Alcoholic ketoacidosis

CASE CONFERENCE alcoholic ketoacidosis

Alcoholic Ketoacidosis [Adams SL, Mathews JJ, Flaherty JJ: Alcoholic ketoacidosis. Ann Emerg Med [anuary 1987;16:90-97.] INTRODUCTION Today's case is that of a patient who presented with a two-day history of nausea, vomiting, abdominal pain, and shortness of breath. The case will be discussed by Stephen L Adams, MD, associate chief, and James J Mathews, MD, chief, Section of Emergency Medicine, Department of Medicine, Northwestern University Medical School.

CASE PRESENTATION John J Flaherty, MD: A 51-year-old man presented to the emergency department with a chief complaint of nausea, vomiting, abdominal pain, and shortness of breath. The patient had been well until two days prior to admission, when he noted the onset of epigastric abdominal pain associated with nausea and vomiting. He denied hematemesis and reported that he was unable to tolerate any food, but was able to drink small amounts of liquids. Thinking that constipation could have been the cause of his discomfort, he ingested 10 oz magnesium citrate the day before admission, resulting in diarrheal stools that resolved quickly. On the day of admission, the patient's nausea worsened and he developed shortness of breath without complaints of chest pain or orthopnea. He reported a recent increase in alcohol intake during the period immediately prior to the onset of his abdominal pain. The patient had a medical history of heavy alcohol abuse and alcoholic liver disease. Medications included diazepam 2 mg daily and vitamin pills. He had been taking an unknown cold remedy and occasional codeine cough syrup for symptoms of an upper respiratory infection the previous week. He denied misuse of any of these medicines. He had no allergies or prior surgical history. Physical examination revealed a thin man in moderate distress. His vital signs were as follows: supine blood pressure, 130/70 m m Hg; supine resting pulse, 140; respirations, 36; and temperature, 35.7 C. Orthostatic vital signs were not obtained because the patient experienced near-syncope with standing. Examination of the head and neck was unremarkable, except for a ketotic odor of the breath. The pupils were equal, round, and reactive to light and accommodation, and the extraocular muscles were intact. Funduscopic examination revealed sharp disc margins. There was no jugular venous distention or lymphadenopathy. The pharynx was clear without erythema or exudate. Auscultation of the chest revealed equal breath sounds that were clear. The cardiac examination was remarkable for a normal S1 and $2; no third or fourth heart sounds were noted. There were no murmurs. Abdominal examination revealed a distended abdomen with epigastric tenderness. Mild voluntary guarding was noted in the epigastrium with rebound tenderness. Bowel sounds were normoactive. The liver was palpable 7 cm below the right costal margin. There was no splenomegaly. Rectal examination was remarkable for normal tone and a normal-size prostate without nodules. Stool was hemoccult positive. Genitourinary examination revealed small atrophic testicles, but was otherwise negative. Extremity and neurologic examinations were within normal limits. Laboratory data were remarkable for a hemoglobin of 15.7 g/100 mL, a I6:1 January 1987

Annals of Emergency Medicine

Stephen L Adams, MD, FACEP James J Mathews, MD, FACEP John J Flaherty, MD Chicago, Illinois From the Section of Emergency Medicine, Department of Medicine, Northwestern University Medical School, Chicago, Illinois. Received for publication December 4, 1985. Revision received April 2, 1986. Accepted for publication April 21, 1986. Address for reprints: Stephen L Adams, MD, 1209 Olson Pavilion, Section of Emergency Medicine, Northwestern University Medical School, 233 East Superior Street, Chicago, Illinois 60611.

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TABLE. Serial arterial blood gases and electrolytes Time pH PCO 2 PO 2 Base deficit

18:30

19:43

21:15

23:35

01:54

14:50

7.16

7.15

7.26

11

11 124

13 117

7.25 12

7.40 17

7.49 38

23

18

118 19

98 11

96 2

121 22 18:35

22:30

08:46

Na

136

135

132

K

5.0

5.1 106

4.3 101

7

13

15 181

10 108

CI HCO3 BUN Glucose

97 5 18 168

hematocrit of 49.5%, and a white cell count of 8,800. Differential revealed 81 polymorphonuclear neutrophils, seven bands, eight lymphs, two monocytes, and two basophils. The platelet count was 243,000. Electrolytes were as follows: sodium, 136 mEq/L; potassium, 5.0 mEq/L; chloride, 97 mEq/L; and bicarbonate, 5 mEq/L. The glucose was 168 mg/dL and the BUN was 18. The anion gap (Na-[C1 + HCO3J) 1 was calculated to be 34 mEq/L. The room air arterial blood gas revealed the following: pH, 7.16; PCO2, 11 m m Hg; and PO2, 121 m m Hg. The serum amylase was 84 units/L. The serum ethanol level was 26 mg/dL. Urinalysis was remarkable for a specific gravity of 1.020, pH of 6, protein of 1 +, glucose of 1 +, ketones of 4 + , and urobilinogen of 0.1 units; urine bile and blood were not detected. Microscopic urinalysis showed three to six white blood cells per high-power field. No bacteria or crystals were present. Serum acetone (acetoacetate and acetone) by nitroprusside reaction was "small," a serum salicylate level was 3.3 mg/dL, and the venous lactate was 3.5 mEq/L. The SGOT was 108 U/L, LDH was 320 U/L, CPK was 257 U/L, alkaline phosphatase was 99 U/L, total protein was 9.3 g/dL, albumin was 5.5 g/dL, phosphorus was 9.7 mg/dL, calcium was 9.7 mg/dL, magnesium was 1.8 mg/ dL, and uric acid was 11.8 mg/dL. The protime was 11.0 seconds and the partial thromboplastin time was 23.9 seconds. The ECG showed a sinus tachycardia with nonspecific T wave flattening. A chest radiograph revealed no cardiomegaly or infiltrates. An upright abdominal film showed no evidence of free air or pancreatic calcifications. Urine toxicology was positive for caffeine, salicylates, and acetone (> 290 mg%), and negative for methanol and isopropyl alcohol.

HOSPITAL COURSE In the ED the patient was treated with 3,100 mL normal saline, 1,900 mL DsW/0.45 saline, and an ampule of bicarbonate over six hours. Thiamine, magnesium, and vitamins were administered. A nasogastric tube was inserted to low intermittent suction. Six hundred milliliters of hemoccultnegative gastric contents were suctioned. Urine output was 1,350 mL. The patient was admitted to the hospital with a pre122/91

sumptive diagnosis of alcoholic ketoacidosis. On the floor he was hydrated with 1 L DsW containing three ampules of bicarbonate over four hours. He was advanced to a clear liquid diet with resolution of his abdominal pain. Serial arterial blood gases revealed that his acidosis was resolving (Table). IV hydration was discontinued on the next day and the patient was able to tolerate a general diet. He was discharged with complete resolution of his symptoms. Available records d o c u m e n t e d multiple previous admissions with a similar presentation and hospital course. DISCUSSION

Stephen L Adams, MD: This patient presented to the ED as one who had an elevated anion gap metabolic acidosis. The anion gap is defined as the difference between the sodium and the sum of the chloride and bicarbonate, that is, the anion gap = N a - ( C 1 + HCO3). The normal range for the anion gap generally is considered to be 12 _+ 4 mEq. 1 An elevation of the anion gap usually is due to the accumulation of an acid in the extracellular space, resulting in a metabolic acidosis, although there are some exceptionsJ The differential diagnosis of an elevated anion gap metabolic acidosis is relatively limited and should be familiar to every physician who practices emergency medicine. The classic differential includes salicylate toxicity; lactic acidosis; uremia; methanol toxicity; paraldehyde toxicity; ethylene glycol toxicity; and the ketoacidoses, such as diabetic ketoacidosis and alcoholic k e t o a c i d o s i s (Figure 1). 1 Hyperosmolar hyperglycemic nonketotic coma also has been included in the differential. 2 Although these are listed in the classic differential diagnosis, the clinician must remember that the list of etiologies includes many more. Lactic acidosis, of course, is not a single disease, but rather must be considered to be the consequence of numerous etiologies including shock, seizures, and acute hypoxemia. 3 Isoniazid (INH), 4 cyanide, s ritodrine, 6 inhaled industrial acetylene, 7 p h e n f o r m i n , 8 c a r b o n monoxide,9 and ethanol3 are among the agents that have been reported as causes of lactic acidosis, and they should be considered as etiologic agents in the appropriate setting. Sodium nitroprusside, povidine-iodine ointment, sorbitol, xylitol, and

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FIGURE 1. Causes of elevated anion gap metabolic acidosis

(see text).

Salicylate toxicity Lactic acidosis Uremia Methanol toxicity Paraldehyde toxicity Ethylene glycol toxicity Ketoacidosis

streptozocin have been listed as drugs causing increased lactic acid formation, lo Other entities that m a y cause an elevated anion gap acidosis include toluene intoxication,11,12 iron intoxication, I3,14 sulfuric acidosis, ~ and short bowel s y n d r o m e (D-lactic acidosis). 15 F o r m a l d e h y d e , n a l i d i x i c acid, m e t h a n a m i n e , m a n d e l a t e , h i p p u r i c acid salt, and rhubarb (oxalic acid) also have been listed as agents capable of causing a high anion gap acidosis. Io Inborn errors of metabolism, such as the m e t h y l m a l o n i c acidemias I6 and isovaleric acidemia, I7 m a y cause a metabolic acidosis with an elevated anion gap; however, these are u n c o m m o n occurrences in the adult. The differential diagnosis of a patient who presents w i t h acidosis m a y be approached in a methodical manner. The patient denied salicylate abuse. It is c o m m o n for an adult with excessive salicylate ingestion to present w i t h a mixed metabolic acidosis and respiratory alkalosis such as this patient had on the initial blood gasJS However, the serum salicylate level measured in this patient was 3.3 mg/dL, certainly not toxic or high enough to affect the anion gap. (A serum sa!icylate level of 70 mg/dL will contribute 5 mEq/L to the anion gap.) A n y further elevation of the anion gap in the toxic patient m a y be due to salicylate-induced increases in organic acid production. 1 A venous lactate level measured in this patient was increased m i n i m a l l y (3.5 mEq/L), again not elevated enough to account for the unmeasured anions.l,3 The patient was not uremic, and only in the advanced stages of uremic acidosis is the anion gap usually elevated. 19 The patient was alert and oriented and denied the ingestion of methanol, paraldehyde, ethylene glycol, or other toxins. The patient had no complaints of visual disturbances or headache, as would be expected in m e t h a n o l intoxication;1,~o did not smell of paraldehyde, as is comm o n with this ingestion; 1,21-26 and had no evidence of calcium oxalate or hippurate crystals in his urine, as is consistent with ethylene glycol ingestion.l,27, 28 These simple clinical observations are i m p o r t a n t in the c o n s i d e r a t i o n of t h e s e causes of acidosis. A s e r u m osm o l a l i t y was not obtained, although this m a y be a very useful test in ingestions. Elevation of the measured serum o s m o l a l i t y above the calculated o s m o l a l i t y m a y indicate the presence of an u n m e a s u r e d osmol such as ethanol, methanol, ethylene glycol, isopropyl alcohol, acetone or isoniazid, a m o n g others.I, 28-30 However, a urine toxicology screen in this patient was positive only for the presence of caffeine, s a l i c y l a t e s , and acetone, and was n e g a t i v e for methanol and isopropyl alcohol. The patient had no history of diabetes mellitus and his blood sugar was but m i n i m a l l y elevated. The lack of a m a r k e d l y elevated blood sugar and of azotemia would speak against hyperosmolar hyperglycemic nonketotic coma. 31 No history was given indicating that any of the u n c o m m o n causes of an elevated anion gap met-

16:1January 1987 i

abolic acidosis required further evaluation in this patient. The patient's serum and urine were both positive for the presence of ketones. To correctly understand the significance of ketones, it is necessary to understand their origin. Fatty acid m e t a b o l i s m occurs in the liver by two major p a t h w a y s , o x i d a t i o n to carbon dioxide and k e t o g e n e s i s . When the rate of oxidation of fatty acids is high, such as is present in insulin deficiency states, the liver's oxidative capacity is overcome and ketogenesis increases.i, 32 Diabetic ketoacidosis, alcoholic ketoacidosis, starvation, and stress hormone excess all enhance ketogenesis. 33 Isopropyl alcohol (rubbing alcohol} ingestion causes ketosis by means of its m e t a b o l i s m to acetone, 34-4~ and cyanide poisoning has been associated with the finding of ketones, although the m e c h a n i s m is not well understood.S,34,3s,37, 42 Ketones are buffered by bicarbonate, but if enough are produced, one m a y see a metabolic acidosis with an elevated anion gap. There are three types of "ketone bodies": b e t a h y d r o x y b u t y r a t e (BHB), a c e t o a c e t a t e (AcAc), a n d acetone. Of these, only BHB and AcAc are acids. 1 AcAc spontaneously decarboxylates to form acetone. 32 The presence of acetone does not change the serum bicarbonate concentration, nor does it affect the anion gap. The ratio of BHB to AcAc is affected by the ratio of reduced and oxidized n i c o t i n a m i d e adenine dinucleotide (NADH/NAD). Poor tissue oxygenation favors an increased level of N A D H and consequently an increased BHB/AcAc ratioJ As tissue oxygenation improves, AcAc becomes more prominent. These metabolic pathways of ketogenesis are important in interpreting the nitroprusside reaction test (Acetest®), the c o m m o n m e t h o d u s e d to t e s t for k e t o n e s . T h i s t e s t is positive only in the presence of AcAc or acetone, and is not affected by BHB. 43 Therefore, it is p o s s i b l e to o b t a i n a "negative" or weakly positive test for serum ketones in the p r e s e n c e of c l i n i c a l l y s i g n i f i c a n t BHB acidosis and low AcAc concentration. 32 In our patient, the s e r u m ketones measured by the nitroprusside reaction were small. This result is c o n s i s t e n t w i t h t h e d i a g n o s i s of a l c o h o l i c k e t o acidosis, because the test does not detect the presence of BHB, the major ketone found in alcoholic ketoacidosis. The ratio of BHB to AcAc in alcoholic ketoacidosis has been reported to be as high as 7.2 in one series. 44 Specific BHB level testing is not available r o u t i n e l y in our institution. Unfortunately, as the patient improved clinically, a repeat nitroprusside reaction was not done. I would expect that the reaction would have become more strongly positive with the p a t i e n t ' s clinical i m p r o v e m e n t , reflecting the conversion of the undetected BHB to AcAc. The finding of acetone in the urine is consistent with the diagnosis of alcoholic ketoacidosis. 45 Isopropyl alcohol (rubbing alcohol) intoxication is a condition seen predominantly in chronic alcoholics, who m a y consume it to satisfy the craving for alcohol. The alcoholic m a y appear intoxicated because the narcotic effect of isopropyl alcohol is 1V2 to 2 times that of ethanol. Other symptoms include nausea, vomiting, cramps, and occasionally gastrointestinal hemorrhage.39-41 Although acetone is seen in isopropyl alcohol intoxication, it is not itself an acid, and one sees n e i t h e r a decreased bicarbonate nor an elevated anion gap as were present in this patient3, 39 A diagnosis of

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ALCOHOLIC KETOACIDOSIS Adams, Mathews & Flaherty

FIGURE 2. Characteristics of alcoholic ketoacidosis. cyanide poisoning is consistent with neither the history nor the clinical course. 5 This patient's history, laboratory findings, and clinical course are, therefore, consistent with those seen in previous reports of patients with alcoholic ketoacidosis 44-54 (Figure 2). The size of the anion gap (35 mEq/L) and the etiology of ketoacidosis also were consistent with the findings of a prospective study of hospitalized patients 51 in that an anion gap of more than 30 mEq/L usually was due to an identifiable organic acidosis, such as lactic acidosis or ketoacidosis. The clinical syndrome of alcoholic ketoacidosis usually is seen in a binge drinker who has recently stopped drinking, often because of the onset of abdominal pain. The pain usually is accompanied by anorexia, nausea and vomiting, and absence of caloric intake. There may be a small amount of alcohol detectable, depending on the time elapsed since the patient's last drink, although it is c o m m o n to have no measurable ethanol. This contrasts with ethanol-induced lactic acidosis, in which affected individuals frequently are intoxicated or experience the disorder shortly after heavy ethanol intake. 39 In 1933, Himwich et a155 showed that a mild acidosis following ethanol ingestion was related to an increase in lactic acid. Since that time, other studies have demons t r a t e d e l e v a t e d l a c t i c acid levels in i n t o x i c a t e d patients, 56-s9 and in both alcoholic and nonalcoholic subjects following ethanol administration.ST,S8, 6o The m e c h a n i s m has been postulated to be due to the metabolism of ethanol and the subsequent conversion of N A D to NADH. Other factors that may contribute to hyperlactatemia in ethanol abusers include convulsive seizures, decreased utilization of lactate for glucose production, thiamine deficiency, and impaired liver function, s9 Usually the lactate levels associated with ethanol-induced lactic acidosis are only moderately increased. Severe lactic acidosis associated with ethanol intoxication is u n c o m m o n and usually short lived. Bicarbonate therapy usually is not needed because the arterial pH is usually more than 7.25 and spontaneous recovery occurs as the ethanol level declines and lactate is metabolized. 3 It is i m p o r t a n t to note, however, t h a t the clearance of a lactate load from the blood may be significantly impaired following ethanol ingestfon, and that those who have a concomitant lactic acidosis with elevated ethanol levels may present with a more severe clinical picture. 3 The patient with alcoholic ketoacidosis usually does not have a history of diabetes mellitus. On physical examination the patient m a y be hypothermic, diaphoretic, and orthostatic. He may show signs of dehydration and rapid Kussmaul respirations. Mental status is usually within normal limits or slightly impaired, although severe obtundation or coma may occur. 39 The patient may have evidence of liver disease secondary to alcohol abuse, and may have abdominal pain related to pancreatitis, liver disease, gastritis, or other causes. The patient may show evidence of alcohol withdrawal. Recurrence of the entity is not uncommon. Laboratory evaluation will show evidence of an elevated anion gap metabolic acidosis. There also may be evidence of a concomitant metabolic alkalosis secondary to vomiting, or a respiratory alkalosis due to liver disease, alcohol withdrawal (with subsequent hyperventilation), infection, or compensatory hyperventilation. The patient will be ketotic; 124/93

History Nausea Vomiting Anorexia Abdominal pain History of alcohol abuse Binge drinking recently terminated Poor caloric intake Laboratory Data Metabolic acidosis Elevated anion gap Ketoacidosis Elevated BHB/AcAc ratio Nitroprusside reaction: positive, weak, or negative Glucose: low, normal, or slightly elevated _+ Elevated liver function tests + Elevated plasma lactate

however, the nitroprusside test may be misleading in estimating the degree of ketosis, depending on the ratio of BHB to AcAc and the amount of AcAc. The classic presentation is that of the patient w i t h ketoacidosis w i t h o u t marked hyperglycemia. There can be a normal, low, or slightly increased blood sugar. There may be a minimal increase in serum lactate. The sodium is usually normal, and the potassium level may be either normal or decreased due to vomiting. Liver enzymes often are elevated, the amylase may be elevated, and the BUN and creatinine may be abnormal. These may reflect the patient's chronic medical problems and may influence the course of the disease, but are thought to be due to processes separate from the acute episode of alcoholic ketoacidosis. 39 Alcoholic ketoacidosis was first described by Dillon et a145 in 1940, when a series of nine patients were reported to have ketosis. Seven of the patients had a history of recent alcoholic binges. The two who did not give a history of recent binge drinking episodes had liver disease consistent with chronic alcohol abuse on post mortem examination. There was no history of diabetes, and glucose levels were normal, slightly elevated, or decreased to the point of requiring IV glucose. The patients presented with upper abdominal pain, anorexia, nausea, vomiting, and weakness. They had a severe ketosis on laboratory evaluation. Dillon et al emphasized that a very severe ketone acidosis can occur in patients who are not diabetic, and suggested that it could be caused by the combination of liver damage and food deprivation, occurring most frequently in association with acute alcoholism. These researchers did not postulate why this syndrome was not observed more frequently, but noted that they had diagnosed it more often as they became aware of it. In 1971, Jenkins et a146 reported on three women, each a chronic alcoholic, who presented after episodes of binge drinking terminated by anorexia. The patients were vomiting, dehydrated, and hyperpneic. They were ketoacidotic with either normal or slightly elevated glucoses, but without glucosuria. The authors noted, as with Dillon's patients, that starvation and alcohol abuse appeared to play a critical role in precipitating ketoacidosis. Their patients usually improved when given only glucose and saline solutions with-

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16:1 January 1987

out insulin. They suggested that the normal, or nearly normal, glucose levels seen in their patients may reflect some failure of peripheral utilization of glucose balanced by an equivalent failure of hepatic gluconeogenesis. They concluded that direct damage to hepatic mitochondria by alcohol, persisting long after the alcohol was gone, appeared to be the best explanation of the underlying defect, but that the rarity of the syndrome may be due to the absence of some additional genetic or acquired factors necessary to influence the development of ketoacidosis. In 1973, Levy et a144 described five patients, three men and two women, with presentations similar to the previously reported alcoholics with ketoacidosis. They noted that ketosis may be due to increased ketone production, decreased ketone degradation, or both. The rate of ketone body synthesis is directly proportional to the quantity of free fatty acid available as substrate. The authors demonstrated markedly elevated levels of free fatty acids in their patients, and suggested that these elevated levels were due to prolonged excessive alcohol intake, although the mechanism was unclear. When measured, low levels of insulin were found. They also noted that alcohol-induced hypoglycemia is a stimulus for growth hormone, epinephrine, and cortisol release. Each of these substances, in turn, may elevate levels of free fatty acids. Consequently, the elevation of free fatty acid levels may increase ketone synthesis. They also suggested that vomiting may be a contributory factor, similar to the association of vomiting and ketosis in the hyperemesis syndrome of early pregnancy. Noting that the proportion of BHB to AcAc was elevated, they ascribed it to a possible alteration in the cellular redox state brought about by the catabolism of alcohol. They indicated that the heretofore infrequent recognition of the syndrome probably belied its true frequency, and attributed the failure of recognition to the lack of reaction of the elevated BHB with the nitroprusside test. Elevated lactate levels were noted in four of their five patients. The patients' acidotic states were corrected with IV fluids, including glucose, saline, and modest amounts of bicarbonate. Cooperman et al in 197447 reported on six women who presented with severe ketoacidosis, one of whom had recurrent episodes. All were chronic alcoholics and had been on drinking binges 48 to 72 hours prior to admission. Blood studies revealed ketoacidoses, with the major portion of ketones being BHB. A modest rise was seen in the serum lactate. All patients were treated with IV bicarbonate and fluids. Resolution of the acidosis to an anion gap of less than 15 mEq/L was rapid, within 12 hours in all cases. The authors noted that rapid lipolysis is a major contributory factor in accelerated ketogenesis, and, as Levy et al, noted, extremely high free fatty acid levels are consistent findings in alcoholic ketoacidosis. Low insulin levels and elevated cortisol and growth hormone levels seen in their patients were suggested as possibly important causes of increased lipolysis. They also postulated that increased hepatic ketone production may occur in alcoholic ketoacidosis, perhaps as a result of damage to the hepatic mitochondria associated with alcohol abuse. Peripheral ketone utilization, shown to be dependent on insulin, may be diminished as a result of decreased insulin levels seen in those with alcoholic ketoacidosis.

Question: Isn't it unusual for a man to have alcoholic ketoacidosis ? 16:1 January 1987

Dr Adams: At the time of Cooperman's article, it was believed that there was a female preponderance of patients with alcoholic ketoacidosis. They speculated that the sex difference may arise through both hormonal and nonhormonal mechanisms because women develop ketonemia and ketonuria more rapidly and more severely in the fasting state than do men, and that ovarian hormones may increase the precursor supply of fatty acids. However, there is now thought to be no sex predisposition for this disorder. 61 The difficulty in making this diagnosis can be appreciated by looking at the series reported by Fulop et al. 48 They reported on 24 chronic alcohol abusers who were hospitalized, suspected of having alcoholic ketoacidosis because they had k e t o n e m i a or k e t o n u r i a with little or no glucosuria. They noted that only 21 patients actually had alcoholic ketoacidosis, and that three of these instead had a lactic acidosis with minor elevations of BHB. The lactic acidosis was attributed to shock in each case. Some patients with alcoholic ketoacidosis had no evidence of ketones in the urine in initial laboratory findings, probably because dehydration impairs the renal excretion of ketones. 46 In contrast to earlier studies, these patients did not have a severe acidosis. One third of the patients were alkalemic secondary to either coexisting respiratory alkalosis from fever or delirium tremens, or to coexisting metabolic alkalosis from vomiting. Many in this series had a concomitant disease, including acute pancreatitis, gastrointestinal bleeding, pneumonia, alcoholic hepatitis, or delirium tremens. Six were considered to be mild diabetics based on mildly abnormal oral glucose tolerance tests or postprandial hyperglycemia during convalescence. A history of poor food intake and the rapid clearing of ketosis with treatment by administration of solutions of glucose and saline led the authors to suggest that acute starvation was an important factor in the pathogenesis of this disorder. This group differed from those in previous reports in that the majority of patients (15 of 21) were men and that the acidosis was mild.

Question: Is hypoglycemia ever seen in these patients? Dr Adams: In 1979 Platia et a]49 described five patients with alcoholic ketoacidosis associated with hypoglycemia. They noted that most of the patients presented in previous studies had had either normal or elevated serum glucose levels. The authors suggested that the factors leading to hypoglycemia were numerous. Patients typically had not eaten for prolonged periods, depleting available hepatic glycogen stores at a time when hepatic gluconeogenesis had been suppressed by ethanol intake. The latter mechanism has been postulated to result from an elevated NADH/NAD ratio generated during ethanol metabolism. They also suggested that decreased levels of circulating alanine may account for diminished gluconeogenesis in the presence of alcohol. The Acetest ® (nitroprusside) reaction for serum and urine ketones was negative in two of their patients, but specific levels of BHB were found to be elevated.

Question: Was this patient's treatment and recovery typical? Dr Adams: The treatment of alcoholic ketoacidosis is relatively straightforward. Volume repletion with saline and glucose has been the mainstay of therapy. Saline, in addition to correcting dehydration, also may promote renal excretion

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FIGURE 3. Potential adverse effects of bicarbonate therapy. of BHB and AcAc. 39 In the patient who does not have concomitant diabetes mellitus, insulin does not appear to be useful and is probably contraindicated because of the resultant tendency for hypoglycemia.g9, 5o Thiamine, magnesium sulfate, and vitamin supplementation should be administered as indicated. Many authors 44,46-48 have used bicarbonate, although some have managed this disease without it.49,so The only study that has been done to evaluate the treatment of alcoholic ketoacidosis compared the effect of saline alone to IV glucose administration. Miller et also evaluated the treatment regimens of ten patients presenting with 18 different episodes of alcoholic ketoacidosis. The blood pH on presentation ranged from 6.96 to 7.28. One group was treated with saline infusions (100 to 125 mL/hr) alone; another was treated with glucose (5% dextrose in water at a dose of 7 to 7.5 g/hr). Glucose administration alone, without the administration of exogenous bicarbonate or insulin, rapidly (within 12 hours) reversed the acidosis in their patients. Patients in the saline-treated group, although showing good results, corrected their acidosis more slowly. The authors noted that there was a quicker decline in both the absolute levels and ratio of BHB/AcAc in the glucose-treated group. Noting that phosphorous is a critical cofactor necessary for N A D H oxidation, and that originally elevated serum phosphorous levels declined over the course of treatment, they proposed that glucose enhances the mitochondrial capacity to oxidize N A D H to N A D by increasing hepatocyte phosphorous. This transport of phosphorous is thought to be enhanced by the participation of insulin. They suggested that additional exogenous insulin is required to effect an increase in endogenous insulin secretion which would, in turn, enhance cellular phosphorous utilization. However, none of their patients was treated with supplemental phosphorous. On the basis of their study, Miller et alSO recommended that patients with alcoholic ketoacidosis be treated only with glucose or glucose in saline, avoiding exogenous bicarbonate or insulin. They also suggested waiting until more data are accumulated before suggesting phosphorous replenishment as a treatment modality for this disease. Palmer, in acknowledging the development of hypophosphatemia in Miller's study, advised caution in the administration of phosphate, citing case reports of complications in diabetic ketoacidotic patients treated with phosphate. 39

Question: Is admission necessary for these patients? Dr Adams: Admission is indicated in patients with persistent rmusea and vomiting, in those with orthostatic hypotension, and in patients in w h o m a significant metabolic acidosis persists, the cause of abdominal pain is unclear, or an associated illness mandating admission is present. Because most cases seem to resolve in 12 to 24 hours, observation in a holding area or overnight admission may be appropriate. The patient should not be discharged until he shows evidence of ability to tolerate fluids, is no longer orthostatic, and has shown resolution of metabolic abnormalities and other underlying or precipitating illness. Question: When does acidosis need treatment with bicarbonate? 126/95

Hypokalemic cardiac toxicity in K+ depleted Hyperosmolality Sodium overload Myocardial depression Alkalemia Paradoxical cerebrospinal fluid acidosis/hypoxia

James J Mathews, MD: As already mentioned, the use of bicarbonate is no longer recommended as automatic treatment in alcoholic ketoacidosis. Although decreased myocardial function exists in the acidotic state, 62-64 it has long been debated as to when bicarbonate therapy is needed. In diabetic ketoacidosis, some guidelines have suggested that bicarbonate should be used when the blood pH is less than 7.10;65, 66 others suggest that it be used for refractory hypotension or refractory severe acidosis at a pH of less than 7.0. 67 I have managed diabetic ketoacidosis patients with much lower blood pH levels than 7.10 without the use of bicarbonate with good results. A recent retrospective study found that even in severe cases of diabetic ketoacidosis, recovery did not differ between acidotic patients who received bicarbonate and those who did not. 68 Recent data have also brought into question the aggressive use of bicarbonate in cardiac arrest69, 70 and highlighted the very significant complications it can cause. Bicarbonate usage in metabolic acidosis is not without its side effects and potential hazards (Figure 3). Among these are hypokalemic cardiac toxicity in patients who are substantially potassium depleted, 71 paradoxical cerebrospinal fluid acidosis and hypoxia due to rapid c h a n g e s in pH after b i c a r b o n a t e therapy,72, 73 hyperosmolality, 74-76 tetany in patients with renal failure or hypocalcemia,71 m y o c a r d i a l depression,77 s o d i u m overload, n, 75 and alkalemia. TM In light of these, it is n o t surprising that the trend is away from the aggressive use of bicarbonate therapy in the treatment of alcoholic ketoacidosis. My goal at present is to attempt to maintain the blood pH above 7.10 in these patients, especially in those who have evidence of myocardial disease or dysfunction and who show signs of ventricular irritability possibly secondary to the acidotic environment. Among drugs that have been investigated as possible substitutes for N a H C O 3 is s o d i u m dichloroacetate (DCA), which activates pyruvate dehydrogenase. This has been studied primarily in lactic acidosis.78, 79 Although initial studies showed efficacy in decreasing lactate levels in patients with diabetes mellitus and hyperlipoproteinemia, 78 others have questioned the potential advantage over bicarbonate in the treatment of lactic acidosis. 80 Its use has been suspended by some workers because of toxicity in animals and a report of polyneuropathy in clinician studies.81, s2 Until a suitable substitute is found, bicarbonate therapy should be used only as indicated and with the clinician mindful of its possibly adverse side effects. One m u s t remember to treat any intercurrent or precipitating illness associated with alcoholic ketoacidosis because the morbidity and mortality appear to reflect the associated illness rather than the acid base disturbance. 83

REFERENCES

1. Emmett M, Narins RG: Clinical use of the anion gap. Medicine

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1977;56:38-54. 2. Oh MS, Carroll HJ: The anion gap. N Engl I Med 1977;297:814817. 3. Oliva PB: Lactic acidosis. Am l Med i970;48:209-225. 4. Neff TA: Isoniazid toxicity: Reports of lactic acidosis and keratitis. Chest 1971;59:245-248. 5. Graham DL, Laman D, Theodore J, et ah Acute cyanide poisoning complicated by lacitic acidosis and pulmonary edema. Arch Intern Med 1977;137:1051-1055. 6. Desir D, Van Coevorden A, Kirkpatrick C, et ah Ritodrine-induced acidosis in pregnancy, Br Med I 1978;2:1194. 7. Foley RJ: Inhaled industrial acetylene. A diabetic ketoacidosis mimic. lAMA 1985;254: I066-1067. 8. Misbin RI: Phenformin-associated lactic acidosis: Pathogenesis and treatment. Ann Intern Med 1977;87:591-595. 9. Buehler JH, Berns AS, Webster JR Jr, et ah Lactic acidosis from carboxyhemoglobJnemia after smoke inhalation. Ann Intern Med 1975; 82:803-805. 10. McAnally JF: Acid-base disorders, in Haddad LM, Winchester JF (eds): Clinica] Management of Poisoning and Drug Overdose. Philadelphia, WB 8aunders Co, I983, p 108-124.

JD, Broadus AE, et al (eds]: Endocrinology and Metabolism. New York, McGraw Hill Book Company, 1981, p 852. 32. Halperin ML: Lactic acidosis and ketoacidosis: Biochemical and clinical implications. Can Med Assoc J 1977;116:1034-1038. 33. Schade DS, Eaton RP: Differential diagnosis and therapy of hyperketonemic state, lAMA 1979;241:2064-2065. 34. Spencer 8E: Causes of hyperketonemia (letter). lAMA 1979;242: 1968. 35. Schade DS: Causes of hyperketonemia (letter). lAMA 1979;242: 1968. 36. Ashkar FS, Miller R: Hospital ketosis in the alcoholic diabetic: A syndrome due to isopropyl alcohol intoxication. South Med I I971; 64:1409-1411. 37. Van de Graft WB, Thompson WL: Isopropyl alcohol intoxication (letter). Arch Intern Med 1978;138:826. 38. Berlin CM: Isopropyl alcohol intoxication (letter). Arch Intern Med 1978;138:826. 39. Palmer JP: Alcoholic ketoacidosis: Clinical and laboratory presentation, pathophysiology and treatment. Clin Endocrinol Metabolism 1983;12:381-389. 40. Vermeulen R: Isopropyl alcohol and diabetes. Pa Med J 1966;69:53-54.

1i. Fischman CM, Oster JR: Toxic effects of toluene. A new cause of high anion gap metabolic acidosis, lAMA 1979;24h1713-1715.

41. Adelson L: Fatal intoxication with isopropyl alcohol (rubbing alcohol). Am l Clin Pathol 1962;38:144-151.

12. Streicher HZ, Gabow PA, Moss AH, et al: Syndromes of toluene sniffing in adults. Ann Intern Med 198i;94:758-762.

42. Berlin C: Cyanide poisoning - - A challenge. Arch Intern Med 1977;137:993-994.

13. Manoguerra AS: Iron poisoning: Report of a fatal case in an adult. Am J Hosp Pharm 1976;33:1088-1090.

43. Alberti KGMM, Hockaday TDR: Rapid blood ketone body estimation in the diagnosis of diabetic ketoacidosis. Br Mecl J 1972;2:565-568.

14. Doolin El, Drueck IIl C: Fatal iron intoxication in an adult. J Trauma 1980;20:518-522.

44. Levy LJ, Duga J, Girgis M, et al: Ketoacidosis associated with alcoholism in nondiahetic subjects. Ann Intern Med 1973;78:213-219.

15. Oh MS, Phelps KR, Traube M, et ah D-Lactic acidosis in a man with the short bowel syndrome. N Engl J Med 1979;301:249-252.

45. Dillon ES, Dyer WW, Srnelo LS: Ketone acidosis in nondiabetic adults. Med Clin North Am 1940;24:1813-1822.

16. Matsui SM, Mahoney MJ, Rosenberg LE: The natural history of the inherited methylmalonic acidemias. N Engl J Med 1983;308:857-861.

46. Jenkins DW, Eckel RE, Craig JW: Alcoholic ketoacidosis, lAMA 1971;217:177-183.

17. Cohn RM, Yudkoff M, Rothman R, et al: Isovaleric acidemia: Use of glycine therapy in neonates. N Engl J Med 1978;299:996-999.

47. Cooperman MT, Davidoff F, Spark R, et ah Clinical studies of alcoholic ketoacidosis. Diabetes 1974;23:433-439.

18. Proudfoot AT, Brown SS: Acidemia and salicylate poisoning in adults. Br Med J I969;2:547-550. 19.'Widmer B, Gerhardt RE, Harrington JT, et al: Serum electrolyte and acid base composition. The influence of graded degrees of chronic renal failure. Arch Intern Med 1979;!39:1099-1102.

48. Fulop M, Hoberman HD: Alcoholic ketosis. Diabetes 1975;24:785-790. 49. Platia EV, Hsu TH: Hypoglycemic coma with ketoacidosis in nondiabetic alcoholics. West l Med 1979;131:270-276. 50. Miller PD, Heinig RE, Waterhouse C: Treatment of alcoholic acidosis. The role of dextrose and phosphorus. Arch Intern Med I978;138:67-72.

20. Bennet IL Jr, Gary PH, Mitchell GL Jr, et al: Acute methyl alcohol poisoning: A review based on experiences in an outbreak of 323 cases. Medicine 1953;38:431-463.

51. Gabow PA, Kaehny WD, Fennessey PV, et aI: Diagnostic importance of an increased serum anion gap. N Engl J Med 1980;303:854-858.

2I. G u t m a n RA, Burnell JM: Paraldehyde acidosis. A m l Med 1967; 42:435-440.

52. Weisberger CL, Hamilton W: Alcohol ketoacidosis (letter). lAMA 1971;217:1865-1866.

22. Hayward JN, Boshell BR: Paraldehyde intoxication with metabolic acidosis. Am J Med 1957;23:965-976.

53. Petersen G : Alcoholism and ketoacidosis (letter). Ann Intern Med 1973;78:983.

23. Elkinton JR, Huth El, Clark JK, et al: Renal tubular acidosis with organic aciduria during paraldehyde ingestion. Am J Med 1957;23:977-986.

54. Podratz KC: Alcoholic ketoacidosis in pregnancy. Obstet Gynecol 1978(Suppi)52:548-578.

24. Waterhouse C, Stern EA: Metabolic acidosis occurring during administration of paraldehyde. Am l Med 1957;23:987-989.

55. Himwich HE, Nahum LH, Rakieten N, et ah The metabolism of alcohol. lAMA 1933;100:651-654. 56. Daughaday WH, Lipicky RJ, Rasinski DC: Lactic acidosis as a cause of nonketotic acidosis in diabetic patients. N Engl [ Med 1962;267:1010-1014.

25. Beier L8, Pitts WH, Gonick HC: Metabolic acidosis occurring during paraldehyde intoxication. Ann Intern Med 1963;58:155-158. 26. Hadden JW, Metzner RJ: Pseudoketosis and hyperacetaldehydemia in paraldehyde acidosis. Am J Med 1969;47:642-647.

57. Lieber CS, Jones DP, Losowsky MS, et ah Interrelation of uric acid and ethanol metabolism in man. l Glin Invest 1962;41:1863-1870.

27. Parry MF, Wallach R: Ethylene glycol poisoning. A m I Meg 1974; 57:143-150.

58. Sullivan JF, Lankford HG, Robertson P: Renal excretion of lactate and magnesium in alcoholism. Am I Clin Nutrit 1966~18:236236.

28. Cadnapaphornchai P, Taher S, Bhathena D, et al: Ethylene glycol poisoning: Diagnosis based on high osmolal and anion gaps and crystalluria. Ann Emerg Med 1981;I0:94-97.

59. Fulop M, Bock J, Ben-Ezra J, et al: Plasma lactate and.3-Hydroxybutyrate levels in patients with acute ethanol intoxication. A m J Med 1986;80:191-194.

29. Smithline N, Gardner KD Jr: Gaps - - anionic and osmolal, lAMA I976;236:1594-1597.

60. Seligson D, Waldstein SS, Giges B, et ah Some metabolic effects of ethanol in humans. Clin Res Proc 1953;1:86.

30. Glasser L, 8ternglanz PD, Combie J, et al: Serum osmolality and its applicability to drug overdose. Am J Clin Pathol 1973;60:695-699.

61. Kreisberg RA: Diabetic ketoacidosis: New concepts and trends in pathogenesis and treatment. Ann Intern Med 1978;88:681-695.

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63. Mitchell JH, Wildenthal K, Johnson RL Jr: The effects of acid-base disturbances on cardiovascular and p u l m o n a r y function. Kidney Int 1972;1:375-389.

73. Bureau MA, Begin R, Berthiaume Y, et al: Cerebral hypoxia from bicarbonate infusion in diabetic acidosis. J Pediatr 1980;96:968-973.

64. Cingolani HE, Faulkner SL, Mattiazzi AR, et al: Depression of human myocardial contractility with "respiratory" and "metabolic" acidosis. Surgery 1975;77:427-432. 65. Hockaday TDR, Alberti KGMM: Diabetic coma. Clin Endocrinol Metab 1972;1:751-788. 66. Kandel G, Aberman A: Selected developments in the understanding of diabetic ketoacidosis. Can Med Assoc J 1983;128:392-397. 67. Carroll P, Matz R: Uncontrolled diabetes mellitus in adults: Experience in treating diabetic ketoacidosis and hyperosmolar nonketotic coma with low dose insulin and a uniform treatment regimen. Diabetes Care 1983;6:579-585. 68. Lever E, Jaspan JB: Sodium bicarbonate therapy in severe diabetic ketoacidosis. A m J Med 1983;75:263-268. 69. Niemann JT, Rosborough JP: Effects of acidemia and sodium bicarbonate therapy in advanced cardiac life support. Ann Emerg Med 1984(Part 2);13:781-784.

74. Ruiz CE, Weil MH, Carlson R: Iatrogenic alkalosis and hyperosmolality following CPR (abstract). Circulation 1979;60(Part II):127. 75. Mattar JA, Weil MH, Shubin H, et al: Cardiac arrest in the critically ill. II. Hyperosmolal states following cardiac arrest. A m J Med 1974; 56:162-168. 76. Bishop RL, Weisfeldt ML: Sodium bicarbonate administration,during cardiac arrest. Effect on arterial pH, pCOz, and osmolality. JAMA 1976;235:506-509. 77. Clancy RL, Cingolani HE, Taylor RR, et ah Influence of sodium bicarbonate on myocardial performance. Am J Physiol 1967;212:917-923. 78. Stacpoole PW, Moore GW, Kornhauser DM: Metabolic effects of dichloroaeetate in patients with diabetes mellitus and hyperlipoproteinemia. N Engl J Med 1978;298:526-530. 79. Relman AS: Lactic acidosis and a possible new treatmenL N Engl J Med 1978;298:654-665. 80. Cohen RD, Iles RA: Dichloroacetate and the treatment of lactic acidosis (letter). N Engl J Med I978;298:1364.

70. Weil MH, Trevino RP, Rackow EC: Sodium bicarbonate during CPR. Does it help or hinder? Chest 1985;88:487.

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72. Posner JB, Plum F: Spinal-fluid pH and neurological symptoms in sys-

83. Anwar A, Hamburger S: Alcoholic ketoacidosis. Missouri Med I981;78:245-248.

Fellowship List Now Available A list of toxicology fellowship programs is now available from the ACEP Toxicology Committee. Please contact Liz Sibley, ACEP, PO Box 619911, Dallas, TX 75261-9911; 214/550-0911. 128/97

Annals of Emergency Medicine

16:1 January 1987