The Prevention of Potential
Hypoglycemiia as a Sequela of SedaionWith Ethanol Jess Hayden, Jr., D.M.D.* Frank M. McCarthy, M.D., D.D.S.**
It is the purpose of this review to briefly summarize for the dentist considerations relating to the etiology, symptoms, treatment, and prevention of alcoholinduced hypoglycemia. In an earlier article we described, based on our clinical experience, "Ethyl Alcohol by the Oral Route as a Sedative in Dentistry. "13 The significance and low level probability of hypoglycemia induced by ethanol briefly was discussed in clinical terms. By attention to the recommendations in this review or a fortuitous population of patients, we have not observed in our practice hypoglycemic episodes due solely to administering ethyl alcohol. However, in some instances we belive preappointment ad libitum ingested alcohol was a contributing factor to observed syncope in conjunction with local anesthesia and accompanying stress. The premise of this summary review of the biochemical or physiological mechanisms associated with alcohol-induced hypoglycemia is that forewarning can prevent untoward hypoglycemic episodes in the dental office, and an understanding of the condition can enable the dentist to provide adequate treatment in hypoglycemic emergency situations unrelated to dentistry. As we noted in the previous article, the significance of hypoglycemia relates to the observation that the brain is unusual among the larger organs in its dependence on glucose. In the presence of low levels ofblood glucose, muscle, liver, and kidney are able to oxidize other substrates and the level of functioning does not immediately change. 14 The brain, when deprived of normal glucose levels, stops normal function in seconds. Within a few minutes its glucose content is exhausted and coma ensues. The actual prevalence of hypoglycemia following a dose of ethanol calculated to produced sedation is undetermined although apparently rare. Two factors presumably bear on the absence of reported cases; the failure either to report a hypoglycemic incident, or to recognize the manifold and bizarre symptoms of the syndrome. As an example, from the time of its discovery in 1941 until 1968, only 101 cases of hypoglycemia *Clinical Professor Dept. of Surgical Dentistry School of Dentistry, University of Colorado Med Ctr Present address: Denver, CO 80262.
**Professor and Director, Section of Anesthesia and Medicine, University of Souithern California School of Dentistry.
96V
associated with ethanol were reported in the medical literature; yet in those areas where the syndrome was recognized, within a short time a number of case reports were published. 11 The balance ofthis discussion will deal with the symptoms and mechanisms of ethanol-induced hypoglycemia in terms that may be related to dental practice. A detailed review is provided by Madison,11 or by examining the literature cited by others.3'6'7'10'19 The clinical symptoms of ethanol-induced hypoglycemia, in part, are the same as those from any causes.6 The patient in hypoglycemic coma must be differentiated from one in diabetic coma. Figure 1 depicts some distinguishing differences. Figure 1
Observed variable food insulin skin tremors blood sugar urine sugar
Coma Diabetic Hypoglycemic deprivation excess normal or excess insufficient moist dry observed absent low high absent profuse
Himwich'0 compares in 5 stages the similarities of the symptoms of hypoglycemia and acute anoxia. We list only the symptoms of hypoglycemia. His description relates the first symptoms to the cerebral cortex, with successive depression at various levels. Figure 2
Hypoglycemia First phase Perspiration
Salivation
Cerebral localizations Depression of cortical and cerebellar activity
Motor excitement Clouded consciousness Second phase Loss of consciousness Release of subcorticodienceMyoclonic twitchings phalic region Clonic spasms Motor restlessness
Dilated pupils Tachycardia
ANESTHESIA PROGRESS
Hypoglycemia
Cerbral localizations
Third phase Bradycardia giving Release of midbrain way to tachycardia during spasms Tonic spasms Torsion spasms Fourth phase Release of upper medulla Extensor spasms Dilated pupils oblongata Bradycardia except during spasms Fifth phase Bradyeardia Release of lower medulla Respiratory depression oblongata adapted from Himwich'0, table 10-1,
p.
242.
The clinician ususally associates the hypoglycemic syndrome with chronic or acute alcoholism, malnutrition, vitamin B deficiency, and/or a dietary fast of two or three days. However, the syndrome may occur in the absence of these conditions, that is, in well nourished adults and adolescents including the occasional drinker and the weekend spree drinker. The fasting period may be only twelve to twenty-four hours. Children are particularly susceptible to ethanol-induced hypoglycemia; and the usual fasting time may be shorter and hypoglycemic effects follow sooner. Adults who are malnourished, glycogendepleted, or taking therapeuctically prescribed hypoglycemic drugs2 also have an increased susceptibility to the hypoglycemic action ofethanol. 11 The observant dentist recognizes that individuals meeting the descriptions are among those regularly seeking dental treatment. Hypoglycemia due to liver disease rarely is observed in alcoholics, but may occur in the presence of minimal or insignificant clinical or laboratory evidence of liver disease. The pathologic liver conditiions which predispose to hypoglycemia requiring hospitalization" will not likely be seen in the dentist's office. Profound, serious and lethal hypoglycemia may occur at blood levels of ethanol less 150 mg/dl.11 That level may follow the ingestion of 2-8 bottles ofbeer or 2-8 oz. (59-237 mg.) of whiskey. The blood level of alcohol typical for recognizable intoxication is in the range of 150-300 mg/dl.'5 There are two phases to the clinical picture of ethanol-induced hypoglycemia. The first is due to an increased secretion of epinephrine in response to low blood glucose levels; the second to a decreased supply of glucose to the brain. In the first phase, if the hypoglycemia occurs after the patient leaves the dental offlce, the epinephrine-induced symptoms are missed. Conversely, hyperepinephrinemia occurring in the office following injection of local anesthetic solution containing epinephrine could be attributed by the dentist solely to effects of the injected epinephrine and/or the endogenous catecholamines produced by anxiety.4 The microgram quantities of catecholamine in local MAY-JUNE, 1978
anesthetics are potent.1 At certain levels, ephinephrine stimulates glycogenolysis (and lipolysis) through the activation of cyclic AMP (cAMP)15 and may lead to early catabolism of available glucose and remaining glycogen stores. We have observed that the anxious patient with presumably high levels of endogenous epinephrine often ingests in beverages surprisingly large amounts of caffeine, a methyl xanthine. 8 The latter, at high enough levels, are associated with a prolongation of epinephrine cAMP. The characteristic second phase of the ethanolcaused hypoglycemia results because the brain does not receive enough glucose to meet its metabolic requirements. The brain of a newborn weighs about one-third as much as that of an adult (but is a greater percentage of body weight). It attains most of its total weight by the end of the second year. The adult brain weights 1100-1400 gms. The brain constitutes only 2% of the body weight, but it requires about 17% (1/6) of the hepatic glucose output.510 The generous blood supply ofthe brain usually delivers each minute 5 to 8 times the requirement of glucose. Himwich'0 estimated, on the basis of cerebral oxygen consumption that the brain consumes 76 mg/min or 4.6 mgs of glucose/hr. Wollman's20 estimate ofthe control rate of glucose in the awake man is less but is consistent with Himwich. The usual equilibrium blood level of glucose is 50 to 100 mg/dl. Levels below 50 mg/dl indicate clinical hypoglycemia. It is stated that, from a practical standpoint, low blood glucose is clinically significant only when associated with "characteristic signs" of cerebral dysfunction.36 However, experienced pediatricians advise that a small child may suffer significant and irreparable brain damage disproportionate to the hypoglycemia associated signs and symptoms.17 Within one-half to one hour following a meal, blood glucose reaches its maximum of approximately 130 mg/dl, and by two and one-half hours falls to its fasting levels. The fasting or equilibrium level is reached through either the metabolic use of glucose (glycolysis) or its storage (synthesis of glycogen). However, glycogen stores are sharply limited, probably not exceeding 0.5 kg in the normal adult.15 Glucose immediately available to the tissues of the body (glucose pool) seldom exceeds 20 grams at any one time. In the fasting state, the glucose which leaves the glucose pool is replaced by glucose from the liver.'2 Glucose is the main carbohydrate of the body, but carbohydrate is usually stored as fat. The body can burn up its glycogen reserve during an overnight fast, and normally turns to gluconeogenesis to produce glucose. The usual precursors in this process are amino acids, but during fasting, lactate, as well as glycerol produced by adipose tissue during lipolysis, are sources of glucose. If gluconeogenesis is depressed, the arterial blood glucose falls below the required level. First the cerebral cortex, then progressively lower brain centers suffer. The clinical picture may show sparing of some brain areas while others are affected. Should a patient suffer from a cerebral vascular disease, the sclerotic 97
vessels may receive less glucose than others with the resulting evidence of focal neurological dysfunction. Madison reported that in a review of 101 cases of hypoglycemia the consistent alteration in vital signs was hypothermia (94-97°F). Pulse rates were slow or fast, blood pressure elevated or lowered, and breathing was stertorous or Cheyne-Stokes. Many neurologic manifestations were observed and, in children, convulsions were frequent complications. "It is both relevant and pertinent to point out that hypoglycemia may masquerade as almost any neurologic syndrome and mimic any psychiatric disorder; its manifestation may vary from subtle mental changes to bizarre neurological alterations."1 Ethanol-induced hypoglycemia is suspected by the clinical signs and history and diagnosed by a finding ofa low level (less than 50 mg/dl) of blood glucose.3 A positive response to the therapeutic intravenous administration of 50% glucose assists the diagnosis. The dramatic cessation of neurologic symptoms and a return to consciousness is expected. A delayed response portends a grave prognosis. The mortality from the complications of prolonged hypoglycemia is high, 11 of the previously mentioned 101 adults died. Three of twelve children succumbed notwithstanding intravenous glucose therapy. Perhaps the 25% mortality rate was due to a failure to recognize the syndrome early and to promptly institute treatment. One-halfofthe children admitted to the hospital had convulsions, a prevalence much greater than that reported in adults. Further, many deaths related to ethanol-induced hypoglycemia probably were attributed to alcoholism or some form of simulated central nervous system disease. 11 There are several considerations for insuring accuracy in blood glucose concentrations. First, in the collection and storage of a blood sample for analysis it is necessary to promptly separate serum or plasma from red blood cells. Samples of whole blood must be analyzed within one-half hour because the glycolysis of glucose is rapid. In serum or plasma glucose levels remain relatively stable up to 48 hours, and such samples are more suitable for automated methods of determination. Of the several methods of determining true blood glucose, enzymatic or ortho-toluidine methods at present are the most specific.9 Madison"1 indicated that at the time of his review all techniques used to measure glucose were not described, and that the reported glucose concentrations likely represent an overestimation oftrue glucose concentrations. In 81 individuals suffering from ethanol-induced hypoglycemia, blood glucose concentrations ranged from 5-57 mg/dl. Further, in 30 patients from whose blood values for glucose and ethanol concentrations were obtained, only 4 had ethanol levels commensurate with coma, the other 26 had ethanol concentrations of less than a level considered to indicate intoxication (150 mg/dl). Profound hypoglycemia with a blood glucose level as low as 30 mg/dl occurred with ethanol concentrations of 120 mg/dl. In dogs, hypoglycemia at times 98
was induced with blood concentrations of ethanol as low as 10-20 mg/dl. Ethanol-induced hypoglycemia is associated with a period of fasting and depleted glycogen stores. The operative factors are those which suddenly alter a given rate of glyconeogenesis in fasting (hours to days) children or adults. It is proposed that the synthesis of phosphoenolpyruvate is depressed, and phosphoenolpyruvate is essential to the functioning of the Krebs (citric acid) cycle and gluconeogenesis. Ethanol is oxidized in the liver, where the enzymes alcohol dehydrogenase and acetaldehyde dehydrogenase convert alcohol to acetaldehyde and acetic acid respectively. Both enzymes are nicotinamide adenine dinucleotide (NAD+) linked. The ratio of NADH*/NAD+ is significantly increased in liver cells during oxidation of alcohol. The body's ability to reoxidize NADH is inhibited by ethanol, which affects several metabolic pathways. As a consequence, the amount of substrate available for the biosynthesis of glucose is depressed. Further, many enzymatic steps in gluconeogenic pathways are NAD + dependent. The increased NADH/NAD+ ratio brought about by the oxidation of ethanol decreases the effective available concentration of NAD+, and therefore inhibits hepatic glyconeogenesis. 18 Evidence for the mechanism proposed is that reducing the NADH/NAD + ratio by injecting the redox dye methylene blue restores gluconeogenesis and increases hepatic glucose. 7,11 Thus, it is hypothesized that ethanol, in the fasting, glycogen-depleted liver, in susceptible children or adults, suppresses gluconeogenesis, and that the
increased NADH/NAD+ ratio generated by the oxidation of ethanol in the hepatic cell blocks gluconeogenesis.18 The, report "Significant pathways of hepatic ethanol metabolism" summarizes the viewpoints regarding oxidation of ethanol at the level of microsome. 19 We believe that ethyl alcohol by the oral route may be administered for sedation without inducing hypoglycemia if the following common sense practices are observed. The patient to receive ethanol should have pretreatment meal 3 hours before the appointment for an adult. For individuals up to 16 years of age, one of us (JHJr) prescribes a meal 1½-2 hours pretreatment. The meal should be light, high carbohydrate, perhaps dry cereal and milk, or as in Figure 3 as described by Nizel.16 Figure 3
Breakfast: 1. 4 oz. fruit juice 2. Cooked cereal with milk 3. Toast with butter
Lunch: 1. Soup (cream of mushroom, chicken, split pea) 2. Custard 3. Milk (4-6 oz.) *NAD, reduced
ANESTHESIA PROGRESS
The ethanol is administered by mouth to the patient while in the dentist's office. The dosage should be calculated to give a blood level not to exceed 50 mg/dl. Thus, Figures 4 and 5. Figure 4
Calculation of theoretical sedative blood levels (50 mg/dl) of ethanol administered orally as elixir USP* Total Body Water** Rx ethanol N N Age/ mg/ yrs lbs kg ml dl x dl = I mg = ml = oz 48 1.6 12 894024,000 240 50 12,000 adult 1808257,400 574 50 28,700 115 4
BIBLIOGRAPHY
*250 mg/ml ** = 60% lean body mass child 70% lean body mass adult
1. Allen G D Everett G B Forsyth W E and Kennedy Jr W F The
2.
Figure 5
Calculating sedative 50 mg ROH/dl 60% HOH/kg 100 ml = 1 dl
ethanol ROH concentration Elixir USP = 25% ROH Elixir USP = 250 mq/ml ROH 30 ml = 1 oz
(kg) (1000) (0.60)
=
dl
100 (dl) (50) = ml ROH
The calculations are clinically applicable, but not precise, for the estimation oftotal body fluid is approximate and total weight rather than lean body weight is used in the calculations except for the obese. In the latter instance an approximate of lean body mass should be attempted. Withhold ethanol from patients on antihypoglycemic medication (Sulfonylureas) unless there is evidence of the patient's ability to tolerate both drugs. If a fasting patient comes to the office for treatment, or exhibits, while in the conscious state, signs of hypoglycemia, "Polycose"* may be administered po. It is tasteless, stable and comes packaged as a powder or liquid which may be mixed with liquids. Its several sugars are rapidly absorbed through the gut. If the patient is unconscious, then the IV injection of 1 ml/kg of 50% glucose in water, a supine position, and 100% oxygen by mask are in order. The hypoglycemic patient, if treated early, will respond rapidly. If there is not a prompt response then one may suspect diabetic coma. It may be postulated that with constant supervision and prompt treatment, an irreversible coma will not likely result. In conclusion, this review has discussed the significant but low prevalence problem of hypoglycemia induced by the ingestion of ethyl alcohol. The symptoms are seen primarily in susceptible individuals who have depleted stores of glycogen. In such individuals alcohol administered during the fasting state may act to *Ross Laboratories, Columbus, Ohio 43216.
MAY-JUNE, 1978
both suppress and block gluconeogenesis. With their glucose pool and glycogen stores exhausted and the gluconeogenic mechanisms inoperable, the individual becomes hypoglycemic. The condition may occur after the ingestion of alcohol in amounts far less than that required to produce intoxication. By administering a calculated dose of alcohol that results in a blood concentration that does not exceed 50 mg/dl, withholding alcohol from patients on hypoglycemic drugs and prescribing a high glucose pretreatment meal, the dentist may prevent a hypoglycemic episode and take advantage of the benefits afforded by ethanol as a sedative.
3. 4.
5. 6.
7. 8.
cardiorespiratory effects ofepinephrine and local anesthetics for dentistry Anesth Prog 20:152-156, 1973. Coleman J H and Evans W P Drug interactions with alcohol. Alcohol Health and Research World. Experimental issue: 1619, Winter 1975/6. DiGeorge A M and Auerbach V H Hypoglycemia p. 1164-1171 In Nelson, W E Vaughn V C and McKay R J Eds. Textbook of Pediatrics. 9th ed Philadelphia, Saunders 1969. Edmondson H D Roscoe B and Vickers M D Biochemical evidence of anxiety in dental patients Br Med J 4:7-9, 7 Oct. 1972. Eyzaguirre C and Fidone S J Physiology of the Nervous System 2nd Ed Chicago Year Book 1975. Finestone A J and Wohl M G Hypoglycemia: A Complex Problem Med Clin N Amer 54:531-542 1970. Freinkel N Alcohol hypoglycemia IV. Current concepts of its pathogenesis Diabet 14:350-61 1965. Gilbert R M Marshman J A Schwieder M Berg R Caffeine content of beverages as consumed Can Med Assoc J 114:205-8
1976. 9. Henry J B Clinical chemistry. In Davidson, Israel and Henry JB
Todd-Sanford Clinical Diagnosis by Laboratory Methods. 15th Ed Philadelphia WB Saunders 1974. 10. Himwich H E Brain Metabolism and Cerebral Disorders 2nd Ed Baltimore Williams and Wilkins 1976. 11. Madison L L Ethanol induced hypoglycemia Advances in Metabolic Disorders V 3 New York Academic Press 1968. 12. Marks V Nutrition in Metabolism In Scurr and Feldman Eds Scientific Foundations of Anaesthesia Philadelphia Davis C 1970. 13. McCarthy F M and Hayden J Jr Ethyl alcohol by the oral route as a sedative in dentistry J Am Dent Assoc 96:1978 14. Mcllwain H Biochemistry and the Central Nervous System 3rd Ed Boston Little Brown & Co 1966. 15. Montgomery R Dryer R L Conway T W and Spector A A Ed Biochemistry -A case-oriented approach St. Louis C V Mosby Co 1974. 16. Nizel A E Nutrition in Preventive Dentistry: Science and Practice Philadelphia W B Saunders 1972. 17. Roberts R J Personal communication Oct. 18, 1976. 18. Sauer J M Ethanol-induced hypoglycemia Department of Pharmacology University of Iowa, Dec. 1, 1972. 19. Thurman R G McKenna W R Brentzel H J Jr and Hesse S Significant Pathways of Hepatic Ethanol Metabolism, In: Symposium on the Biology ofAlcohol and Alcoholism. Fed Proceed, 34:2038-81, 1975. 20. Woilman H and Cohen P S Hyperventilation and cerebral oxygenation In Gray, T C and Nunn, J F General Anesthesia. 3rd ed. Vol. 1 Basic Sciences New York Appleton-CenturyCrofts 1971.
99
Hypoglycemiia as a Sequela of SedaionWith Ethanol Jess Hayden, Jr., D.M.D.* Frank M. McCarthy, M.D., D.D.S.**
It is the purpose of this review to briefly summarize for the dentist considerations relating to the etiology, symptoms, treatment, and prevention of alcoholinduced hypoglycemia. In an earlier article we described, based on our clinical experience, "Ethyl Alcohol by the Oral Route as a Sedative in Dentistry. "13 The significance and low level probability of hypoglycemia induced by ethanol briefly was discussed in clinical terms. By attention to the recommendations in this review or a fortuitous population of patients, we have not observed in our practice hypoglycemic episodes due solely to administering ethyl alcohol. However, in some instances we belive preappointment ad libitum ingested alcohol was a contributing factor to observed syncope in conjunction with local anesthesia and accompanying stress. The premise of this summary review of the biochemical or physiological mechanisms associated with alcohol-induced hypoglycemia is that forewarning can prevent untoward hypoglycemic episodes in the dental office, and an understanding of the condition can enable the dentist to provide adequate treatment in hypoglycemic emergency situations unrelated to dentistry. As we noted in the previous article, the significance of hypoglycemia relates to the observation that the brain is unusual among the larger organs in its dependence on glucose. In the presence of low levels ofblood glucose, muscle, liver, and kidney are able to oxidize other substrates and the level of functioning does not immediately change. 14 The brain, when deprived of normal glucose levels, stops normal function in seconds. Within a few minutes its glucose content is exhausted and coma ensues. The actual prevalence of hypoglycemia following a dose of ethanol calculated to produced sedation is undetermined although apparently rare. Two factors presumably bear on the absence of reported cases; the failure either to report a hypoglycemic incident, or to recognize the manifold and bizarre symptoms of the syndrome. As an example, from the time of its discovery in 1941 until 1968, only 101 cases of hypoglycemia *Clinical Professor Dept. of Surgical Dentistry School of Dentistry, University of Colorado Med Ctr Present address: Denver, CO 80262.
**Professor and Director, Section of Anesthesia and Medicine, University of Souithern California School of Dentistry.
96V
associated with ethanol were reported in the medical literature; yet in those areas where the syndrome was recognized, within a short time a number of case reports were published. 11 The balance ofthis discussion will deal with the symptoms and mechanisms of ethanol-induced hypoglycemia in terms that may be related to dental practice. A detailed review is provided by Madison,11 or by examining the literature cited by others.3'6'7'10'19 The clinical symptoms of ethanol-induced hypoglycemia, in part, are the same as those from any causes.6 The patient in hypoglycemic coma must be differentiated from one in diabetic coma. Figure 1 depicts some distinguishing differences. Figure 1
Observed variable food insulin skin tremors blood sugar urine sugar
Coma Diabetic Hypoglycemic deprivation excess normal or excess insufficient moist dry observed absent low high absent profuse
Himwich'0 compares in 5 stages the similarities of the symptoms of hypoglycemia and acute anoxia. We list only the symptoms of hypoglycemia. His description relates the first symptoms to the cerebral cortex, with successive depression at various levels. Figure 2
Hypoglycemia First phase Perspiration
Salivation
Cerebral localizations Depression of cortical and cerebellar activity
Motor excitement Clouded consciousness Second phase Loss of consciousness Release of subcorticodienceMyoclonic twitchings phalic region Clonic spasms Motor restlessness
Dilated pupils Tachycardia
ANESTHESIA PROGRESS
Hypoglycemia
Cerbral localizations
Third phase Bradycardia giving Release of midbrain way to tachycardia during spasms Tonic spasms Torsion spasms Fourth phase Release of upper medulla Extensor spasms Dilated pupils oblongata Bradycardia except during spasms Fifth phase Bradyeardia Release of lower medulla Respiratory depression oblongata adapted from Himwich'0, table 10-1,
p.
242.
The clinician ususally associates the hypoglycemic syndrome with chronic or acute alcoholism, malnutrition, vitamin B deficiency, and/or a dietary fast of two or three days. However, the syndrome may occur in the absence of these conditions, that is, in well nourished adults and adolescents including the occasional drinker and the weekend spree drinker. The fasting period may be only twelve to twenty-four hours. Children are particularly susceptible to ethanol-induced hypoglycemia; and the usual fasting time may be shorter and hypoglycemic effects follow sooner. Adults who are malnourished, glycogendepleted, or taking therapeuctically prescribed hypoglycemic drugs2 also have an increased susceptibility to the hypoglycemic action ofethanol. 11 The observant dentist recognizes that individuals meeting the descriptions are among those regularly seeking dental treatment. Hypoglycemia due to liver disease rarely is observed in alcoholics, but may occur in the presence of minimal or insignificant clinical or laboratory evidence of liver disease. The pathologic liver conditiions which predispose to hypoglycemia requiring hospitalization" will not likely be seen in the dentist's office. Profound, serious and lethal hypoglycemia may occur at blood levels of ethanol less 150 mg/dl.11 That level may follow the ingestion of 2-8 bottles ofbeer or 2-8 oz. (59-237 mg.) of whiskey. The blood level of alcohol typical for recognizable intoxication is in the range of 150-300 mg/dl.'5 There are two phases to the clinical picture of ethanol-induced hypoglycemia. The first is due to an increased secretion of epinephrine in response to low blood glucose levels; the second to a decreased supply of glucose to the brain. In the first phase, if the hypoglycemia occurs after the patient leaves the dental offlce, the epinephrine-induced symptoms are missed. Conversely, hyperepinephrinemia occurring in the office following injection of local anesthetic solution containing epinephrine could be attributed by the dentist solely to effects of the injected epinephrine and/or the endogenous catecholamines produced by anxiety.4 The microgram quantities of catecholamine in local MAY-JUNE, 1978
anesthetics are potent.1 At certain levels, ephinephrine stimulates glycogenolysis (and lipolysis) through the activation of cyclic AMP (cAMP)15 and may lead to early catabolism of available glucose and remaining glycogen stores. We have observed that the anxious patient with presumably high levels of endogenous epinephrine often ingests in beverages surprisingly large amounts of caffeine, a methyl xanthine. 8 The latter, at high enough levels, are associated with a prolongation of epinephrine cAMP. The characteristic second phase of the ethanolcaused hypoglycemia results because the brain does not receive enough glucose to meet its metabolic requirements. The brain of a newborn weighs about one-third as much as that of an adult (but is a greater percentage of body weight). It attains most of its total weight by the end of the second year. The adult brain weights 1100-1400 gms. The brain constitutes only 2% of the body weight, but it requires about 17% (1/6) of the hepatic glucose output.510 The generous blood supply ofthe brain usually delivers each minute 5 to 8 times the requirement of glucose. Himwich'0 estimated, on the basis of cerebral oxygen consumption that the brain consumes 76 mg/min or 4.6 mgs of glucose/hr. Wollman's20 estimate ofthe control rate of glucose in the awake man is less but is consistent with Himwich. The usual equilibrium blood level of glucose is 50 to 100 mg/dl. Levels below 50 mg/dl indicate clinical hypoglycemia. It is stated that, from a practical standpoint, low blood glucose is clinically significant only when associated with "characteristic signs" of cerebral dysfunction.36 However, experienced pediatricians advise that a small child may suffer significant and irreparable brain damage disproportionate to the hypoglycemia associated signs and symptoms.17 Within one-half to one hour following a meal, blood glucose reaches its maximum of approximately 130 mg/dl, and by two and one-half hours falls to its fasting levels. The fasting or equilibrium level is reached through either the metabolic use of glucose (glycolysis) or its storage (synthesis of glycogen). However, glycogen stores are sharply limited, probably not exceeding 0.5 kg in the normal adult.15 Glucose immediately available to the tissues of the body (glucose pool) seldom exceeds 20 grams at any one time. In the fasting state, the glucose which leaves the glucose pool is replaced by glucose from the liver.'2 Glucose is the main carbohydrate of the body, but carbohydrate is usually stored as fat. The body can burn up its glycogen reserve during an overnight fast, and normally turns to gluconeogenesis to produce glucose. The usual precursors in this process are amino acids, but during fasting, lactate, as well as glycerol produced by adipose tissue during lipolysis, are sources of glucose. If gluconeogenesis is depressed, the arterial blood glucose falls below the required level. First the cerebral cortex, then progressively lower brain centers suffer. The clinical picture may show sparing of some brain areas while others are affected. Should a patient suffer from a cerebral vascular disease, the sclerotic 97
vessels may receive less glucose than others with the resulting evidence of focal neurological dysfunction. Madison reported that in a review of 101 cases of hypoglycemia the consistent alteration in vital signs was hypothermia (94-97°F). Pulse rates were slow or fast, blood pressure elevated or lowered, and breathing was stertorous or Cheyne-Stokes. Many neurologic manifestations were observed and, in children, convulsions were frequent complications. "It is both relevant and pertinent to point out that hypoglycemia may masquerade as almost any neurologic syndrome and mimic any psychiatric disorder; its manifestation may vary from subtle mental changes to bizarre neurological alterations."1 Ethanol-induced hypoglycemia is suspected by the clinical signs and history and diagnosed by a finding ofa low level (less than 50 mg/dl) of blood glucose.3 A positive response to the therapeutic intravenous administration of 50% glucose assists the diagnosis. The dramatic cessation of neurologic symptoms and a return to consciousness is expected. A delayed response portends a grave prognosis. The mortality from the complications of prolonged hypoglycemia is high, 11 of the previously mentioned 101 adults died. Three of twelve children succumbed notwithstanding intravenous glucose therapy. Perhaps the 25% mortality rate was due to a failure to recognize the syndrome early and to promptly institute treatment. One-halfofthe children admitted to the hospital had convulsions, a prevalence much greater than that reported in adults. Further, many deaths related to ethanol-induced hypoglycemia probably were attributed to alcoholism or some form of simulated central nervous system disease. 11 There are several considerations for insuring accuracy in blood glucose concentrations. First, in the collection and storage of a blood sample for analysis it is necessary to promptly separate serum or plasma from red blood cells. Samples of whole blood must be analyzed within one-half hour because the glycolysis of glucose is rapid. In serum or plasma glucose levels remain relatively stable up to 48 hours, and such samples are more suitable for automated methods of determination. Of the several methods of determining true blood glucose, enzymatic or ortho-toluidine methods at present are the most specific.9 Madison"1 indicated that at the time of his review all techniques used to measure glucose were not described, and that the reported glucose concentrations likely represent an overestimation oftrue glucose concentrations. In 81 individuals suffering from ethanol-induced hypoglycemia, blood glucose concentrations ranged from 5-57 mg/dl. Further, in 30 patients from whose blood values for glucose and ethanol concentrations were obtained, only 4 had ethanol levels commensurate with coma, the other 26 had ethanol concentrations of less than a level considered to indicate intoxication (150 mg/dl). Profound hypoglycemia with a blood glucose level as low as 30 mg/dl occurred with ethanol concentrations of 120 mg/dl. In dogs, hypoglycemia at times 98
was induced with blood concentrations of ethanol as low as 10-20 mg/dl. Ethanol-induced hypoglycemia is associated with a period of fasting and depleted glycogen stores. The operative factors are those which suddenly alter a given rate of glyconeogenesis in fasting (hours to days) children or adults. It is proposed that the synthesis of phosphoenolpyruvate is depressed, and phosphoenolpyruvate is essential to the functioning of the Krebs (citric acid) cycle and gluconeogenesis. Ethanol is oxidized in the liver, where the enzymes alcohol dehydrogenase and acetaldehyde dehydrogenase convert alcohol to acetaldehyde and acetic acid respectively. Both enzymes are nicotinamide adenine dinucleotide (NAD+) linked. The ratio of NADH*/NAD+ is significantly increased in liver cells during oxidation of alcohol. The body's ability to reoxidize NADH is inhibited by ethanol, which affects several metabolic pathways. As a consequence, the amount of substrate available for the biosynthesis of glucose is depressed. Further, many enzymatic steps in gluconeogenic pathways are NAD + dependent. The increased NADH/NAD+ ratio brought about by the oxidation of ethanol decreases the effective available concentration of NAD+, and therefore inhibits hepatic glyconeogenesis. 18 Evidence for the mechanism proposed is that reducing the NADH/NAD + ratio by injecting the redox dye methylene blue restores gluconeogenesis and increases hepatic glucose. 7,11 Thus, it is hypothesized that ethanol, in the fasting, glycogen-depleted liver, in susceptible children or adults, suppresses gluconeogenesis, and that the
increased NADH/NAD+ ratio generated by the oxidation of ethanol in the hepatic cell blocks gluconeogenesis.18 The, report "Significant pathways of hepatic ethanol metabolism" summarizes the viewpoints regarding oxidation of ethanol at the level of microsome. 19 We believe that ethyl alcohol by the oral route may be administered for sedation without inducing hypoglycemia if the following common sense practices are observed. The patient to receive ethanol should have pretreatment meal 3 hours before the appointment for an adult. For individuals up to 16 years of age, one of us (JHJr) prescribes a meal 1½-2 hours pretreatment. The meal should be light, high carbohydrate, perhaps dry cereal and milk, or as in Figure 3 as described by Nizel.16 Figure 3
Breakfast: 1. 4 oz. fruit juice 2. Cooked cereal with milk 3. Toast with butter
Lunch: 1. Soup (cream of mushroom, chicken, split pea) 2. Custard 3. Milk (4-6 oz.) *NAD, reduced
ANESTHESIA PROGRESS
The ethanol is administered by mouth to the patient while in the dentist's office. The dosage should be calculated to give a blood level not to exceed 50 mg/dl. Thus, Figures 4 and 5. Figure 4
Calculation of theoretical sedative blood levels (50 mg/dl) of ethanol administered orally as elixir USP* Total Body Water** Rx ethanol N N Age/ mg/ yrs lbs kg ml dl x dl = I mg = ml = oz 48 1.6 12 894024,000 240 50 12,000 adult 1808257,400 574 50 28,700 115 4
BIBLIOGRAPHY
*250 mg/ml ** = 60% lean body mass child 70% lean body mass adult
1. Allen G D Everett G B Forsyth W E and Kennedy Jr W F The
2.
Figure 5
Calculating sedative 50 mg ROH/dl 60% HOH/kg 100 ml = 1 dl
ethanol ROH concentration Elixir USP = 25% ROH Elixir USP = 250 mq/ml ROH 30 ml = 1 oz
(kg) (1000) (0.60)
=
dl
100 (dl) (50) = ml ROH
The calculations are clinically applicable, but not precise, for the estimation oftotal body fluid is approximate and total weight rather than lean body weight is used in the calculations except for the obese. In the latter instance an approximate of lean body mass should be attempted. Withhold ethanol from patients on antihypoglycemic medication (Sulfonylureas) unless there is evidence of the patient's ability to tolerate both drugs. If a fasting patient comes to the office for treatment, or exhibits, while in the conscious state, signs of hypoglycemia, "Polycose"* may be administered po. It is tasteless, stable and comes packaged as a powder or liquid which may be mixed with liquids. Its several sugars are rapidly absorbed through the gut. If the patient is unconscious, then the IV injection of 1 ml/kg of 50% glucose in water, a supine position, and 100% oxygen by mask are in order. The hypoglycemic patient, if treated early, will respond rapidly. If there is not a prompt response then one may suspect diabetic coma. It may be postulated that with constant supervision and prompt treatment, an irreversible coma will not likely result. In conclusion, this review has discussed the significant but low prevalence problem of hypoglycemia induced by the ingestion of ethyl alcohol. The symptoms are seen primarily in susceptible individuals who have depleted stores of glycogen. In such individuals alcohol administered during the fasting state may act to *Ross Laboratories, Columbus, Ohio 43216.
MAY-JUNE, 1978
both suppress and block gluconeogenesis. With their glucose pool and glycogen stores exhausted and the gluconeogenic mechanisms inoperable, the individual becomes hypoglycemic. The condition may occur after the ingestion of alcohol in amounts far less than that required to produce intoxication. By administering a calculated dose of alcohol that results in a blood concentration that does not exceed 50 mg/dl, withholding alcohol from patients on hypoglycemic drugs and prescribing a high glucose pretreatment meal, the dentist may prevent a hypoglycemic episode and take advantage of the benefits afforded by ethanol as a sedative.
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cardiorespiratory effects ofepinephrine and local anesthetics for dentistry Anesth Prog 20:152-156, 1973. Coleman J H and Evans W P Drug interactions with alcohol. Alcohol Health and Research World. Experimental issue: 1619, Winter 1975/6. DiGeorge A M and Auerbach V H Hypoglycemia p. 1164-1171 In Nelson, W E Vaughn V C and McKay R J Eds. Textbook of Pediatrics. 9th ed Philadelphia, Saunders 1969. Edmondson H D Roscoe B and Vickers M D Biochemical evidence of anxiety in dental patients Br Med J 4:7-9, 7 Oct. 1972. Eyzaguirre C and Fidone S J Physiology of the Nervous System 2nd Ed Chicago Year Book 1975. Finestone A J and Wohl M G Hypoglycemia: A Complex Problem Med Clin N Amer 54:531-542 1970. Freinkel N Alcohol hypoglycemia IV. Current concepts of its pathogenesis Diabet 14:350-61 1965. Gilbert R M Marshman J A Schwieder M Berg R Caffeine content of beverages as consumed Can Med Assoc J 114:205-8
1976. 9. Henry J B Clinical chemistry. In Davidson, Israel and Henry JB
Todd-Sanford Clinical Diagnosis by Laboratory Methods. 15th Ed Philadelphia WB Saunders 1974. 10. Himwich H E Brain Metabolism and Cerebral Disorders 2nd Ed Baltimore Williams and Wilkins 1976. 11. Madison L L Ethanol induced hypoglycemia Advances in Metabolic Disorders V 3 New York Academic Press 1968. 12. Marks V Nutrition in Metabolism In Scurr and Feldman Eds Scientific Foundations of Anaesthesia Philadelphia Davis C 1970. 13. McCarthy F M and Hayden J Jr Ethyl alcohol by the oral route as a sedative in dentistry J Am Dent Assoc 96:1978 14. Mcllwain H Biochemistry and the Central Nervous System 3rd Ed Boston Little Brown & Co 1966. 15. Montgomery R Dryer R L Conway T W and Spector A A Ed Biochemistry -A case-oriented approach St. Louis C V Mosby Co 1974. 16. Nizel A E Nutrition in Preventive Dentistry: Science and Practice Philadelphia W B Saunders 1972. 17. Roberts R J Personal communication Oct. 18, 1976. 18. Sauer J M Ethanol-induced hypoglycemia Department of Pharmacology University of Iowa, Dec. 1, 1972. 19. Thurman R G McKenna W R Brentzel H J Jr and Hesse S Significant Pathways of Hepatic Ethanol Metabolism, In: Symposium on the Biology ofAlcohol and Alcoholism. Fed Proceed, 34:2038-81, 1975. 20. Woilman H and Cohen P S Hyperventilation and cerebral oxygenation In Gray, T C and Nunn, J F General Anesthesia. 3rd ed. Vol. 1 Basic Sciences New York Appleton-CenturyCrofts 1971.
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