Potassium administration is often required. This cation may be normal in serum even if the total body content is decreased. When the plasma level is low, 30–40 mmol/h of potassium should be infused, and a lower dose (20 mmol/h) should also be given when serum potassium is normal, because with the beginning of therapy a further fall in serum potassium occurs as a result of the eVect of insulin (which causes a shift of potassium into the cells) and ﬂuid replacement (that dilutes serum potassium). ECG represents a useful tool to assess intracellular potassium concentration, showing ﬂat or inverted T waves when intracellular potassium is low and peaked T waves when in-tracellular potassium is high.
Bicarbonateadministrationisonlyrequiredinpatientswithsevereacidosis (pH=7). Bicarbonate should be given at a slow rate (about 44 mEq during 1 or 2 h) and discontinued when the pH rises to 7.1. In DKA, 2,3-diphospho-glycerate (2,3-DPG) is low in red cells, which decreases oxygen delivery. This is counterbalanced by acidosis, which favors oxygen delivery. A rapid correc-tion of acidosis with bicarbonate may leave the eVect of the 2,3-DPG unop-posed, causing impaired oxygen release which, in presence of volume depletion and reduced tissue perfusion may favor the development of tissue hypoxia and lactic acidosis.
In presence of infections, antibiotic therapy should be employed. When the patient is comatose, insert a nasogastric tube, use a urinary catheter (if no urine passes within 3 h) and heparinize in case of hyperosmolar coma development or in presence of thrombosis risk factors.
After the recovery from a diabetic ketoacidotic episode, it is useful to accurately review the causes to reduce the risk of recurrence.
Hyperosmolar nonketotic syndrome (HNKS) is an acute complication observed most often in type 2 diabetic patients and is characterized by symp-toms and signs due to volume depletion (caused by excessive hyperglycemia and consequent hyperosmolality and osmotic diuresis), with varying degree of clouding of sensorium, ranging from absence of mental impairment (about 10%) to frank coma (about 10%). HNKS is a serious complication, which entails a mortality rate as high as ?40%.
Pneumonia (favored by sensory clouding which facilitates aspiration of oropharyngeal secretions) may develop in HNKS patients, as well as other infections. The dehydration elevates plasma viscosity and may favor throm-bosis. Disseminated intravascular coagulation (DIC) may also occur, with bleeding manifestations.
Laboratory ﬁndings include a marked hyperglycemia (usually higher than that occurring in DKA, reaching a level of ?800 mg/dl or 44 mmol/l) which causes increase in serum osmolality (which may be as high as ?350 mosm/l), whereas sodium is normal or slightly changed. Urea nitrogen and creatinine are elevated, together with inorganic acids (phosphates and sulfates) because of prerenal azotemia consequent to volume depletion. In contrast to DKA, inHNKSthemetabolicacidosisisabsentormild,andbicarbonatesareslightly changed. When present, acidosis is due to retention of inorganic acids (see above), i.e. a small amount of ketone bodies as well as a certain amount of lactate (due to tissue hypoperfusion consequent to volume depletion).
The extreme hyperglycemia with the ensuing hyperosmolality may be favored by the abundant hyperglycemic diuresis in patients who are unable to compensate the large ﬂuid loss with urine by adequate water drinking, as it often occurs in old patients, who have an attenuated sensation of thirst and who often live alone or in nursing homes. However, it should be kept in mind that HNKS may be precipitated by several factors, including infections, cerebrovascular events, hypertonic peritoneal dialysis, parenteral nutrition or administration of the osmotic agent mannitol or diuretics as well as corticoste-roids and phenytoin.
The lack of acidosis in HNKS may be the result of several factors. (1) HNKS develops in type 2 diabetic patients, who possess a varying degree of residual endogenous insulin secretion. Since lipolysis is more sensitive to insulinthantheglucosehomeostaticmechanisms,itispossiblethattheresidual insulin secretion, while unable to stimulate glucose utilizaton and to repress hepatic glucose production, is able to refrain lipolysis, thus limiting the FFA aZux to liver and therefore the ketogenic process. (2) The endogenously se-creted insulin reaches, through the portal vein, the liver, which is insulinized to a suYcient degree to prevent activation of ketogenesis (i.e. to allow glucose to be utilized in suYcient amount to produce enough malonyl-CoA, which inhibits the ketogenic process at the level of CPT-1. (3) There may be glucagon resistance, which prevents glucagon to exert its ketogenic eVects (see under DKA). (4) There may be an enhanced activity of the Cori cycle, with increased aZux of lactate to the liver, where it may be in part metabolized to malonyl-CoA, thus refraining ketogenesis.
HNKStreatmentisprimarilydirectedtorestorebloodvolumeandcorrect hyperosmolality. This may require the supply of intravenous ﬂuid in the total amount up to 8–10 liters. Therapy may be started by intravenous infusion of saline at the rate of 1.5 liters/h for the ﬁrst 2 h, followed by infusion of 0.5 liter/h of half-normal saline (0.45%) adjusted according to the clinical and laboratory response. Insulin should also be given. This may be done according to the small dose regimen described under DKA, although some patients may
Clinical Emergencies in Diabetes 109
require larger doses. Potassium should be supplied (see under DKA) with special attention because, in the absence of acidosis, the intracellular K+ transfer induced by insulin administration is more pronounced. Attention should also be paid to the possible development of infections or thrombosis or DIC to start timely the appropriate therapy.
Foster DW, McGarry JD: The metabolic derangements and treatment of diabetic ketoacidosis. N Engl J Med 1983;309:159–169.
Genuth SM: Diabetic ketoacidosis and hyperglycemic hyperosmolar coma. Curr Ther Endocrinol Metab 1997;6:438–447.
Gonzalez-Campoy JM, Robertson RP: Diabetic ketoacidosis and hyperosmolar nonketotic state: Gaining control over extreme hyperglycemic complications. Postgrad Med 1996;99:143–152.
Silink M: Practical management of diabetic ketoacidosis in childhood and adolescence. Acta Paediatr 1998;425(suppl):63–66.
Siperstein MD: Diabetic ketoacidosis and hyperosmolar coma. Endocrinol Metab Clin North Am 1992; 21:415–432.
Umpierrez GE, Khajavi M, Kitabchi AE: Review: Diabetic ketoacidosis and hyperglycemic hyperosmolar nonketotic syndrome. Am J Med Sci 1996;311:225–233.
Whiteman VE, Homko CJ, Reece EA: Management of hypoglycemia and diabetic ketoacidosis in preg-nancy. Obstet Gynecol Clin North Am 1996;23:87–107.
F. Belﬁore, Institute of Internal Medicine, University of Catania, Ospedale Garibaldi, I–95123 Catania (Italy)
Tel. +39 095 330981, Fax +39 095 310899, E-Mail francesco.belﬁore@iol.it
Belﬁore F, Mogensen CE (eds): New Concepts in Diabetes and Its Treatment. Basel, Karger, 2000, pp 111–124
............................ ClinicalEmergenciesinDiabetes. 2:Hypoglycemia
F. Belﬁore, S. Iannello
Institute of Internal Medicine, University of Catania, Ospedale Garibaldi, Catania, Italy
Thetermhypoglycemiareferstoabiochemicalconditionresultingfroman abnormally low plasma glucose level, less than the lower value of the normal range(50–45 mg%or2.8–2.5 mmol/l).Thus,thetermhypoglycemiaseemsinap-propriate to deﬁne a variety of clinical manifestations associated with abnor-mally low blood glucose and consisting of signs and symptoms of adrenergic activation and neuroglycopenia, responsive to glucose administration.
In infants, during the ﬁrst 48 h of life, hypoglycemia may occur, with glycemic values =30 mg% or 1.7 mmol/l, with a frequency of about 10% of live births. A brief hypoglycemic episode can cause moderate alterations of the brain whereas prolonged hypoglycemia can cause profound dysfunctions, tissue damage and also death of the brain. This depends on the fact that the deposit of glycogen in brain is negligible (the reserve of energy lasts 2–3 min) and that glucose is not synthesized by the central nervous system (CNS). Thus, glucose (together with oxygen) is an obligate primary energy substrate for the brain tissue and is entirely derived from the circulation. The brain tissue utilizes 120 g/day of glucose and about 90% of total energy needed for cerebral functions derives from glucose oxidation. The brain cannot utilize alternative substrates (as circulating FFA) as energy fuel thus being very sensitive to hypoglycemia. In some particular situations, at least some parts of the brain might utilize ketoacids.
Hypoglycemiaisaveryuncommonevent,apartfrompersonswithdiabetes treated with insulin or hypoglycemic drugs. The diagnosis of hypoglycemia is baseduponWhipple’striad,i.e.hypoglycemia,symptomsofhypoglycemia,and correction of the symptoms with the normalization of blood glucose.
Insulin regulates glycemia through modulation of hepatic glucose produc-tion in the postabsorptive state and glucose utilization in the postprandial state, and it is the only hormone able to physiologically reduce glycemic level. In catabolic states (fasting), insulin concentration falls and the levels of counterregulatory hormones rise; in fact, hypoglycemia is capable of inducing the release of counterregulatory hormones, including glucagon, catechola-mines (epinephrine and norepinephrine – released both from adrenal medulla and the sympathetic neurons), cortisol and GH. The glucagon secretory re-sponse to hypoglycemia is largely CNS-independent whereas catecholamine, cortisol and GH responses are prevailingly CNS-dependent. Glucagon acts within minutes and is the primary hormone of glucose maintenance (by stimu-lating hepatic glucose production through increase in glycogenolysis and glu-coneogenesis). Catecholamines also act swiftly, stimulating glucose production and limiting glucose utilization in humans through both b2- and a2-adrenergic mechanisms. Cortisol and GH, on the contrary, act within several hours with a delayed glucoregulatory action (antagonizing insulin action, mobilizing substrate and activating hepatic gluconeogenesis through the induction of the relative gluconeogenic enzymes). All these hormones have a synergic action on the induction of hyperglycemia and on the prevention and correction of hypoglycemia. Glucagon plays the most important counterregulatory action whereas catecholamines play a minor role, that becomes important when there is glucagon deﬁciency, as it often happens early during the course of diabetes mellitus. Catecholamines are the warning system in hypoglycemia through the symptoms and signs of adrenergic overactivity. Cortisol and GH play no role in short-term hypoglycemia but have a substantial role in the recovery from long-term hypoglycemia. The relevance of other hormones or neurotransmit-ters in preventing and correcting hypoglycemia has been debated but it is not deﬁnitely established. In type 1 diabetic patients, counterregulation is often altered and, in some patients it may be very deﬁcient. It has been reported that almost all diabetic patients show a deﬁcient glucagon secretory response to hypoglycemia, perhaps as a result of the long-term hyperglycemia (glucose toxicity) or the loss of the regulating eVect of insulin on glucagon secretion. Inthepresenceofadefectiveglucagonsecretion,type1diabeticpatientsduring hypoglycemic episodes became dependent upon catecholamines to correct low glycemic level, i.e. epinephrine response compensates for deﬁcient glucagon response. Some diabetic patients with long-standing disease have also a deﬁ-cient catecholamine response to hypoglycemia and this combined disorder impairs glucose counterregulation and represents a high risk of iatrogenic hypoglycemia in these subjects. GH and cortisol responses to hypoglycemia
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