Metabolic Acidosis During Treatment of Mushroom Poisoning: a Diagnostic Pitfall

□ CASE REPORT □

Metabolic Acidosis during Treatment of Mushroom Poisoning: A Diagnostic Pitfall

Nikolaos K. Gatselis 1,GeorgeLiamis2, Konstantinos P. Makaritsis 1 and George N. Dalekos 1

Abstract

Metabolic acidosis is a frequently encountered acid-base disturbance in hospitalized patients that occasion- ally develops in the course of treatment with medications used in everyday clinical practice, including propylene glycol-containing drugs (lorazepam, diazepam, etomidate, pentobarbital). Disruption of enterohepatic circulation with activated charcoal is a common practice for several intoxications, including mushroom poisoning. Herein, we present a patient who was hospitalized due to mushroom intoxication and developed severe metabolic acidosis as a treatment side effect rather than from the mushroom poisoning. Τo the best of our knowledge, this is the first report on propylene glycol-containing activated charcoal-induced metabolic acidosis.

Key words: metabolic acidosis, lactate, anion gap, propylene glycol toxicity, charcoal, mushroom poisoning

(Intern Med 51: 1077-1080, 2012) (DOI: 10.2169/internalmedicine.51.6405)

reversible hepatic failure have been described (3, 5, 6). Introduction Herein we report a patient who developed severe metabolic acidosis with no profound etiology during conven- Metabolic acidosis is a frequently encountered acid-base tional treatment for mushroom poisoning. The aim of this disturbance in hospitalized patients; it is associated with report is to emphasize an unusual side effect and therapeutic substantial morbidity and mortality (1). Many drugs may re- pitfall that may arise during the management of such cases. sult in metabolic acidosis and consequently play a significant role in the clinical presentation, evolution of the disease Case Report and therapeutic intervention (2). On the other hand, certain plants, such as mushrooms, contain very strong toxins. For- A 70-year-old woman was admitted to our department be- aging for wild mushrooms is a popular activity in late sum- cause of sudden onset of nausea and abdominal cramps 30- mer and autumn in Greece, although some mushrooms, es- 60 minutes after eating fried wild mushrooms. Her past pecially Amanita phalloides, contain exceptionally powerful medical history included well controlled diabetes mellitus toxins (3). Mushroom poisoning with Amanita phalloides is and hypertension requiring oral medication with metformin a medical emergency. Early and aggressive general suppor- (500 mg twice a day) and telmisartan (80 mg/day). tive therapy must be initiated with fluid and electrolyte re- The vital signs on admission were normal and physical placement, gastric lavage, activated charcoal and laxatives in examination was unremarkable. Her biochemical blood re- order to remove toxins from the gastrointestinal tract and sults were within normal limits. HbA1c was 6.7%. Arterial disrupt enterohepatic circulation (4); silibinin or penicillin blood gas revealed: pH=7.42, PCO2=38 mmHg, PO2=98 are given to inhibit protein binding and cellular uptake of mmHg, and bicarbonate=23 mmol/L. Accordingly, she was the toxin (3, 5). Extracorporeal dialysis techniques to re- treated as mushroom poisoning. After performing a gastric move the toxin and replace coagulation deficits and ortho- lavage via a nasogastric tube, activated charcoal was given topic liver transplantation in cases of fulminant non- to the patient and continued at a dose of 20 gr every 3

１Department of Medicine and Research Lab of Internal Medicine, Thessaly University Medical School, Greece and ２Department of Internal Medicine, Medical School, University of Ioannina, Greece Received for publication August 17, 2011; Accepted for publication January 29, 2012 Correspondence to Dr. Nikolaos K. Gatselis, [email protected]

1077 Intern Med 51: 1077-1080, 2012 DOI: 10.2169/internalmedicine.51.6405

Figure 1. Variation of acidosis parameters and blood glucose levels. PG: propylene glycol

hours together with laxatives. Simultaneously, silibinin was L) metabolic acidosis and increased serum lactate concentra- initiated i.v. at a bolus dose of 5 mg/kg, followed by a con- tions (>5 mEq/L). The patient was carefully evaluated for tinuous i.v. infusion of 20 mg/kg/day. Both above-mentioned causes of the elevated serum lactate level, but there were no doses for activated charcoal and silibinin are the recom- clinical or laboratory signs of infection or tissue hypoperfu- mended doses for mushroom poisoning treatment (7). sion and hypoxia. The patient did not mention any previous The patient developed progressively worsening metabolic use of alcohol or drugs except for metformin and telmisar- acidosis. In fact, on the second day, 36 hours after the treat- tan. However, metabolic acidosis could not be attributed to ment was initiated, arterial blood gas revealed a pH of 7.26, metformin, taking into account that the blood gasses were aPCO2 of 28 mmHg, and PO2 of 98 mmHg, with a bicar- normal at the first evaluation and worsened during the hos- bonate of 13.9 mmol/L. Laboratory data revealed sodium pitalization and after cessation of metformine. The patient’s 142 mmol/L, potassium 4.1 mmol/L, chloride 104 mmol/L, serum osmolality was 314 mOsm/kg (reference range 280- anion gap (SAG) 24 mmol/L, lactate 8.3 mmol/L, creatine 295), with an osmolal gap of 18 mOsm/kg (reference value kinase (CK) 182 U/L, and albumin 4.2 mg/dL. Serum anion <10). After other causes of acidosis were ruled out, propyl- gap (SAG) was calculated from the equation Na+-(Cl-+ ene glycol (PG) toxicity from the activated charcoal was - - HCO3 ). Delta AG/delta HCO3 ratio was 1.3. considered the most likely cause for the laboratory abnor- There were no abnormal findings in urinalysis (including malities and the administration of charcoal was stopped. microscopy). She also became markedly hyperglycemic Over the next few hours the metabolic acidosis and hyper- (blood glucose 571 mg/dL) but a diagnosis of diabetic ke- glycemia started to improve and a day later metabolic status toacidosis (DKA) could not established because of the re- returned to normal (Fig. 1). She was discharged 8 days after peatedly absence of ketones in the urine and deterioration of mushroom ingestion and two weeks later, she was re- acidosis despite rehydration with normal saline and insulin evaluated and all of her physical findings and laboratory continuous i.v. administration. Indeed, in spite of all suppor- data were normal. tive measures, the acidosis worsened. Arterial blood gas revealed: pH=7.03, PCO2=20 mmHg, PO2=94 mmHg, and bi- Discussion carbonate=6.6 mmol/L. Laboratory data also revealed sodium 142 mmol/L, potassium 3.9 mmol/L, chloride 119 Lactic acidosis is a high anion gap (AG) metabolic acido- mmol/L, anion gap 17 mmol/L, lactate 6.5 mmol/L, Delta sis (AG>12 mmol/L) with increased serum lactate concen- - AG/delta HCO3 ratio 0.3, while the hepatic and renal func- trations (>5 mEq/L); it is the most frequent cause of meta- tion remained stable. bolic acidosis in hospitalized patients and it often carries a It is known that the development of DKA in a patient significant risk for mortality. It is commonly associated with with well-controlled type II diabetes is usually associated clinical situations such as shock and sepsis, as a result of with severe precipitating factors (infection, myocardial in- tissue hypoperfusion and hypoxia (1). However, the present farction, cerebrovascular accident, or pancreatitis) (8). Based patient developed this acid-base abnormality in the presence on both the physical examination and laboratory tests the of normal tissue perfusion and oxygenation. Many drugs precipitating events of DKA were not identified in the pre- have been implicated in the pathogenesis of lactic acido- sent case. Additionally, though, a moderate degree of lactic sis (2). Consequently, a detailed history of medications re- acidosis may be seen in some patients with diabetic ketoaci- ceived is fully warranted as part of the diagnostic approach dosis this is due mainly to marked hypovolemia that was to patients presenting with unexplained lactic acidosis. Spe- not evident in our patient (9). cifically, the emergence of lactic acidosis in a diabetic pa- The present patient fulfilled the criteria required for the tient on metformin should always raise the question with diagnosis of lactic acidosis, namely high AG (AG>12 mmol/ reference to the causality between metformin and elevated

1078 Intern Med 51: 1077-1080, 2012 DOI: 10.2169/internalmedicine.51.6405 lactate levels, given that the mortality rate of metformin- tributed to fulminant hepatic failure and tubular necro- associated lactic acidosis (MALA) is as high as 50% (2). In sis (7, 14). Although amatoxin is rapidly cleared by the kid- the present patient MALA was highly unlikely taking into neys, its direct nephrotoxicity to the proximal and distal consideration the fact that the blood gasses were normal at convoluted tubules may lead to acute tubular necro- the first evaluation and worsened during the hospitalization sis (6, 14). However, in the present case there was no evi- and after cessation of metformine. Furthermore, MALA is dence of hepatic failure or tubular necrosis (e.g. granular - uncommon in the absence of predisposing factors such as casts in urinalysis). Moreover, the delta AG/delta HCO3 ra- drug overdose, advanced age, alcoholism, renal and hepatic tio in our patient (1.3) is more compatible with an uncom- failure. The present patient developed a syndrome of high plicated high anion gap metabolic acidosis. In fact, this ratio AG metabolic acidosis with elevated osmolar gap and lactate in a pure high anion gap metabolic acidosis should be be- levels. The constellation of these findings strongly suggests tween 1 and 2, while values lower than 1:1 indicate mixed PG toxicity. PG is used as a stabilizing vehicle for several normal and high anion gap acidosis (15). It is possible, hydrophobic drugs as etomidate, phenytoin, diazepam, however, that the deterioration of metabolic acidosis ob- lorazepam, phenopharbital, nitroglycerin, digoxin, hydra- served during the treatment could at least in part be attrib- lazine and trimethoprim-sulfamethoxazole (10, 11). In uted to saline administration (16). In fact, it is known that - healthy subjects, the half-life of PG is around 4 hours and the administration of HCO3 free solutions may induce mild its average total body clearance is approximately 0.1 L/kg hyperchloremic metabolic acidosis by causing rapid volume - per hour. Approximately 12% to 45% of absorbed PG is ex- expansion. In the present case, the delta AG/delta HCO3 ra- creted unchanged in the urine and the remaining is metabo- tio (0.3) detected at the nadir of pH is in accordance with lized in the liver, by alcohol dehydrogenase, to pyruvate, this assumption. lactate, or acetate. Although the agent is generally consid- As far as the treatment of PG toxicity is concerned it in- ered to be safe, rapid and prolonged administration of large cludes cease of administration and supportive measures (17). doses increases the risk of toxicity (2). Indeed, PG- Because the PG half-life in blood is short, once the admini- containing drugs can induce a hyperosmolar, high anion gap stration is discontinued, serum osmolality will return rapidly metabolic acidosis that is life threatening if untreated. The to baseline and acidocis will be corrected in less than 24 hyperosmolarity with an elevated osmolar gap can be as- hours in most patients (10). In cases of extremely high cribed to PG, which is a hyperosmolar substance, while the blood concentrations, hemodialysis is extremely effective in accumulation of lactic acid is the cause of the acidosis with rapidly reducing serum PG levels (17, 18). Intermittent increased anion gap. Moreover, administration of large hemodialysis is the most efficient method of rapidly lower- quantities of PG causes acute tubular necrosis and hemoly- ing serum alcohol levels or removing the organic acid ani- sis, while clinical signs of toxicosis include central nervous ons, although continuous renal replacement therapy can also system depression, weakness, ataxia and seizures. Reports of be used. Base administration has also been postulated to in- toxicity with drugs containing PG, particularly intravenous crease renal excretion of metabolites, but should be kept lorazepam, diazepam, etomidate and pentobarbital have been only for cases where severe lactic acidosis is present and di- well described in the literature (2). Some types of activated alysis is not available (19). charcoal solutions also contain PG. Of note, experimental In conclusion, the present case indicates that PG toxicity data has shown that the administration of these solutions, is a potential complication associated with per os adminis- even at a clinically relevant dose, can increase serum osmo- tration of activated charcoal. Practitioners should be aware lality, osmolal gap, and lactate concentration in dogs (12). of the PG content of charcoal and should be familiar with According to our knowledge, however, this is the first report the signs and symptoms associated with PG toxicity. How- of activated charcoal-related metabolic acidosis in man. In- ever, the latter complication of activated charcoal adminis- terestingly, this adverse effect took place in the absence of tration should not affect the usual way of management in predisposing factors of PG-associated metabolic acidosis, cases of mushroom poisoning, given its high morbidity and namely alcoholism, renal and hepatic failure, age <4 years, mortality. pregnancy, and severe underlying conditions (e.g. sepsis). It might be hypothesized however, that a coexisting normal an- The authors state that they havenoConflictofInterest(COI). ion gap metabolic acidosis might also be present in the current patient leading to a further reduction in arterial pH. In References fact, renal tubular acidosis type IV (hypoaldosteronism) is frequently encountered in diabetic patients especially when 1. Adrogué HJ. Metabolic acidosis: pathophysiology, diagnosis and they also receive drugs that blockade the renin-angiotensin- management. 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