in snow. Many drugs, such as tricyclic antidepressants, phenothiazines, or barbiturates, can lead to hypothermia either when used at toxic levels for self-poisoning or when administered in normal dose range for therapeutic purpose. Endocrine dysfunction, such as hypothyroidism, hypopituitarism, hypoglycemia, or diabetic ketoacidosis, may also result in hypothermia. Additional risk factors include central nervous system lesions (stroke, hemorrhage, trauma, tumor), spinal cord injuries, Parkinson's disease, Wernicke's encephalopathy, Alzheimer's disease, schizophrenia, anorexia nervosa, agenesis of the corpus callosum, or...

Management before hospital admission

Warm drinks, but not alcohol, can be given to the conscious patient with stable hemodynamic parameters. Humidified and warmed oxygen should be delivered by face mask. Endotracheal intubation for apnea or low respiratory rate (2-4 breaths min) should be performed without delaying hospital admission. Insertion of a catheter into a peripheral vein is difficult due to the intense venoconstriction, and central access may be necessary. Hypoglycemia should be suspected in a comatose person in whom hypothermia is obviously not due to an accident, and glucose should be administered intravenously.

Preparation for transport

Typed and cross-matched blood likely to be used in transit is checked, reserving 'universal donor' O-negative blood for life-threatening situations. Central venous catheters needed for some infusions (inotropes, total parenteral nutrition in extended missions) are placed. If parenteral nutrition is stopped, rebound hypoglycemia should be prevented by intravenous glucose 10 per cent.

Initial assessment of the patient with falciparum malaria

Pulmonary edema, hypoxia, or acidosis 10. hypoglycemia (glucose below 2.2 mmol l). Where neurological signs or coma are present, hypoglycemia should be immediately excluded since it is caused by both severe malaria and antimalarial drugs. Pregnant women are at particular risk. In the absence of these, the following factors indicate a potentially complicated case

Altered mental status

Occasionally, patients emerging from general anesthesia exhibit unusual mental reactions, ranging from lethargy to confusion and or aggressive physical behavior. These phenomena may occur quite suddenly, resulting in the potential for patient injury or disconnection from monitors, airways, and intravenous or arterial cannulas. While treatment is generally supportive, with symptoms usually resolving within 5 to 15 min from the time of onset, due care must be taken to protect and reassure the patient, while at the same time evaluating underlying causes. An adverse psychological response to emergence from general anesthesia is the most common cause of these reactions, but other factors, including premedication with long-acting sedatives, preoperative intoxication, or postoperative withdrawal, can also elicit bizarre emergence behavior. Anesthetic drugs such as ketamine can also cause postoperative dysphoria, although acute reactions are rare. When patient evaluation reveals that altered...

Maintenance of normoglycemia

The administration of glucose-containing solutions does not produce a significant increase in blood glucose, but may predispose patients to a worsened outcome. Therefore it seems prudent to withhold glucose-containing solutions from neurosurgical patients, except those in whom the onset of hypoglycemia may be rapid and have severe consequences such as diabetics. Hyperglycemia should be corrected prior to a likely ischemic event so as not to exacerbate it.

Differential Diagnosis A Seizures

Seizures have many etiologies, including cerebral malformations, hypoxia, head trauma, structural or destructive lesions (neoplasm, stroke, vascular anomalies), infections (meningitis or encephalitis), toxicity (lidocaine, theophylline, psychotropic agents, isoniazid, chemotherapeutic agents, cocaine, amphetamines, heroin, PCP, methanol, ethylene glycol, or carbon monoxide), metabolic alterations (hypo-glycemia, hyponatremia, hypocalcemia, or phenylketonuria), or degenerative disorders. Systemic disorders may be associated with seizures (tuberous sclerosis, neurofibromatosis, sickle cell anemia, or acute lymphocytic leukemia).

Glycogen Storage Diseases

Glycogen storage diseases include more than 10 genetic differences involving either enzymes or transporters. They are characterized as storing glycogen in abnormal quantity, location, or structure. Five types of glycogen storage disease have been described ( 53) type I (glucose-6-phosphatase deficiency), type II (acid a-glucoside deficiency), type III (amylo-1,6-glycosidase deficiency), type IV (branching enzyme deficiency), and type V (muscle phosphorylase deficiency), which was later expanded to at least seven types (type Vi, liver phosphorylase or phosphorylase B kinase deficiency type VII, muscle fructokinase deficiency). For details, consult the review by Hers (54). In types I, III, and VI, the liver cannot convert glycogen into glucose, causing hepatomegaly (enlarged liver), hypoglycemia, hypoinsulinism, hyperglucagonemia, hyperlipidemia, and growth retardation. In types V and VII (but also in type II and a subgroup of type VI), the muscle is affected and cannot provide...

Neurological Disorders and Neurodegenerative Diseases

Result in early onset of obesity, together with red hair color (suggesting a role for melanocortins in hair pigmentation in humans), and in deficiency of adrenal corticoid synthesis as a result of defective ACTH biosynthesis. A decrease in the activity of prohormone convertase 1 (PC 1 an important enzyme in POMC processing) has been reported in a woman with childhood obesity and a mutation of the PC 1 gene. This patient exhibited several endocrine abnormalities, including adrenal insufficiency, hypogonadotrophic hypogonadism, impaired glucose tolerance and reactive hypoglycemia, presumably due to impaired processing of POMC and proinsulin.

Diagnosis of Carbohydrate Intolerance

Oral Tolerance Tests and the Glycemic Index. Nutritionists use a form of oral tolerance test to assess the so-called glycemic potential of different foods. A carbohydrate load is ingested and the level of blood sugar is measured over a period of time. The increments in blood glucose are then compared with equivalent increments from different foods by normalizing these values to a baseline obtained with glucose, usually by using the area under the 2-h glucose curve after feeding a 50-g carbohydrate portion, and expressing it as a percentage of the mean obtained after 50 g of glucose. This normalized figure, designated the glycemic index of the food (61), enjoyed considerable popularity in the dietetic management of diabetes and hypoglycemia. However, there is a large scatter in glycemic index for each group of foodstuffs, attributed to many factors such as its form when eaten, the way it is processed, how it is chewed, how it is emptied from the stomach, and the physiologic and...

Aerosolized Pentamidine Rationale And Experimental Animal Studies

Pentamidine is an aromatic diamidine that was initially synthesized in the 1930s in a search for hypoglycemic agents. Because of its antiprotozoal activity, pentamidine has been used extensively for treatment and chemoprophylaxis of African trypanosomiasis. The exact mechanism of action of pentamidine is not known in vitro, it has been found to interfere with folate metabolism, anaerobic glycolysis, oxidative phosphorylation, and nucleic acid replication 1 . Pentamidine usually is given parenterally in a dose of 4mg kg day as the isethionate salt, the only preparation available in the United States 1 . Administration must be parenteral because gastrointestinal absorption is poor. Adverse reactions to pentamidine appear to be dose dependent, in that a 3-g total dose, which usually is reached in the second week of parenteral therapy, frequently causes toxicity 2 .

Sepsis and should be considered in all acutely sick neonates In

Most often caused by enzyme or cofactor deficiencies in the catabolism of branched chain amino acids (valine, leucine, and isoleucine). Organic acid and a positive gap acidosis develop from metabolites built up behind the enzymatic block. Other effects of metabolite excess include inhibition of enzymes of the urea cycle with secondary hyperammonemia. Many of these metabolites have direct CNS toxicity. Marrow suppression and altered glucose metabolism (hyperglycemia or hypoglycemia) also can occur as secondary effects.

Disorders Involving Energy Production

Patients classically present with enlarged liver and subsequent preprandial hypoglycemia and may manifest acute hypoglycemia with intercurrent illness or fast. Lactic acidosis from the chronic energy depletion state provides a source of energy for the brain, and often the hypoglycemia goes unnoticed until an illness occurs. Long-term sequelae can include liver adenomas, progressive renal insufficiency, and gout. 2. Fatty acid oxidation (FAO) defects. Involve enzymatic defects in fatty acid 0-oxidation. In fasting states, when glycogen stores are depleted, fats must be mobilized for energy production. If 0-oxidation is impaired, hypoglycemia develops with relative hypoketosis or aketosis. Metabolites are organic acids, with resultant positive gap acidosis, and may have a direct toxic effect on the CNS. Myopathy, cardiomyopathy, retinopathy, and other systemic manifestations can occur over time in some patients with FAO defects. 3. Primary lactic acidosis....

Radiographic and Other Studies

Essential in acute treatment of hypo-glycemia of any etiology. Ensuring a constant source of glucose until an appropriate diet can be established for FAO defects and glycogen storage disorders can prevent further hypoglycemic episodes. Providing an energy source to stop catabolism can prevent worsening of the clinical status in disorders involving protein metabolism (urea cycle disorders and organic acidemias). For neonates, 8-10 mg kg min, and for children, 6-8 mg kg min of IV dextrose is recommended. In organic acidemias, FAO defects, and primary urea cycle defects, a forced diuresis may help to rid the body of toxic metabolites, which are excreted in the kidneys. If a central line has not yet been established or in children with known metabolic disease presenting with acute exacerbations but without significant mental status changes, D10 at 2 times maintenance with appropriate electrolytes may suffice. This treatment is appropriate in all of the common...

Endocrine system

E The first step in the treatment of hypo-glycemia in a child is initiation of dextrose bolus followed by an infusion of 10 dextrose. All of these conditions are characterized either by the inability to release glycogen from the liver or depletion of glyco-gen from the liver, and therefore, glucagon is unlikely to be effective. (Rogers MC, et al. Textbook of Pediatric Intensive Care, 3rd Edition pp. 1273,1274 Kogut M. Gluck L, Kone T, Dodge P, eds. Current Problems in Pediatrics, Chicago Yearbook, 1974, p. 3.) 7. E The stimulus for the mechanisms which elevate blood glucose in the setting of hypoglycemia is primarily CNS hypoglycemia. The body's measures which help to remedy hypoglycemia are primarily the release of epinephrine and glucagon with their effects being additive. The neonate requires a considerable amount of glucose, especially in the perioperative period. There is a significant decline in glycogen storage within the liver within the first 3 postnatal hours. If...

Acute Encephalopathies

Although much of the damage inflicted by acute metabolic insults, such as hypoxia, hypoglycemia, and carbon monoxide poisoning, is on gray matter, secondary wallerian degeneration may correlate with clinical deficits. Thus, in an MR study of verbal memory deficits after carbon monoxide poisoning, these deficits were correlated with fornix atrophy at 6 months (Kesler et al., 2001). Considerable damage to white matter has been demonstrated pathologically in carbon monoxide poisoning (Dolinak et al., 2000a). In hypoxia occurring after cardiac arrest, diffuse axonal injury has also been described (Kaur et al., 1999 Lambri et al., 2001), and this can be distinguished from that resulting from trauma based on its distribution and the appearance of the damaged axons on APP immunostaining (Lambri et al., 2001 Dolinak et al., 2000a, 2000b). Severe hypoglycemia can also be associated with axonal injury, although in this condition, as well as in hypoxia, raised intracranial pressure can...

Somatostatin Analogue

Octreotide is useful in inhibiting the secretion of various autacoids and peptide hormones by metastatic carcinoid tumors (serotonin) and islet cell carcinomas of the pancreas (gastrin, glucagon, insulin, vasoactive intestinal peptide). The diarrhea and flushing associated with the carcinoid syndrome are improved in 70 to 80 of the patients treated with octreotide. Its side effects, which are usually mild, include nausea and pain at the injection site. Mild transient hypoglycemia or hyper-glycemia may result from alterations in insulin, glucagon, or growth hormone secretion.

Preoperative Preparation

When an operation is planned in advance, preparation of the transplant recipient does not differ substantially from other patients. Maintenance medications, especially the immunosuppressants, antihypertensives and cardiac drugs should be administered with a minimal volume of water. Diabetics should reduce the dose of long and intermediate acting insulin, usually by one half. If hypoglycemia occurs or the start of the operation is delayed, intravenous dextrose must be initiated. When bowel preparation is necessary, preoperative overnight hospital-ization to include intravenous fluids is important to avoid dehydration and the potential for intra- operative hypotension.

Contraindications And Drug Interactions

The oral contraceptives also may decrease the effectiveness of anticoagulants, anticonvulsants, tricyclic an-tidepressants, guanethidine, and hypoglycemic agents. The causes of such drug interactions include alterations in hepatic microsomal drug-metabolizing enzymes, competition for binding sites on plasma proteins, and enhanced excretion.

Provision of daily fluid requirement

Crystalloid fluids are used to provide the daily requirements of water and electrolytes. They should be administered to critically ill patients as a continuous background infusion to supplement fluids given during feeding or to carry drugs. For those who are not taking any nutritional fluid, the total body fluid requirement is usually provided as crystalloid. Higher-concentration glucose infusions may be used to prevent hypoglycemia.

Hyaline Replacement Amyloid of Islets of Langerhans

After total or partial gastrectomy, dumping syndrome followed by secondary hypoglycemia may occur. Early dumping syndrome is due to the rapid passage of ingested food, which causes distension of the jejunum. The rapid absorption of carbohydrate produces marked hyperglycemia, an excessive stimulus 28 that causes the islets to became hyperactive, and this, finally, results in their hyalinization.

Measures to Assure Metabolic Control Self BloodGlucose Monitoring

Since incretin mimetics will be used at fairly standardized doses (vide supra), and not based on individual titration (like in the case of insulin), and since incretin mimetics alone do not provoke hypoglycemic episodes, there will be a rather limited need for blood-glucose self-control in addition to regular determinations of HbA1c. The frequency of glucose control will primarily depend on other antidiabetic agents used in combination and their potential to elicit hypo-glycemia. Certainly, in comparison with any insulin regimen, the requirement for blood glucose-self control will be much smaller. This could affect the acceptability of such treatment regimens to patients and on the overall cost-benefit relationship. DPP-4 inhibitors, in their most likely use, in combination with metformin, do not require additional measures of blood-glucose self-control, since they are administered at a standard dosage and do not provoke hypoglycemia. Thus, only occasional profiles to assess glycemic...

Clinical Management Of Diabetes

Diet is the cornerstone of the management of diabetes, regardless of the severity of the symptoms or the type of diabetes. Exercise is also an important component in managing diabetes, particularly in obese individuals with NIDDM who may have a component of insulin resistance as a consequence of obesity. Treatment regimens that have proved effective include a calorie-restricted diet in combination with exogenous insulin or oral hypoglycemic drugs. However, since diet, exercise, and oral hypoglycemic drugs (Table 67.2), often because of noncompliance by the patient, will not always achieve the clinical objectives of controlling the symptoms of diabetes, insulin remains universally important in therapeutic management. The administration of insulin is required for the treatment of type I (IDDM) and in cases of type II (NIDDM) that are refractory to management with oral hypoglycemic drugs. Because the spectrum of patients with diabetes extends from the totally asymptomatic individual to...

Oral Agents For Treating Diabetes Mellitus

Although insulin has the disadvantage of having to be injected, it is without question the most uniformly effective treatment of diabetes mellitus. Some milder forms of diabetes mellitus that do not respond to diet management or weight loss and exercise can be treated with oral hypoglycemic agents. The success of oral hy-poglycemic drug therapy is usually based on a restoration of normal blood glucose levels and the absence of glycosuria. Traditionally, the term oral hypoglycemic was used interchangeably with sulfonylureas, but more recently the development of several new drugs has broadened this designation to include all oral medications for diabetes. Because these drugs do not have to be injected, oral agents enhance compliance in type II diabetics. These classes of drugs are not generally used in type I diabetes. The pharmacokinetic profile of oral agents for diabetes is depicted in Table 67.4.

Side Effects of Incretin Mimetics

As is typical for the administration of native GLP-1 184 , a considerable proportion of patients receiving exenatide experience gastrointestinal side effects, such as nausea and more rarely vomiting or diarrhea 119-121 . In the phase 3 trials with exenatide, the frequence of these adverse effects was reported to be as high as 48 during treatment with 10 g of exenatide 119-121 . However, it should be noted that, though frequent, these side effects were mostly mild to moderate in intensity and usually transient. Overall, the percentage of patients who discontinued exenatide treatment as a result of side effects was low. When considering all patients enrolled in the exenatide phase 3 trials, there also seemed to be an increase in the frequency of hypoglycemic events 119-121 , but this was limited to the patients receiving additional treatment with sulfonylurea drugs 185 . In contrast, the incidence of hypo-glycemia was unchanged in patients treated with metformin 119,121 . In the...

Key Issues in the Treatment Strategy

Their inability to cause hypoglycemia unless combined with other antidiabetic agents that have the potential to initiate hypoglycemia, their weight effects (promotion of weight loss in the case of incretin mimetics, weight neutrality in the case of DPP-4 inhibitors), and their safety and tolerability, especially the absence of a potential to cause specific severe adverse events.

Pharmacologytoxicology

Many of the pharmacokinetic factors that limit the applicability of diagnosis are not significant during hemoperfusion. Thus, molecular weight, degree of protein, binding in the plasma, and water solubility are not limiting factors during hemop-erfusion because of the high adsorbent area that comes in contact with the blood. The Vd remains important however. Drugs with a large Vd may be completely extracted from the blood as they pass through the adsorbent, but if only a small amount is present in the plasma compartment, only a small total amount may be removed from the body. The most frequent complications are hypotension and thrombocytopenia. Other complications are hypoglycemia, hypocalcemia and hypothermia.

Reasonable Care and the Sudden Blackout Doctrine

Under these principles, knowledge of one's sleep apnea and a propensity for drowsy driving alone will likely be insufficient to invoke the defense. An OSA driver who has been properly warned against sleepy driving and placed on a treatment regimen would very likely have knowledge sufficient to make a sleep episode foreseeable. Thus, much like the diabetic driver who crashed after he skipped lunch and felt hypoglycemic, but neglected to stop and eat (23), the sleepiness of a noncompli-ant CPAP driver with OSA is likely foreseeable, opening the recalcitrant OSA patient to liability for injuries caused by falling asleep at the wheel.

Stimuli for activation of the sympathetic nervous system and adrenal medulla

Fig. 7.6 Plasma glucagon, adrenaline and noradrenaline concentrations in response to rapid lowering of the blood glucose concentration (by injection of insulin). Based on Gerich, J., Davis, J., Lorenzi, M. et al. (1979) Hormonal mechanisms of recovery from insulin-induced hypoglycemia in man. Am J Physiol 236 E380-E385. With permission of the American Physiological Society. Fig. 7.6 Plasma glucagon, adrenaline and noradrenaline concentrations in response to rapid lowering of the blood glucose concentration (by injection of insulin). Based on Gerich, J., Davis, J., Lorenzi, M. et al. (1979) Hormonal mechanisms of recovery from insulin-induced hypoglycemia in man. Am J Physiol 236 E380-E385. With permission of the American Physiological Society.

Sulfonylurea Sensitivity and MODY

Heterozygous mutations in the HNF-1 a gene are the most common cause of MODY accounting for between 1 and 2 of all cases of DM (57). Isolated case reports have suggested that patients with HNF-1 a MODY (MODY3) are more sensitive to the hypoglycemic effects of sulfonylureas, compared with the patients with type 2 DM (58-61). Hyperexcitability of the pancreas to sulfonylureas has been described in one healthy glucose-tolerant person with an HNF-1 a mutation who showed a greater response to intravenous tolbutamide than healthy controls (62). This has subsequently been demonstrated in a randomized cross-over trial comparing the response to a sulfonylurea and metformin in patients with diabetes caused by either HNF-1 a mutations or type 2 DM (63). Patients with diabetes caused by mutations in the HNF-1a gene showed a greater improvement in glycemia in response to treatment with the sulfonylurea gliclazide, in comparison with matched (for body-mass index and degree of glycaemia) patients...

AGlucosidase Inhibitors

Observed side effects of the a-glucosidase inhibitors. These effects can be minimized by starting patients on a low dose and then slowly advancing the dose as tolerance develops curtailment of carbohydrate consumption also can alleviate these effects. Patients should be counseled that these side effects will occur and that tolerance should develop otherwise, compliance will be low and about one-third of patients will stop their medication. Unlike the sulfonylureas, insulin, and the thia-zolidinediones, a-glucosidase inhibitors do not cause weight gain. Insulin levels do not change in the presence of a-glucosidase inhibitors, so fasting hypoglycemia does not occur when a-glucosidase inhibitors are used as monotherapy. Although the a-glucosidase inhibitors may be used as monotherapy, they are usually used in combination with metformin, sulfonylureas, or insulin. Under the best circumstances, a-glucosidase inhibitors can be expected to promote a 0.5 to 1 reduction in a patient's...

Levels of explanation and the reduction of mental processes

A further case makes a different point. The man is in the field and there is no bull, or at least he hasn't seen one. Nevertheless he feels anxious and has a tachycardia. The explanation is that he has not eaten for some time, and is hypoglycaemic (has low blood sugar). In this case his state has intentionality with respect to glucose metabolism, but not anxiety-provoking agents. There is then an intentional cause of his state, but not in relation to anxiety-provoking agents. Inasmuch as he is not anxious about anything the anxiety does not have an intentional cause. In this example we see the intrusion of the effect of intentional processes at one level (physiology) into another level, the psychological.

Metabolic disorders

B, C, A, D Slight elevation of ammonia is noted with organic acidemias however, this is usually minimal compared with the significant hyperammone-mia that is noted with urea cycle defects. Maple syrup urine disease (a disorder of branched chain amino leucine, isoleucine, and valine) is characterized by metabolic acidosis and ketosis and significant hypo-glycemia. The level of lactic acid will be significantly elevated with congenital lactic acidosis. (Fuhrman BP, et al. Pediatric Critical Care, 2nd Edition pp. 820-825.) 5. A Hypoglycemia produces selective necrosis of the superficial cortical layers sparing the non-neu-ronal elements (unless hypoglycemia is profound and prolonged). Infarction is usually absent even after severe hypoglycemia. In Reye's syndrome, nonspecific cytotoxic cerebral edema is seen with swelling of astro-cyte foot processes. The hallmark of HE is proliferation and enlargement of the so-called Alzheimer -type astrocyte, which is basically a protoplasmic...

Gcp Ii Inhibitors In The Clinic

In further trials, daily doses of 375 mg and 750 mg were administered for 14 consecutive days to healthy volunteers and to patients with diabetes. In normal volunteers, the safety and tolerability profile was similar to placebo at doses up to 750 mg in the fasted state. In diabetic patients, complaints of mild hypoglycemia were reported at the highest dose, but were not associated with documented laboratory changes. In neither group were there any apparent effects on glutamate sensitive parameters.

Complications of falciparum malaria

Technically, cerebral malaria is unrousable coma without fits in the preceding 30 min with no cause except for malaria. Hypoglycemia should always be excluded. Mortality from cerebral malaria can be up to 30 per cent even with ideal treatment. Despite this, patients who survive seldom have significant neurological sequelae. Anemia and hypoglycemia are common in pregnancy. Risk of abortion is increased, and congenital malaria is well recognized when malaria occurs near term, although it is more common in P. vivax cases. Low-birth-weight babies are common after malaria in pregnancy.

Bioadhesives And Drug Targeting To The Lung

In some cases, cell surface expression of certain species can be induced for example, interleukin-1 has been shown to induce the biosynthesis and cell surface expression of procoagulant activity in human vascular endothelial cells 197 . Such materials may also be exploitable as candidates for bioadhesion studies. Millions of lives of patients with diabetes have been saved since the introduction of insulin therapy. However, several daily injections of insulin are required to maximize glucose control in diabetic patients. Insulin is administered by subcutaneous injection, but this route of administration has a slow onset and subsequent prolonged duration of action. These limitations show up more when higher doses of insulin are injected, which results in a long duration of action and forces the patients to consume additional amounts of food to limit the risk of hypoglycemia 198 .

First Generation Sulfonylureas

Chlorpropamide (Diabinese) has a relatively slow onset of action, with its maximal hypoglycemic potential often not reached for 1 or 2 weeks. Similarly, several weeks may be required to eliminate the drug after discontinuation of therapy. This drug can cause flushing, particularly when taken with alcohol, and can also cause hyponatremia. This effect has been employed to treat some patients who have partial central diabetes in-sipidus, an unrelated condition due to a pituitary ADH deficiency. Tolbutamide (Orinase) is a relatively short-acting compound that may be useful in patients who are prone to hypoglycemia.

Adverse Reactions And Effects Of Aerosolized Pentamidine

Inadequate experience has been obtained to determine the incidence of the infrequent adverse reactions that will be associated with aerosolized pentamidine therapy for acute PCP. In case reports, bronchial bleeding has been reported with high-dose therapy in one center 43 . This was associated with an invasive procedure and has not been seen in the large prospective treatment trial. Case reports of hypoglycemia, rash, and conjunctivitis have also been reported 44,45 . The conjunctivitis is not unexpected it would be the direct consequence of The systemic side effects of aerosolized pentamidine when used as prophylaxis reported to date occur at a frequency of less than 1 and include mild hypoglycemia and pancreatitis 36 . Airway irritation with cough (10-20 ) or bronchospasm (1-2 ) occurs commonly 36 . The cough apparently responds to bronchodilators 36 . The long-term pulmonary effects of aerosolized pentamidine do not appear to cause permanent airflow obstruction or decreases in...

Adverse Reactions to Insulin Therapy

The most common side effect associated with insulin therapy is hypoglycemia, which may result in such CNS symptoms as tremors, lethargy, hunger, confusion, motor and sensory deficits, seizures, and unconsciousness. Adrenergic manifestations include anxiety, palpitations, tachycardia, and diaphoresis. In many cases, diabetics are aware that hypoglycemia is developing, and prompt administration of oral carbohydrates (e.g., fruit juice or glucose tablets) can restore normoglycemia. In more severe cases (e.g., unconsciousness, seizures), intravenous glucose or intramuscular glucagon is required to reverse the hypoglycemia.

Secretion and Action of Incretin Hormones in Physiology

GLP-1 does not only display glucose-dependent insulinotropic (incretin) activity 15,17,18,68 , but also inhibits glucagon secretion 11,69 , decelerates gastric emptying 70-73 and reduces food ingestion 74-78 , and promotes enhanced glucose disposal via neural mechanisms involving receptors in the hepatoportal region 79 . All these actions, which are summarized in Fig. 2 and Table 1, potentially contribute to glucoregulation. It is of interest that GLP-1 effects on glucagon secretion, like those on insulin secretory responses, are glucose-dependent, whereas counter-regulatory release of glucagon in response to hypoglycemia remains undisturbed even in the presence of pharmacological concentrations of GLP-1 68 .

Molecular Genetics In Endocrinology

Severe Igf Deficiency Pathophysiology

Autosomal Recessive Isolated Growth Hormone Deficiency The most severe form of IGHD, called IGHD IA (OMIM 262400 and139250) has an autosomal recessive mode of inheritance. Affected neonates occasionally have mildly decreased birth lengths and hypoglycemia in infancy. All develop severe dwarfism by 6 mo of age. Although replacement therapy with recombinant human growth hormone (rhGH) gives a good initial growth response in individuals with IGHD IA, this response is often temporary because of formation of anti-GH antibodies, which, in sufficient titer, cause GH resistance and an arrest of the response to rhGH replacement.

HaiLu Zhao Peter CY Tong Juliana CN Chan

This review focuses on the efficacy and safety of Chinese medicine in the treatment of type-2 diabetes. Included were 84 controlled clinical studies of type-2 diabetes treated with Chinese medicine for at least 1 month. Reported outcomes were symptom relief improvement in glycemia, insulin resistance and secondary failure, and adverse events. Symptom relief was achieved in most (> 80 ) of the patients receiving Chinese medicine. Compared with orthodox drugs, Chinese medicine had a 1.2-fold (95 CI 1.2-1.3) increase in symptom relief. The relative risk of achieving a fasting blood glucose of < 7.3mmol l or a postprandial blood glucose of < 8.2mmol l was 3.0 (95 CI 1.4-6.5) for Chinese medicine plus diet versus diet 2.0 (95 CI 1.4-3.0) for Chinese medicine versus placebo 1.8 (95 CI 1.4-2.3) for combined Chinese medicine and orthodox drugs versus Yuquan Wan (a classic Chinese herbal formula for diabetes), 1.5 (95 CI 1.4-1.7) for combined Chinese medicine and orthodox drugs vs....

Absorption Distribution Metabolism and Excretion

Some populations, most notably East Asians, exhibit an unusual response after drinking ethanol. The symptoms include facial flushing, vasodilation, and tachycardia. These individuals apparently have a genetic deficiency of the enzyme aldehyde dehydrogenase, which leads to an accumulation of acetaldehyde even after they drink relatively small amounts of ethanol. If drugs such as metronidazole, griseofulvin, quinacrine, the hypoglycemic sulfonylureas, phenothiazines, and phenylbutazone are coadministered with ethanol, a similar accumulation of acetaldehyde may occur.

Clinical Manifestations of Hypothyroidism

The most extreme manifestation of untreated hypothyroidism is myxedema coma, which even if detected early and appropriately treated, carries a mortality rate of 30 to 60 . Myxedema coma is a misnomer. Most patients exhibit neither the myxedema nor coma. Patients with myxedema coma usually have longstanding hypothyroidism with the classic symptoms of hypothyroidism. Decompensation into myxedema coma may occur when the homeostatic mechanisms of the severely hypothyroid patient are subject to a stressful precipitating event (e.g., infection, trauma, some medications, stroke, surgery). The principal manifestation of myxedema coma is a deterioration of mental status (apathy, confusion, psychosis, but rarely coma). Other common clinical features include hypothermia, diastolic hypertension (early), hypotension (late), hypoventilation, hypoglycemia, and hyponatremia. If myxedema coma is suspected, the patient is usually admitted to an intensive care unit for pulmonary and cardiovascular...

Central nervous sysytem

D In experimentally induced status epilepti-cus, which is divided into phase I and phase II, it has been shown that phase I is characterized by hypertension, lactic acidosis, hyperglycemia, and hyper- or normokalemia, whereas phase II is characterized by hypoglycemia, hyperkalemia, hyperthermia, and respiratory compromise. (Lothman E. Neurology 1990 40 13.)

Status epilepticus

Since hypoglycemia may be associated with status epilepticus, either as an etiology or as a consequence of prolonged seizure activity with autonomic failure, the blood glucose should be rapidly determined. Since the techniques employed for bedside determination lose accuracy outside the normal range, 'borderline' hypoglycemic values should be treated (along with thiamine administration). Non-ketotic hyperglycemia frequently presents with epilepsia partialis continua, which does not typically respond to antiseizure agents, but which usually remits with rehydration and control of the blood sugar.

Clinical Diagnosis Of Brain Death

Other conditions that may cause deep coma include hypoglycemia, uremia, hepatic failure, Reye's syndrome, hyponatremia, hyperosmolar coma, hypercalce-mia, panhypopituitarism, myxedema and adrenocortical failure. Before any attempt at determining brain death these conditions must be excluded and remedied if established. Shock (systolic blood pressure less than 90 mm Hg) or low cardiac output may also cause reversible suppression of cerebral function because of reduced cerebral blood flow. Hypothermia (below 90 F 32.2 C) can also mimic brain death and can protect against neurological damage due to hypoxia.

Molecular Basis of the Disease

Because fatty acid oxidation fuels hepatic ketogenesis, the symptoms of the disorder appear after periods of prolonged fasting or intercurrent infections and include hypoketotic hypoglycemia, lethargy, seizures, coma, and, without treatment, death. Complications of the disease can include hepatomegaly, acute liver disease, and brain damage. The disease typically presents before 2 years of age but after the newborn period. However, individuals have been described who present with symptoms within the first few days of life as well as those who present as adults.

Alterations at cellular level

In hypoglycemia loss of substrate leads to increased metabolism of endogenous substrates in the brain, membrane depolarization, energy depletion, and increased levels of intracellular calcium. The neuronal injury and death induced by sustained glucose deprivation also result in part from the neurotoxic effects of glutamate, acting through NMDA receptors to stimulate the cellular uptake of calcium and to activate lipases, in a manner analogous to the mechanism of anoxic neuronal injury.

Choice of Antidiabetic Agents to be Used in Combination

A number of potential combinations are depicted in Fig. 6b. Based on available clinical studies, a combining exenatide with metformin has the most obvious advantages A substantial reduction in HbA1c is associated with the numerically largest weight loss 119 (compared with combinations including sulfonylureas) 120,121 and no increased risk of hypoglycemia (despite better glycemic control) 119 . If exenatide is to be combined with sulfony-lureas 120,121,124,125 , the benefit of better glycemic control has to be weighed against the risk of hypoglycemia and less weight reduction. DPP-4 inhibitors can safely be combined with metformin and thiazolidinediones. A combination with sulfonylureas does not suggest particular advantages, since both agents, through different mechanisms, enhance insulin secretion. This combination would, most likely, not be as safe regarding hypoglycemic episodes 182 . No studies are available regarding a potential combination with a-glucosidase inhibitors or...

Treatment of fulminant hepatic failure

The management of fulminant hepatic failure resulting from acetaminophen overdose is based on good intensive care. Optimum management should be directed towards resuscitation and preparation for urgent and safe transfer. Control and protection of the airway is fundamental, particularly as these patients can rapidly become deeply encephalopathic. Sedatives are contraindicated, and patients who cannot be managed safely should be ventilated. Intravenous fluid resuscitation is always necessary and is best directed by either central venous or pulmonary artery pressures. Hypotension may require intravenous vasopressors as well as intravenous fluid. Volume expansion can often correct a mild metabolic acidosis, but bicarbonate infusions should be avoided as the trend in serum bicarbonate is crucial with respect to prognosis (Table2). These patients often experience profound metabolic disturbances, particularly hypoglycemia and hypophosphatemia, which need to be corrected with infusions of 10...

Safety Considerations

Coronary heart disease, as in non-diabetic patients with heart disease, exercise may theoretically precipitate angina, myocardial infarction, arrhythmias or even sudden death. As with other patients with coronary heart disease, physical activity is contraindicated in the presence of unstable angina. High intensity aerobic exercise and isometric exercise are contraindicated in the patient with proliferative retinopathy because of an increased risk of developing retinal or vitreous hemorrhages and retinal detachment. However, moderate intensity aerobic exercise, such as walking, is an acceptable modality of treatment. Patients with peripheral neuropathy should not engage in exercise which may traumatize the insensitive foot (such as jogging). In addition, properly fitted footwear and checking of the feet for injury after exercise are recommended precautions. Data evaluating the potential problem of exercise-induced hypo-glycemia in type-2 diabetes patients taking oral agents or insulin...

Carbohydrates

The human body, especially the brain, needs a constant supply of glucose. There are hormonal mechanisms that regulate glucose metabolism, a process that can go awry in cases of obesity and diabetes. Glucose levels that drop too low can result in weakness and fatigue. (A condition of low blood sugar is recognized as hypoglycemia. Minimizing sugar in the diet and eating small frequent meals focusing on whole grains, seeds, nuts, legumes, fresh fruits, and vegetables, low-fat dairy, yogurt, and fish can aid in stabilizing blood sugar levels. Blood sugar levels can be stabilized with 200 mcg of chromium GTF. Hypo-glycemia is often an indication of an underlying health condition.)

Cyp2c9

Three defective alleles have been reported in the CYP2C9 enzyme, two of which confer decreased activity. Their frequency ranges from 1 to13 in different populations (13-15). Substrates of CYP2C9 include nonsteroidal anti-inflammatory drugs and hypoglycemic agents (13-15). The clinical relevance of CYP2C9 is particularly noticed in the metabolism of drugs that are used to treat Type II diabetes, wherein decreased clearance of these drugs may result in severe hypoglycemia. Another relevant example is S-warfarin, where major bleeding may occur (10).

Study Questions

He is taking a thiazide diuretic (A) for mild hypertension, digitalis (B) for congestive heart failure, and an oral hypoglycemic agent (C) for mild type 2 diabetes. An opioid analgesic (D) that gave him considerable pain relief when he broke his arm 30 years ago is prescribed. About a week later Mr. Johnson is seen in the emergency department complaining of shortness of breath and a feeling of suffocation. Which of the drugs he is receiving is a likely possible cause of this particular symptom

Nutritive Sweeteners

Polyols or sugar alcohols like sorbitol, xylitol, mannitol and isomalt are bulk or nutritive sweeteners which contain calories and raise blood glucose levels. They must still be accounted for in meal planning. They have a slightly lower glycaemic response than sucrose and a slightly lower calorie value (2.4kcal g) because they are not completely digested and absorbed. Polyols may therefore cause diarrhoea, particularly if consumed in large amounts (> 25 g). Although they have a lower cardiogenic effect compared to sucrose, polyols offer no special benefit to people with diabetes.

Figure

C EBPa is expressed immediately prior to the transcription of a number of adipocyte-specific genes. Analyses of the upstream regulatory regions of aP2, stearoyl CoA desaturase 1 (SCD1), Glut4, PEPCK, leptin, and the insulin receptor have revealed functional C EBP consensus sequences in the proximal promoters.2 Ectopic expression of C EBPa in 3T3-L1 preadipo-cytes has been shown to be sufficient for inducing adipogenesis without the use of external hormonal inducers.73 Furthermore, ectopic expression of C EBPa or C EBPp has resulted in potent induction of adipogenesis in non-progenitor fibroblasts under adipogenic conditions.101174 The observation that antisense expression of C EBPa inhibits differentiation of cultured preadipocytes provides further evidence supporting a regulatory role for C EBPs during adipogenesis.16 Mice targeted for C EBPa gene ablation die within 8 h postpartum due, in part, to hypoglycemia since administration of glucose can rescue these animals for up to 40...

Assessment

Assessment of the patient with ALF firstly involves determination of the need for urgent life-saving intervention and resuscitation. Such measures may include endotracheal intubation and mechanical ventilation, treatment of shock, and administration of glucose if hypoglycemia is present. The next concern is assessment of the need and urgency for transfer of the patient to a liver unit. This will depend upon the expertise and facilities available at the place of presentation, the grade of encephalopathy and severity of illness at presentation (see adverse prognostic indicators below), and assessment of the rate of progression from the clinical history and examination. Regardless of these factors, the patient should be discussed with a specialist from a liver unit. If transportation is necessary, the patient should be accompanied by an experienced medical escort, and full monitoring and equipment to initiate therapy should be available. Endotracheal intubation and mechanical ventilation...

General management

It arises as a consequence of impaired circulating insulin, impaired gluconeogenesis, and an inability to mobilize glycogen stores. Hypophosphatemia and hypomagnesemia are also frequent problems, particularly when urine output is maintained. A metabolic acidosis may be seen this carries a poor prognosis and prompts consideration of transplantation. The etiology is multifactorial, relating to hepatic dysfunction, impaired lactate metabolism, and also tissue hypoxia in patients who are inadequately volume resuscitated. Patients with AHF are at increased risk of infections, both bacterial and fungal this appears to be related to compromised immune function with impaired neutrophil and Kupffer cell function and deficiency of opsonins. Bacterial infection rates of up to 80 per cent occur within a few days of admission. Some centers use prophylactic antibiotic regimens however, a high index of suspicion should be maintained in all patients. All patients are given...

Metabolic management

Hypoglycemia develops at some time in almost 50 per cent of patients with ALF (MunozJ993). It should be prevented by a continuous infusion of 10 per cent glucose and must be considered during any deterioration in mental state. Both hyper- and hyponatremia may be present. The former is a consequence of treatment of cerebral edema with dehydration and is treated by judicious rehydration. Hyponatremia appears to be dilutional and is managed by volume restriction. Hypokalemia is present in approximately 50 per cent. It is closely related to the presence of metabolic alkalosis and may be both cause and result of this abnormality. It is treated with potassium supplementation, intravenously or via the nasogastric tube. Primary respiratory alkalosis is common in patients allowed to breathe spontaneously. It is a consequence of hepatic encephalopathy but the mechanism is unknown. No treatment is usually necessary. Metabolic alkalosis occurs in 25 to 50 per cent of patients predisposing factors...

Acromegaly

Reduction of growth hormone levels results in an early cessation of sweating. Diabetes mellitus becomes easier to control and many patients can be managed on diet or oral hypoglycemic alone. On the second day, it is useful to carry out a glucose tolerance test with GH levels (i.e. before discharge). GH will fall to below 2 mlU l, and ideally below 0.5 mlU l if cured. If the patient is not cured, early re-exploration is often worthwhile.

Hunger

Why would any lifelong craving for a certain food suddenly change You need to consider again what was said earlier about insulin levels. When a large amount of insulin is suddenly released in response to a large spike of glucose into the blood, another consequence in addition to fat formation from that glucose is that the insulin effect will overshoot, and roughly two to three hours later, your blood glucose will be lower than normal, or hypoglycemic. This sudden decrease of fuel to the brain (which requires adequate amounts of glucose at all times to function properly) will prompt you to immediately eat more carbohydrate to restore that glucose

Further Sugar Damage

Let's look at a pattern of eating shared by many, if not most, Americans today. The day starts around 7 00 a.m. with the great American breakfast orange juice, a sugar-releasing refined cereal with more sugar added, milk, and coffee (usually sweetened with sugar). The glucose skyrockets and the insulin skyrockets in response. Around 10 00 a.m. the glucose has dropped precipitously low from the insulin overshoot provoked by breakfast. The resulting state of hypoglycemia now causes a feeling of sluggishness. Solution the coffee break Remember that even without added sugar, the caffeine hit releases sugar from internal stores and initiates another surge of insulin into the blood to metabolize it. Once the coffee break is over, there's generally enough sugar-stimulated energy to finish out the morning. Then, around noon, it's time for lunch. Since the overshoot of insulin at 10 00 a.m. again does not have enough glucose to metabolize, the carbohydrate craving sets in, and the great...

Discrete seizures

Seizures occurring during another critical illness usually represent a central nervous system manifestation of a systemic disorder. In a prospective study of neurological complications of critical medical illnesses, seizures were the second most common problem encountered (and were almost as frequent as metabolic encephalopathy). The most frequent causes were cerebrovascular disease, central nervous system infections, metabolic encephalopathies, neoplasms, hypoglycemia, and osmolar disorders (including non-ketotic hyperglycemia). A retrospective analysis found that drug withdrawal was the most common etiology of seizures. Table 1 summarizes common causes of seizures in ICU patients. Acute metabolic disturbances commonly produce seizures in ICU patients, but one must consider that seizures may be symptoms of structural disorders which are made manifest by metabolic disorders. Generalized convulsions are typical of metabolic disturbances, but two common exceptions are seizures due to...

Carl Erik Mogensen

Glucagon acts by activating the enzymes in hepatic cells that increase glycogenolysis and thereby increase the hepatic glucose production. Quite often, immediate clinical improvement is necessary to avoid the risk of neurological damage associated with severely low blood glucose. One problem might be that glucagon can be useless if hepatic stores of glycogen are depleted.

History

A history should elicit what may have precipitated this diabetic crisis. The most common causes are infection, upper respiratory tract infection and gastroenteritis, or inadequate insulin therapy (Berger,aQd.,Kel er,.1992). Check the patient's recent oral food and fluid intake, as well as his or her insulin and oral hypoglycemic drug use. Ask about other drugs, particularly illicit drugs and alcohol. Discuss the patient's normal diabetic control and diabetic complications such as nephropathy, neuropathy, and retinopathy. A history may be available from relatives or ambulance officers if the patient is unconscious.

Organ failure

Extensive liver disease is required to cause hypoglycemia. This can happen with fulminant hepatitis, fatty liver from starvation or alcohol ingestion, and cholangitis with biliary obstruction. Hypoglycemia is unusual with common forms of cirrhosis or hepatitis, although glucose metabolism may be altered. Severe cardiac failure may lead to hypoglycemia the pathogenesis is not known, but is thought to be from hepatic congestion, cellular hypoxia, or substrate limitation. Some patients with renal failure develop hypoglycemia, and this is not well understood either. It may be due to cachexia with limited substrate for glucose production or to inhibition of gluconeogenesis itself. Sepsis commonly leads to hypoglycemia. A combination of increased glucose utilization and failure of glucose production seem to be involved.

Tumors

Insulinomas have an incidence of approximately one in one million people. They account for 66 to 85 per cent of patients with endogenous hyperinsulinism. They usually have dimensions of 1 to 2 cm and 99 per cent of them occur within the mass of the pancreas 5 to 10 per cent are malignant. Typical symptoms of hypoglycemia tend to occur in the late afternoon or some hours after a meal. Diagnosis requires demonstration of Whipple's triad low serum glucose, spontaneous symptoms during documented hypoglycemia, and resolution of symptoms with glucose administration. Rare non-b-cell tumors can cause related syndromes. Most are mesenchymal, but occasional epithelial neoplasms such as hepatomas and adrenocortical and carcinoid tumors can cause hypoglycemia. Post-hypoglycemic. .coma Chapter Reference

Glucagon

Endogenous glucose production can sometimes be increased by stimulating the counter-regulatory mechanisms of glycogenolysis and gluconeogenesis. Since a glucose infusion requires venous access, intramuscular glucagon (1 mg) is an effective and portable alternative to intravenous glucose for the majority of hypoglycemic episodes in insulin-dependent diabetics. It will often awaken a comatose patient in 10 to 15 min to the stage where an oral glucose load can be safely ingested. A second dose may be needed, but further doses should be resisted as failure to respond implies glycogen exhaustion, inadequate gluconeogenesis, or the onset of cerebral edema, for which alternative therapy should be instituted. In other circumstances, glucagon may increase morbidity. Where residual b-cell activity exists, glucagon stimulates rebound insulin secretion which acts to reduce its glycemic effect. This response is exaggerated and can lead to rebound hypoglycemia in conditions with hyperinsulinism and...

Glucose infusions

Given an average glucose pool of 15 to 20 g in the adult and glucose consumption between 120 and 180 mg min, the standard therapy is 25 g of glucose given intravenously (50 ml of 50 per cent glucose), which usually reawakens a comatose patient in 5 to 10 min. With a plasma half-life of 60 to 80 min, the blood glucose level will fall after this initial bolus depending on the hypoglycemic stimulus and the metabolic state, potentially leading to a relapse into neuroglycopenic symptoms.

Sulfonylureas

Sulfonylureas, such as glipizide (Glucotrol, Glucotrol XL), glyburide (DiaBeta, Micronase) and glimepiride (Amaryl), increase insulin secretion and may reduce insulin resistance. They are typically used twice per day (except for Glucotrol XL and Amaryl). They may precipitate hypoglycemia. May cause hypoglycemia, weight gain. Maximum dose should be used only in combination with insulin therapy Check bilirubin and liver function test results every two weeks for first six months may cause hypoglycemia, weight gain Mechanism of action similar to that of sulfonylureas may cause hypoglycemia take at mealtimes

Troglitazone Rezulin

This agent is associated with weight gain and hypoglycemia. Starting dose is 200 mg once per day, which may be slowly increased to up to 600 mg once per day. Troglitazone should be administered with a meal and is often taken with breakfast. Metformin is more potent and usually associated with less serious side effects therefore, troglitazone is a second-line agent.

Approach to therapy

When stable, self-monitoring of blood glucose is performed twice per day on alternate days, rotating among breakfast, lunch, dinner and bedtime checks. For patients receiving intensive therapy and those undergoing medication adjustments, more frequent monitoring is needed. Readings taken during the night or two hours after eating may uncover significant hyper- or hypoglycemia.

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