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Medical Emergencies in Diabetes
Medical Emergencies In Diabetes ROGER H. UNGER, M.D. Chief of Gastroenterology, Veterans Administration Hospital; Assistant Professor of Internal Medicine, University of Texas Southwestern Medical School, Dallas, Texas
DIABETIC KETOACIDOSIS
FEW MEDICAL EMERGENCIES are as dramatic as diabetic ketoacidosis or as demanding of prompt and proper therapy. In this disorder, an absolute or relative lack of insulin action leads to profound derangement of carbohydrate, fat and protein metabolism, and of water, acid-base and electrolyte balance; ultimately, the function of virtually every vital system may, to a varying degree, become impaired. A broad understanding of the complex cycle of pathophysiologic events is a prerequisite for optimal therapy. P hysiologic Considerations
INSULIN ACTION. Insulin acts both upon the liver, decreasing its output of glucose,!' 7 and upon certain extrahepatic tissues such as fat and muscle, increasing the permeability of their cell membranes for glucose. 5 . 9. 10 The insulin normally.secreted in reponse to a glucose load returns the blood sugar to normal by diminishing hepatic production of glucose and increasing its uptake by extrahepatic tissues. The glucose thus gained by liver cells and by muscle cells is stored as glycogen or utilized; the glucose entering fat cells is converted to fat, the breakdown of the glucose providing the 2-carbon fragments from which fatty acids are synthesized. Since fat is the principal storage form of the energy of glucose, the stimulation of lipogenesis must be considered a major effect of insulin. CONSEQUENCES OF INSULIN LACK. In the total absence of insulin action the output of glucose from the liver is completely unrestrained. Despite depletion of hepatic glucose stores, new glucose is formed by the liver cells and poured into the circulation. 2 Hyperglycemia is further increased by reduced entry of glucose into extrahepatic tissues. In fat cells, the lack of intracellular glucose is marked by a cessation of lipogenesis and rapid mobilization of stored fat. The concentration of free fatty acids rises in the blood3 and they reach the liver where they are very rapidly oxidized to 2-carbon fragments 6 which, in the absence of'
487
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insulin, cannot be disposed of through usual channels. For reasons not thoroughly understood, they are synthesized to keto-acids at an increasing rate, and hyperketonemia results. Thus, the primary consequences of insulin lack, hepatic overproduction of glucose and underpenetration of glucose into the cells of the peripheral tissues, account for the hyperglycemia and hyperketonemia, each of which in turn produces profound and far-reaching alterations. CONSEQUENCES OF HYPERGLYCEMIA. Hyperglycemia results in hyperosmolarity of extracellular fluid and initiates a movement of water out of the cells. The resulting intracellular dehydration may jeopardize the integrity of cellular function. In addition, the massive glucose load filtered through the glomeruli induces an osmotic diuresis; large volumes of water and, in addition, variable quantities of sodium, potassium and other electrolytes are lost. These losses may be intensified by vomiting and diarrhea and infection which often complicate the clinical picture. With contraction of the extracellular space, glomerular filtration falb;, prerenal azotemia appears, and hypotension and peripheral circulatory collapse may supervene. CONSEQUENCES OF HYPERKETONEMIA. The excessive production of acetoacetic acid and beta-hydroxybutyric acid by the diabetic liver results in an exceSR of hydrogen iOllR which combine with bicarbonate ions as followR,
driving the reactions to the right. Bicarbonate concentration falls, CO 2 tension riscs and the volume of respiration increases in an effort to excrete CO 2 and maintain a normal pH. The kidneys also participate in this endeavor by excreting hydrogen ion and ammonia. However, as dehydration and hypovolemia impair glomerular filtration and renal blood flow, the ability to maintain compensation will ultimately wanc, and the pH of the blood will fall. Kussmaul respirations add the mURcular work of hyperventilation to a generally deteriorating situation. Cerebral function is depressed, possibly through accumulation of acetoacetate in the presence of cerebral dehydration and acidosis, and coma ultimately supervenes. Clinical Considerations
DIAGNOSIS The diagnosis of diabetic ketoacidosis and coma is ordinarily quite obvious. In rare instances, an erroneous diagnosis of diabetic ketoacidosis may be made and lead to unnecessary and potentially hazardous treatment. Such an error may occur when acidosis or coma occurs in a diabetic from a cause other than absolute or relative insulin lack, or
Medical Emergencies in Diabetes
489
when tests for glycosuria and ketonuria are positive in relatively mild diabetics after a fast. They may also be positive in labile diabetics during overaggressive therapy with phenformin (DBI), after severe hypoglycemic insulin shoek when the blood sugar is rebounding, and in salicylate poisoning. In general, however, the clinical and laboratory findings in "true" diabetic ketoacidosis, dominated by increasing polyuria and dehydration, are unmistakable. A blood sugar of 400 mg./lOO ml. or above associated with a 4+ Acetest reaction in plasma is virtually diagnostic of true diabetic ketoacidosis. Blood and urine specimens should be obtained immediately to confirm the diagnosis and to provide a therapeutic baseline. An acetone test on plasma should be done in varying dilutions at the bedside with an Acetest tablet as therapy is begun. Rapid bedside methods for semiquantitation of blood glucose concentrations are also available if requiredY. 14 THERAPY
A flow sheet should be used to record vital signs every half hour, urine tests hourly, and blood levels of glucose, CO 2 and plasma acetone at intervals of two to six hours, if possible. Continuous bedside attendance by a physician will be required until recovery. Without delaying the start of therapy, a careful search for precipitating infection and other disease should be made, so that appropriate therapy of coexisting disease may be instituted if necessary. If danger of aspiration exists because of vomiting, the stomach should be emptied by tube. Because of the changing circumstances during the therapy of ketoacidosis, it is helpful to distinguish between the critical first phase of therapy which, although varying, ordinarily lasts about three to six hours, and the second phase, which continues until recovery. In the first phase, the objectives of therapy are to reinstitute insulin action, irrespective of the dose required, and to replace salt and water loss so as to maintain extracellular volume and prevent circulatory collapse. In the second phase, the objectives are to maintain and extend the gains achieved in the first phase, without causing hypoglycemia or alkalosis or permitting deficits of intracellular ions to develop. Insulin. Unless insulin action is reinstituted, death is certain. Yet most severely ketoacidotic patients display a major degree of resistance to the action of insulin. Whether the target cells, abused by dehydration and loss of intracellular ions, have temporarily lost their responsiveness to insulin, or whether some circulating antagonists such as an adrenal steroidS or an alpha globulin4 is responsible, is unclear. Whatever its cause, the need to overcome it is vital and a large dose of insulin should be introduced without delay. In severe acidosis, 100 to 250 units should be given, most of it by vein. At this stage of therapy, the danger of
490
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UNGER
underdosage is much greater than the danger of overdosage, and timidity here is unwarranted. Hourly doses of 50 to 100 units are continued as needed until the blood sugar declines to about 300 to 350 mg. per cent or the urine sugar falls. When such evidence of responsiveness to insulin appears, the aggressive first phase of treatment has ended and the danger of hypoglycemia now exists. Fluids. The longstanding unresolved controversy as to the best of several therapeutic approaches to fluid and electrolyte deficits suggests that differences between the various regimens are, at most, slight. In the initial phase of therapy, about 3 liters of fluid will be administered. In restoring extracellular fluid volume, 2000 cc. at least may be given as isotonic saline or Ringer's solution. However, since water has been lost in excess of electrolytes, water should be replaced in excess of electrolytes. The use of 5 per cent glucose in water for this purpose is contraindicated in the first phase of therapy, since the infused glucose will remain in the extracellular compartment and intensify the hyperosmolarity. Fructose, however, can enter cells in the absence of insulin; about 1000 cc. of a 5 per cent fructose solution is, therefore, a reasonable approach to the problem of water replacement, as is the use of hypotonic saline. As soon as insulin effect becomes apparent and the blood sugar has fallen below 300 mg. per cent, 5 per cent glucose solutions, coordinated with the insulin therapy, should be used to replace water loss until fluids can be administered by mouth; this will prevent hypoglycemia and speed the fall in blood ketone levels. Although many consider it unnecessary, the use of a single liter of ~ molar lactate will not be harmful and may be justified in extreme acidosis. In the second phase of therapy, fluid administration is continued at a less urgent pace in accordance with estimated needs. As a consequence of rehydration and of the re-entry of glucose into cells, the serum potassium, which may have been elevated earlier, will fall because of its re-entry into cells and its continuing loss in the urine. If, at this time, the patient still cannot take potassium-rich fluids (orange juice, beef broth) by mouth, a total of 100 to 1.50 mEq. of potassium as the phosp hate or chloride should be administered in low concentration at a rate never exceeding 20 mEq. per hour. In addition to hypokalemia, hypomagnesemia may complicate the recovery phase. Peripheral circulatory collapse is a major hazard that may occur at any time during therapy of ketoacidosis. It will ordinarily respond to replacement of fluid loss. If it should not, despite adequa te restoration of extracellular fluid, more aggressive therapy with pressor amines is indicated, since long-continued shock may persist even after restoration of extracellular volume, and proceed to complete irreversibility. Hypoglycemia, metabolic alkalosis and hyperkalemia are not uncommon consequences of overtreatment which may seriously complicate therapy. Hypoglycemia can be avoided by the timely use of glucose in
Medical Emergencies in Diabetes
491
the second phase of therapy, as suggested above. Alkalosis and hyperkalemia often result from efforts to "normalize" via the intravenous route. Such hazardous iatrogenic complications can be avoided by aiming, not for precise normalization, but merely for the correction or prevention of serious abnormalities. This policy will permit the patient to reach the recovery stage, in which the finer adjustments in electrolyte composition will occur spontaneously upon resumption of oral feeding. HYPOGLYCEMIA
Severe hypoglycemia is a serious medical emergency that may arise in any diabetic receiving effective antihyperglycemic therapy. A declining arterial blood glucose concentration threatens the vital glucosedependent tissues of the central nervous system by jeopardizing their access to glucose, their only source of energy. The initial symptoms of hypoglycemia are generally considered to include nervousness, pallor, sweating, tremor, tachycardia, etc. These symptoms are not the result of the low blood sugar level per se but of an increase in circulating epinephrine, secreted by the adrenal medulla in an effort to restore the blood sugar level by stimulating hepatic glycogenolysis. If, for any of several reasons, this protective device fails or is unequal to the task, the blood sugar will decline to a level incompatible with normal cerebral function. Then, unless glucose becomes available to these cells without delay, psychotic behavior, unconsciousness, convulsions and death may ensue. Repeated or prolonged hypoglycemic episodes can lead to chronic and irreversible brain damage. CAUSES
Insulin therapy is, of course, the most common cause of hypoglycemia among diabetics. Many severe ketoacidosis-prone diabetics display a remarkable degree of sensitivity to insulin. An increase in exercise, delay in a meal, or deliberate or inadvertent overdosage with insulin may cause a severe episode of hypoglycemia in such a patient and, to a lesser degree, in any diabetic. In newly treated diabetics, sudden changes in insulin requirements may occur after the first few days or weeks of insulin therapy, and profound hypogJycemia may result. The orally administered antihyperglycemic agents may also cause severe and even fatal hypoglycemia. Because tolbutamide (Orinase) is rapidly inactivated by the normal liver, it is an uncommon cause of serious hypoglycemia. In rare patients with severe liver disease, inactivation of tolbutamide may be impaired, and serious hypo glycemia may ensue. Another possible hypoglycomic hazard in sulfonylurea-treated patients stems from the ingestion of large doses of salicylates which may potentiate hypoglycemic activity. This possibility should be pointed out to all patients receiving this form of therapy.
492
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UNGER
Chlorpropamide (Diabinese) is a long-acting sulfonylurea which is excreted rather than inactivated. As a result, cumulative effects are more common than with tolbutamide, and hypoglycemia is more co mmon.1 2 Because the hypoglycemia may develop quite insidiously, the typical warning symptoms of epinephrine secretion may not be prominent and the neurological manifestations of hypoglycemia may dominate the clinical picture. The resulting atypical nature of the symptoms may delay the identification of their cause, thereby increasing the danger. Phenformin (DBI), when used alone, has not been reported to cause hypoglycemia. When it is used in combination with the sulfonylureas or with insulin, however, severe hypo glycemia may be encountered. 13 TREATMENT
The treatment of severe hypoglycemia is to provide an abundance of glucose in order to restore cerebral function to normal as rapidly as possible. Epinephrine and glucagon have been used for this purpose, as they raise the blood sugar concentration by activating hepatic enzymes which accelerate the breakdown of hepatic glycogen, thereby increasing the hepatic output of glucose into the circulation. However, if insufficient hepatic glycogen is present, their hyperglycemic action may be inadequate. For this reason, glucose, as the 50 per cent solution, administered rapidly by vein, remains the treatment of choice. In psychotic and convulsing patients, if a venipuncture is difficult, a subcutaneous injection of glucagon or epinephrine may be a useful alternative, until administration of glucose becomes possible. All patients with cerebral manifestations of hypoglycemia should, in our view, receive an intravenous glucose infusion, which should be continued until consciousness and orientation are fully restored. In all such patients, the danger of recurrent hypoglycemia persists for at least 24 hours after the start of therapy, ami a round-the-clock oral source of carbohydrate should be provided after consciousness has been restored. Ordinarily, restoration of cerebral function is prompt and dramatic. In rare instances, however, little or no response is noted initially, despite maintenance of hyperglycemia for long periods of time. In such a situation, glucose administration should be continued until consciousness is fully restored or until another cause for persistent unconsciousness has been found and all danger of recurrent hypoglycemia eliminated, since failure to respond promptly to glucose administration does not exclude the diagnosis of hypoglycemic coma. SUMMARY
Although diabetics are at least as prone as nondiabetics to the medical emergencies discussed elsewhere in this issue, diabetic ketoacidosis and
Medical Emergencies in Diabetes severe iatrogenic hypoglyeemia are two emergencies encountered only in the diabetie population. An attempt has been made to explain the pathophysiologic disturbances that produce these dramatic clinical syndromes and to place therapy on a physiologic rather thau an empirical base. REFERENCES 1. Bearn, A. G., Billing, B. H. and Sherlock, S.: Response of the Liver to Insulin
in Normal Subjects and in Diabetics. Clin. Sc. 11: 151, 1952. 2. Bondy, P. K., Bloom, W. L., Whitner, V. S. and Fararr, B. W.: Studies on thc Role of the Liver in Human Carbohydrate Metabolism by the Venous Catheter Technic. n. Patients with Diabetic Aeidosis Before and After the Administration of Insulin. J. Clin. Invest. 28: 1021, 1948. 3. Dole, V. P.: Significance of the Nonesterified Fatty Acids in Plasma. A.M.A. Arch. Int. Med. 101: 1005, 1958. 4. Field, .r. B. and Stetten, De W. Jr.: Humoral Insulin Antagonism Associakd with Diabetic Acidosis. Am. J. Med. 81: 3:~9, 1956. 5. Levine, R. and Goldstein, M. S.: On the Mechanism of Action of Insulin. Ree. Progr. in Hormone Hesearch 11: 343, 19.55. 6. Lossow, W. J., Brown, G. W. Jr. and Chaikoff, I. L.: Action of Tnsltlin in 8paring Fatty Acid Oxidation: A Study with Palmitic Acid-I-Cl and Octanoate-l-C14]. 7. Madison, L. L., Combes, B., Strickland, W., Unger, R. H. and Adams, H.: Evidence for a Direct Effect of Insulin on Hepatic Glucose Output. Metabolism 8: 469, 1959. 8. McArthur, J. W. and others: Studies Concerning the Role of the Adrenal Cortex in the Pathologic Physiology of Diabetic Acidosis. I. Temporal Relations Between the Metabolic Events of Experimental Diabetic Acidosis and the Level of Adrenal Cortical Function. J. Clin. Invest. 88: 410, 1954. H. Park, C. R., Johnson, L. H., Wright, J. H. and Betsel, H.: Effect of Insulin on Transport of Several Hexoses and Pentoses into Cells of Muscle and Brain. Am. J. Physiol. 191: 13, 1957. 10. Ross, E. J.: The "Permeability" Hypothesis of the Action of Insulin. Medicine 85: 355, 1956. ]]. Seltzer, H. S.: Rapid Estimation of Blood Glucose Concentration with Ordinary Tes-Tape. J.A.M.A. 162: 1235, 1956. 12. Unger, R. H., Madison, L. L. and Carter, N. W.: The Proper Choice of Oral Antihyperglycemic Therapy in Diabetes Mellitus. Postgrad. Med. 29: 40, 1961. 1:1. Unger, It. H., Madison, L. L. and Carter, N. W.: Tolbutamide-Phenformin in Ketoacidosis-Resistant Patients. J.A.M.A. 174: 2132, 1960. 14. Welt, L. G.: Clinical Disorders of Hydration and Acid-Base Equilibrium. BostoIl, Little, Brown & Co., 1955. 15. Wilkerson, H. L. C. and Heftmann, E.: Screening Method for Blood Glucose. J. Lab. & Clin. Med. 3: 236, 1948. 16. Williams, It. H.: Diabetes. New York, Paul B. Hoeber, 1960.
DIABETIC KETOACIDOSIS
FEW MEDICAL EMERGENCIES are as dramatic as diabetic ketoacidosis or as demanding of prompt and proper therapy. In this disorder, an absolute or relative lack of insulin action leads to profound derangement of carbohydrate, fat and protein metabolism, and of water, acid-base and electrolyte balance; ultimately, the function of virtually every vital system may, to a varying degree, become impaired. A broad understanding of the complex cycle of pathophysiologic events is a prerequisite for optimal therapy. P hysiologic Considerations
INSULIN ACTION. Insulin acts both upon the liver, decreasing its output of glucose,!' 7 and upon certain extrahepatic tissues such as fat and muscle, increasing the permeability of their cell membranes for glucose. 5 . 9. 10 The insulin normally.secreted in reponse to a glucose load returns the blood sugar to normal by diminishing hepatic production of glucose and increasing its uptake by extrahepatic tissues. The glucose thus gained by liver cells and by muscle cells is stored as glycogen or utilized; the glucose entering fat cells is converted to fat, the breakdown of the glucose providing the 2-carbon fragments from which fatty acids are synthesized. Since fat is the principal storage form of the energy of glucose, the stimulation of lipogenesis must be considered a major effect of insulin. CONSEQUENCES OF INSULIN LACK. In the total absence of insulin action the output of glucose from the liver is completely unrestrained. Despite depletion of hepatic glucose stores, new glucose is formed by the liver cells and poured into the circulation. 2 Hyperglycemia is further increased by reduced entry of glucose into extrahepatic tissues. In fat cells, the lack of intracellular glucose is marked by a cessation of lipogenesis and rapid mobilization of stored fat. The concentration of free fatty acids rises in the blood3 and they reach the liver where they are very rapidly oxidized to 2-carbon fragments 6 which, in the absence of'
487
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insulin, cannot be disposed of through usual channels. For reasons not thoroughly understood, they are synthesized to keto-acids at an increasing rate, and hyperketonemia results. Thus, the primary consequences of insulin lack, hepatic overproduction of glucose and underpenetration of glucose into the cells of the peripheral tissues, account for the hyperglycemia and hyperketonemia, each of which in turn produces profound and far-reaching alterations. CONSEQUENCES OF HYPERGLYCEMIA. Hyperglycemia results in hyperosmolarity of extracellular fluid and initiates a movement of water out of the cells. The resulting intracellular dehydration may jeopardize the integrity of cellular function. In addition, the massive glucose load filtered through the glomeruli induces an osmotic diuresis; large volumes of water and, in addition, variable quantities of sodium, potassium and other electrolytes are lost. These losses may be intensified by vomiting and diarrhea and infection which often complicate the clinical picture. With contraction of the extracellular space, glomerular filtration falb;, prerenal azotemia appears, and hypotension and peripheral circulatory collapse may supervene. CONSEQUENCES OF HYPERKETONEMIA. The excessive production of acetoacetic acid and beta-hydroxybutyric acid by the diabetic liver results in an exceSR of hydrogen iOllR which combine with bicarbonate ions as followR,
driving the reactions to the right. Bicarbonate concentration falls, CO 2 tension riscs and the volume of respiration increases in an effort to excrete CO 2 and maintain a normal pH. The kidneys also participate in this endeavor by excreting hydrogen ion and ammonia. However, as dehydration and hypovolemia impair glomerular filtration and renal blood flow, the ability to maintain compensation will ultimately wanc, and the pH of the blood will fall. Kussmaul respirations add the mURcular work of hyperventilation to a generally deteriorating situation. Cerebral function is depressed, possibly through accumulation of acetoacetate in the presence of cerebral dehydration and acidosis, and coma ultimately supervenes. Clinical Considerations
DIAGNOSIS The diagnosis of diabetic ketoacidosis and coma is ordinarily quite obvious. In rare instances, an erroneous diagnosis of diabetic ketoacidosis may be made and lead to unnecessary and potentially hazardous treatment. Such an error may occur when acidosis or coma occurs in a diabetic from a cause other than absolute or relative insulin lack, or
Medical Emergencies in Diabetes
489
when tests for glycosuria and ketonuria are positive in relatively mild diabetics after a fast. They may also be positive in labile diabetics during overaggressive therapy with phenformin (DBI), after severe hypoglycemic insulin shoek when the blood sugar is rebounding, and in salicylate poisoning. In general, however, the clinical and laboratory findings in "true" diabetic ketoacidosis, dominated by increasing polyuria and dehydration, are unmistakable. A blood sugar of 400 mg./lOO ml. or above associated with a 4+ Acetest reaction in plasma is virtually diagnostic of true diabetic ketoacidosis. Blood and urine specimens should be obtained immediately to confirm the diagnosis and to provide a therapeutic baseline. An acetone test on plasma should be done in varying dilutions at the bedside with an Acetest tablet as therapy is begun. Rapid bedside methods for semiquantitation of blood glucose concentrations are also available if requiredY. 14 THERAPY
A flow sheet should be used to record vital signs every half hour, urine tests hourly, and blood levels of glucose, CO 2 and plasma acetone at intervals of two to six hours, if possible. Continuous bedside attendance by a physician will be required until recovery. Without delaying the start of therapy, a careful search for precipitating infection and other disease should be made, so that appropriate therapy of coexisting disease may be instituted if necessary. If danger of aspiration exists because of vomiting, the stomach should be emptied by tube. Because of the changing circumstances during the therapy of ketoacidosis, it is helpful to distinguish between the critical first phase of therapy which, although varying, ordinarily lasts about three to six hours, and the second phase, which continues until recovery. In the first phase, the objectives of therapy are to reinstitute insulin action, irrespective of the dose required, and to replace salt and water loss so as to maintain extracellular volume and prevent circulatory collapse. In the second phase, the objectives are to maintain and extend the gains achieved in the first phase, without causing hypoglycemia or alkalosis or permitting deficits of intracellular ions to develop. Insulin. Unless insulin action is reinstituted, death is certain. Yet most severely ketoacidotic patients display a major degree of resistance to the action of insulin. Whether the target cells, abused by dehydration and loss of intracellular ions, have temporarily lost their responsiveness to insulin, or whether some circulating antagonists such as an adrenal steroidS or an alpha globulin4 is responsible, is unclear. Whatever its cause, the need to overcome it is vital and a large dose of insulin should be introduced without delay. In severe acidosis, 100 to 250 units should be given, most of it by vein. At this stage of therapy, the danger of
490
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H.
UNGER
underdosage is much greater than the danger of overdosage, and timidity here is unwarranted. Hourly doses of 50 to 100 units are continued as needed until the blood sugar declines to about 300 to 350 mg. per cent or the urine sugar falls. When such evidence of responsiveness to insulin appears, the aggressive first phase of treatment has ended and the danger of hypoglycemia now exists. Fluids. The longstanding unresolved controversy as to the best of several therapeutic approaches to fluid and electrolyte deficits suggests that differences between the various regimens are, at most, slight. In the initial phase of therapy, about 3 liters of fluid will be administered. In restoring extracellular fluid volume, 2000 cc. at least may be given as isotonic saline or Ringer's solution. However, since water has been lost in excess of electrolytes, water should be replaced in excess of electrolytes. The use of 5 per cent glucose in water for this purpose is contraindicated in the first phase of therapy, since the infused glucose will remain in the extracellular compartment and intensify the hyperosmolarity. Fructose, however, can enter cells in the absence of insulin; about 1000 cc. of a 5 per cent fructose solution is, therefore, a reasonable approach to the problem of water replacement, as is the use of hypotonic saline. As soon as insulin effect becomes apparent and the blood sugar has fallen below 300 mg. per cent, 5 per cent glucose solutions, coordinated with the insulin therapy, should be used to replace water loss until fluids can be administered by mouth; this will prevent hypoglycemia and speed the fall in blood ketone levels. Although many consider it unnecessary, the use of a single liter of ~ molar lactate will not be harmful and may be justified in extreme acidosis. In the second phase of therapy, fluid administration is continued at a less urgent pace in accordance with estimated needs. As a consequence of rehydration and of the re-entry of glucose into cells, the serum potassium, which may have been elevated earlier, will fall because of its re-entry into cells and its continuing loss in the urine. If, at this time, the patient still cannot take potassium-rich fluids (orange juice, beef broth) by mouth, a total of 100 to 1.50 mEq. of potassium as the phosp hate or chloride should be administered in low concentration at a rate never exceeding 20 mEq. per hour. In addition to hypokalemia, hypomagnesemia may complicate the recovery phase. Peripheral circulatory collapse is a major hazard that may occur at any time during therapy of ketoacidosis. It will ordinarily respond to replacement of fluid loss. If it should not, despite adequa te restoration of extracellular fluid, more aggressive therapy with pressor amines is indicated, since long-continued shock may persist even after restoration of extracellular volume, and proceed to complete irreversibility. Hypoglycemia, metabolic alkalosis and hyperkalemia are not uncommon consequences of overtreatment which may seriously complicate therapy. Hypoglycemia can be avoided by the timely use of glucose in
Medical Emergencies in Diabetes
491
the second phase of therapy, as suggested above. Alkalosis and hyperkalemia often result from efforts to "normalize" via the intravenous route. Such hazardous iatrogenic complications can be avoided by aiming, not for precise normalization, but merely for the correction or prevention of serious abnormalities. This policy will permit the patient to reach the recovery stage, in which the finer adjustments in electrolyte composition will occur spontaneously upon resumption of oral feeding. HYPOGLYCEMIA
Severe hypoglycemia is a serious medical emergency that may arise in any diabetic receiving effective antihyperglycemic therapy. A declining arterial blood glucose concentration threatens the vital glucosedependent tissues of the central nervous system by jeopardizing their access to glucose, their only source of energy. The initial symptoms of hypoglycemia are generally considered to include nervousness, pallor, sweating, tremor, tachycardia, etc. These symptoms are not the result of the low blood sugar level per se but of an increase in circulating epinephrine, secreted by the adrenal medulla in an effort to restore the blood sugar level by stimulating hepatic glycogenolysis. If, for any of several reasons, this protective device fails or is unequal to the task, the blood sugar will decline to a level incompatible with normal cerebral function. Then, unless glucose becomes available to these cells without delay, psychotic behavior, unconsciousness, convulsions and death may ensue. Repeated or prolonged hypoglycemic episodes can lead to chronic and irreversible brain damage. CAUSES
Insulin therapy is, of course, the most common cause of hypoglycemia among diabetics. Many severe ketoacidosis-prone diabetics display a remarkable degree of sensitivity to insulin. An increase in exercise, delay in a meal, or deliberate or inadvertent overdosage with insulin may cause a severe episode of hypoglycemia in such a patient and, to a lesser degree, in any diabetic. In newly treated diabetics, sudden changes in insulin requirements may occur after the first few days or weeks of insulin therapy, and profound hypogJycemia may result. The orally administered antihyperglycemic agents may also cause severe and even fatal hypoglycemia. Because tolbutamide (Orinase) is rapidly inactivated by the normal liver, it is an uncommon cause of serious hypoglycemia. In rare patients with severe liver disease, inactivation of tolbutamide may be impaired, and serious hypo glycemia may ensue. Another possible hypoglycomic hazard in sulfonylurea-treated patients stems from the ingestion of large doses of salicylates which may potentiate hypoglycemic activity. This possibility should be pointed out to all patients receiving this form of therapy.
492
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H.
UNGER
Chlorpropamide (Diabinese) is a long-acting sulfonylurea which is excreted rather than inactivated. As a result, cumulative effects are more common than with tolbutamide, and hypoglycemia is more co mmon.1 2 Because the hypoglycemia may develop quite insidiously, the typical warning symptoms of epinephrine secretion may not be prominent and the neurological manifestations of hypoglycemia may dominate the clinical picture. The resulting atypical nature of the symptoms may delay the identification of their cause, thereby increasing the danger. Phenformin (DBI), when used alone, has not been reported to cause hypoglycemia. When it is used in combination with the sulfonylureas or with insulin, however, severe hypo glycemia may be encountered. 13 TREATMENT
The treatment of severe hypoglycemia is to provide an abundance of glucose in order to restore cerebral function to normal as rapidly as possible. Epinephrine and glucagon have been used for this purpose, as they raise the blood sugar concentration by activating hepatic enzymes which accelerate the breakdown of hepatic glycogen, thereby increasing the hepatic output of glucose into the circulation. However, if insufficient hepatic glycogen is present, their hyperglycemic action may be inadequate. For this reason, glucose, as the 50 per cent solution, administered rapidly by vein, remains the treatment of choice. In psychotic and convulsing patients, if a venipuncture is difficult, a subcutaneous injection of glucagon or epinephrine may be a useful alternative, until administration of glucose becomes possible. All patients with cerebral manifestations of hypoglycemia should, in our view, receive an intravenous glucose infusion, which should be continued until consciousness and orientation are fully restored. In all such patients, the danger of recurrent hypoglycemia persists for at least 24 hours after the start of therapy, ami a round-the-clock oral source of carbohydrate should be provided after consciousness has been restored. Ordinarily, restoration of cerebral function is prompt and dramatic. In rare instances, however, little or no response is noted initially, despite maintenance of hyperglycemia for long periods of time. In such a situation, glucose administration should be continued until consciousness is fully restored or until another cause for persistent unconsciousness has been found and all danger of recurrent hypoglycemia eliminated, since failure to respond promptly to glucose administration does not exclude the diagnosis of hypoglycemic coma. SUMMARY
Although diabetics are at least as prone as nondiabetics to the medical emergencies discussed elsewhere in this issue, diabetic ketoacidosis and
Medical Emergencies in Diabetes severe iatrogenic hypoglyeemia are two emergencies encountered only in the diabetie population. An attempt has been made to explain the pathophysiologic disturbances that produce these dramatic clinical syndromes and to place therapy on a physiologic rather thau an empirical base. REFERENCES 1. Bearn, A. G., Billing, B. H. and Sherlock, S.: Response of the Liver to Insulin
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