American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning

EPIDEMIOLOGY: Almost all cases of acute methanol toxicity result from ingestion, though rarely cases of poisoning have followed inhalation or dermal absorption. The absorption of methanol following oral administration is rapid and peak methanol concentrations occur within 30-60minutes. MECHANISMS OF TOXICITY: Methanol has a relatively low toxicity and metabolism is responsible for the transformation of methanol to its toxic metabolites. Methanol is oxidized by alcohol dehydrogenase to formaldehyde. The oxidation of formaldehyde to formic acid is facilitated by formaldehyde dehydrogenase. Formic acid is converted by 10-formyl tetrahydrofolate synthetase to carbon dioxide and water. In cases of methanol poisoning, formic acid accumulates and there is a direct correlation between the formic acid concentration and increased morbidity and mortality. The acidosis observed in methanol poisoning appears to be caused directly or indirectly by formic acid production. Formic acid has also been shown to inhibit cytochrome oxidase and is the prime cause of ocular toxicity, though acidosis can increase toxicity further by enabling greater diffusion of formic acid into cells. FEATURES: Methanol poisoning typically induces nausea, vomiting, abdominal pain, and mild central nervous system depression. There is then a latent period lasting approximately 12-24 hours, depending, in part, on the methanol dose ingested, following which an uncompensated metabolic acidosis develops and visualfunction becomes impaired, ranging from blurred vision and altered visual fields to complete blindness. MANAGEMENT: For the patient presenting with ophthalmologic abnormalities or significant acidosis, the acidosis should be corrected with intravenous sodium bicarbonate, the further generation of toxic metabolite should be blocked by the administration of fomepizole or ethanol and formic acid metabolism should be enhanced by the administration of intravenous folinic acid. Hemodialysis may also be required to correct severe metabolic abnormalities and to enhance methanol and formate elimination. For the methanol poisoned patient without evidence of clinical toxicity, the first priority is to inhibit methanol metabolism with intravenous ethanol orfomepizole. Although there are no clinical outcome data confirming the superiority of either of these antidotes over the other, there are significant disadvantages associated with ethanol. These include complex dosing, difficulties with maintaining therapeutic concentrations, the need for more comprehensive clinical and laboratory monitoring, and more adverse effects. Thus fomepizole is very attractive, however, it has a relatively high acquisition cost. CONCLUSION: The management of methanol poisoning includes standard supportive care, the correction of metabolic acidosis, the administration of folinic acid, the provision of an antidote to inhibit the metabolism of methanol to formate, and selective hemodialysis to correct severe metabolic abnormalities and to enhance methanol and formate elimination. Although both ethanol and fomepizole are effective, fomepizole is the preferred antidote for methanol poisoning.     

Lack of a role for formaldehyde in methanol poisoning in the monkey.

Methanol was administered either to untreated cynomolgus monkeys or to a folate-deficient cynomolgus monkey which exhibits exceptional sensitivity to the toxic effects of methanol. Marked formic acid accumulation in the blood and in body fluids and tissues was observed. No formaldehyde accumulation was observed in the blood and no formaldehyde was detected in the urine, cerebrospinal fluid, vitreous humor, liver, kidney, optic nerve, and brain in these monkeys at a time when marked metabolic acidosis and other characteristics of methanol poisoning were observed. Following intravenous infusion into the monkey, formaldehyde was rapidly eliminated from the blood with a half-life of about 1.5 min and formic acid levels promptly increased in the blood. Since formic acid accumulation accounted for the metabolic acidosis and since ocular toxicity essentially identical to that produced in methanol poisoning has been described after formate treatment, the predominant role of formic acid as the major metabolic agent for methanol toxicity is certified. Also, results suggest that formaldehyde is not a major factor in the toxic syndrome produced by methanol in the monkey.     

Expert opinion: fomepizole may ameliorate the need for hemodialysis in methanol poisoning

Fomepizole is now the antidote of choice in methanol poisoning. The use of fomepizole may also change the indications for hemodialysis in these patients. We have addressed this change in a review of articles on methanol poisonings. Review of the literature (through PubMed) combined with our own experiences from two recent methanol outbreaks in Estonia and Norway. The efficiency of dialysis during fomepizole treatment was reported in only a few reports. One recent study challenged the old indications, suggesting a new approach with delayed or even no hemodialysis. Methanol-poisoned patients on fomepizole treatment may be separated into two categories: 1) The critically ill patient, with severe metabolic acidosis (base deficit >15 mM) and/or visual disturbances should be given buffer, fomepizole and immediate hemodialysis: dialysis removes the toxic anion formate, and assists in correcting the metabolic acidosis, thereby also reducing formate toxicity. The removal of methanol per se is not important in this setting because fomepizole prevents further production of formic acid. 2) The stable patient, with less metabolic acidosis and no visual disturbances, should be given buffer and fomepizole. This treatment allows for the possibility to delay, or even drop, dialysis in this setting, because patients will not develop more clinical features from methanol poisoning when fomepizole and bicarbonate is given in adequate doses. Indications and triage for hemodialysis in methanol poisonings should be modified. Delayed hemodialysis or even no hemodialysis may be an option in selected cases.     

Therapeutic response to single intravenous bolus administration of formate dehydrogenase in methanol-intoxicated rats

Methanol remains to be a major public and environmental health hazard. Formic acid is the toxic metabolite responsible for the metabolic acidosis observed in methanol poisoning in humans, in non-human primates and in folate-depleted rodents. Cytochrome oxidase inhibition by formate leads to lactic acid accumulation, which contributes significantly to metabolic acidosis. Toxic effects in human beings are characterized by formic acidemia, metabolic acidosis, ocular toxicity, nervous system depression, blindness, coma and death. Elimination of formate is one of the principles of management in methanol poisoning. Hemodialysis facility is not readily available in all the places, in developing countries like India. Formate dehydrogenase (EC 1.2.1.2) acts directly over formate and converts formate into CO(2) in the presence of NAD. Effect of single intravenous bolus infusion of formate dehydrogenase, obtained from Candida boidinii; in methanol-intoxicated folate deficient rat model was evaluated. Folate depletion induced by methotrexate (MTX) treatment. Carbicarb (Carb) (equimolar solution of sodium carbonate and sodium bicarbonate) was used to treat metabolic acidosis. Experimental design consists of seven groups, namely Saline control, methanol control, MTX control, Enzyme control, MTX-methanol control, MTX-methanol-Carb and MTX-methanol-Carb-Enz group. Male wistar rats treated with MTX (0.3mg/kg) for a week, were injected (i.p.) with methanol (4 gm/kg), 12h latter, Carbicarb solution was infused, following this enzyme was infused (i.v.) in bolus. Blood samples were collected every 15 min for an hour from the cannulated left jugular vein and blood methanol, formate were estimated, respectively, with HPLC and fluorimetric assay. Blood pH, blood gases pO(2), pCO(2) and bicarbonate were monitored with blood gas analyzer in order to evaluate acid base status of the animal. Results obtained show that there is significant elimination of formate within 15 min. It may be concluded that single bolus infusion of formate dehydrogenase facilitates fast removal of formate, a highly toxic metabolite in methanol poisoning.     

鼻咽癌放疗致颞叶损伤的MR分型及意义

目的探讨颞叶放射性脑损伤的MRI形态学改变特性及其MRI分型的意义。方法回顾性分析51例鼻咽癌放疗后颞叶放射性脑损伤患者的临床及MR影像资料。按病变的主要发病部位及MR表现将其分为灰质型及白质型,其中白质型进一步分为白质型Ⅰ期和白质型Ⅱ期。结果51例放射性脑损伤按照分型及分期标准,包括40例白质型及11例灰质型,其中40例白质型包括白质型Ⅰ期24例、白质型Ⅱ期16例。结论颞叶放射性脑损伤的MR分型与分期能够反映其形态学改变特性,使病变的受累部位及病程更加明确,对指导临床治疗及病变间的定量研究比较有重要意义。     

脑卒中后抑郁障碍的^1H—MRS研究

目的：探讨脑卒中后抑郁障碍（PSD）患者^1H—MRS的变化特征及规律。方法：对35例脑卒中后抑郁症患者及26例健康对照组行MRI、^1H—MRS扫描,兴趣区为双侧额叶背外侧白质及前部扣带回皮质。结果：（1）PSD组前额叶背外侧白质内Cho／Cr比值明显高于对照组（P〈0．01）;而NAA／Cr比值两组间差异无统计学意义（P〉0．05）。（2）PSD组患者前额叶扣带回皮质内Cho／Cr比值明显高于对照组（P〈0．01）;而NAA／Cr比值两组间差异无统计学意义（P〉0．05）。结论：^1H—MRS能够揭示PSD时前额叶背外侧白质及扣带回皮质存在着细胞膜磷脂代谢的异常和细胞内信号转导异常。     

Experimental methanol toxicity in the primate: analysis of metabolic acidosis.

Methanol was administered to rats, rhesus monkeys (Macaca mulatta), and pigtail monkeys (Macaca nemestrina). Of these animals, only the pigtail monkey reliably developed a severe metabolic organic acidosis resembling that observed in humans. Blood and urine specimens drawn from methanol-treated pigtail monkeys were analyzed for organic acid content by gas chromatography-mass spectroscopy and specific assays were performed for formate. The anion gap resulting during methanol acidosis was accounted for in full by increased blood concentrations of formate. Systemic formate concentrations remained low in rats and monkeys which failed to become acidotic following methanol administration.     

The toxicity of inhaled methanol vapors

Methanol could become a major automotive fuel in the U.S., and its use may result in increased exposure of the public to methanol vapor. Nearly all of the available information on methanol toxicity in humans relates to the consequences of acute, rather than chronic, exposures. Acute methanol toxicity evolves in a well-understood pattern and consists of an uncompensated metabolic acidosis with superimposed toxicity to the visual system. The toxic properties of methanol are rooted in the factors that govern both the conversion of methanol to formic acid and the subsequent metabolism of formate to carbon dioxide in the folate pathway. In short, the toxic syndrome sets in if formate generation continues at a rate that exceeds its rate of metabolism. Current evidence indicates that formate accumulation will not challenge the metabolic capacity of the folate pathway at the anticipated levels of exposure to automotive methanol vapor.     

Profound metabolic acidosis and oxoprolinuria in an adult

Introduction

Profound metabolic acidosis in critically ill adults sometimes remains unexplained despite extensive evaluation.

Case Report

A 58-year-old female presented in a confused state to the emergency department; she had been confused for several days. Laboratory evaluation revealed a high anion gap metabolic acidosis and modestly elevated acetaminophen level. Lactic acid was only modestly elevated. There was no evidence of ketoacids, salicylate, methanol, or ethylene glycol. A urine sample submitted on day 1 of hospitalization revealed a markedly elevated level of 5-oxoproline.

Discussion

Originally described in children with an inherited defect of glutathione synthetase, 5-Oxoproline is an unusual cause of metabolic acidosis. More recently this disturbance has been recognized in critically ill adults without a recognized inherited metabolic disorder. In most of these cases there has been the concomitant use of acetaminophen. Any causal relationship between acetaminophen and this disturbance is speculative.

Conclusion

In critically ill adults with unexplained metabolic acidosis, 5-Oxoproline should be considered in the differential.     

Increased serum formate in the diagnosis of methanol poisoning

Early diagnosis is essential for successful treatment in methanol poisoning. Methanol detection by gas chromatography is not available in most hospitals. Methanol increases the osmolal gap in serum and its metabolite formate increases the anion gap. The sensitivity of these indirect diagnostic methods is not good at low concentrations of methanol or formate. We therefore studied the usefulness of formate measurement in diagnosing methanol poisoning. In 15 patients poisoned with methanol, serum formate was measured enzymatically on a Cobas Mira analyzer using formate dehydrogenase and nicotinamid adenine dinucleotid. Day-to-day coefficient of variation was 5%, and the upper reference limit was 2 mg/dL (0.4 mmol/L). Methanol was detected in all 15 patients of whom 14 had elevated serum formate concentrations. Anion gap was increased in 11 of 11, and osmolal gap in 11 patients of 15 examined. Metabolic acidosis was present in 12 of 15 patients, but pH was below 7.30 in only 9 of them. Four patients with no symptoms had formate concentrations in the range 2-38 mg/dL (0.5-8.3 mmol/L), indicating that increased serum formate was a sensitive indicator of methanol poisoning. Our results proved formate analyzes to be a simple, sensitive, and specific way of diagnosing methanol poisoning. Confounders are patients admitted early, or concomitant ethanol ingestion, and therefore no acidosis. This problem may, however, be omitted by repeated formate analysis in patients developing metabolic acidosis.     

感音神经性耳聋者的脑白质结构基于体素形态学研究

目的利用基于体素形态学技术比较听力正常人与感音神经性耳聋人的脑白质之间差异。方法分别对20例听力正常人及20例感音神经性耳聋人进行常规T2-WI与三维（3D）快速扰相梯度回波（FSPGR）采集脑结构图像。用VBM技术运算,然后观察2组脑质差异并显示出差异脑区的MNI坐标及差异容积,然后对所得数据进行相应统计学分析。结果听力正常组脑白质增多的区域有（P〈0.01,Clustersize=30）：左侧颞上回、左侧额中回、左侧顶叶（半卵圆中心）、左侧楔前叶、左侧额下回、左侧颞上回、左侧中央后回、左侧小脑半球、右侧颞上回。结论感音神经性聋人在左、右侧颞上回白质减少,提示其白质发生萎缩。     

Rational treatment of acid-base disorders

Acid-base derangements are encountered frequently in clinical practice and many have life-threatening implications. Treatment is dependent on correctly identifying the acid-base disorder and, whenever possible, repairing the underlying causal process. Bicarbonate is the agent of choice for the treatment of acute metabolic acidosis. Controversy surrounds the use of alkali therapy in lactic acidosis and diabetic ketoacidosis, but bicarbonate should clearly be administered for severe acidosis. In most patients with mild to moderate chloride-responsive metabolic alkalosis, providing an adequate amount of a chloride salt will restore acid-base balance to normal over a matter of days. In contrast, therapy of the chloride-resistant metabolic alkalosis is best directed at the underlying disease. When alkalemia is severe, administering hydrochloric acid or a hydrochloric acid precursor may be necessary. Treatment of respiratory acidosis should be targeted at restoring ventilation; alkali should be administered only for superimposed metabolic acidosis. The therapy of respiratory alkalosis is centred on reversal of the root cause; short of this goal, there is no effective treatment of primary hypocapnia. The coexistence of more than one acid-base disorder (i.e. a mixed disorder) is not uncommon. When plasma bicarbonate concentration and arterial carbon dioxide tension (paCO2) are altered in opposite directions, extreme shifts in pH may occur. In such cases, it is imperative that the nature of the disturbance is identified early and therapy directed at both disorders.     

Formate kinetics in methanol poisoning

OBJECTIVE: The objective is to describe the kinetics of formate, the main toxic metabolite of methanol, in a series of consecutive patients treated in the same intensive care unit for severe methanol poisoning. METHODS: The charts of the patients admitted between 1987 and 2001 were reviewed. Inclusion criteria were: a history of deliberate methanol ingestion, with a blood methanol concentration greater than 20 mg/dL (6.2 mmol/L) or a high anion gap metabolic acidosis. Indications for hemodialysis were: blood methanol concentration >50 mg/dL (15.8 mmol/L), metabolic acidosis (bicarbonate <15 mmol/L, arterial pH <7.30), visual toxicity. Antidotal therapy included ethanol administration in 22 cases, and fomepizole in three cases. Serial blood measurements were obtained for pH, bicarbonate, methanol and formate. Endogenous and hemodialysis elimination half-lives were calculated as t1/2 =0.693/Ke. Fick principle was applied for hemodialysis clearance calculation. RESULTS: The records of 25 methanol poisoned patients were analysed. Among them, 18 patients had sufficient data to allow accurate determinations of formate kinetics. Formate half-life elimination during hemodialysis was 1.80+/-0.78 h, which was statistically different from the values observed before or in the absence of dialysis (6.04+/-3.26 h, P =0.004). The mean hemodialysis formate clearance rate calculated in eight cases was 176+/-43 mL/min. A rebound in plasma formate concentration was observed in three patients after the discontinuation of hemodialysis. CONCLUSIONS: In accordance with previous isolated case reports and in contrast with a recent case series, our data document that hemodiaysis is effective in reducing formate elimination half-life. The impact on clinical outcome is still debatable.     

Head CT in patient with metabolic acidosis

An unresponsive 30-year-old female with a history of anxiety and chronic alcohol abuse presented to an emergency department with altered mental status and a severe metabolic acidosis. The patient was intubated for airway protection, and she empirically received folic acid, bicarbonate, and 5% ethanol continuous infusion for suspected ingestion of toxic alcohol. Following transfer to our institution, the patient was minimally responsive to noxious stimuli. She received fomepizole at dosing corrected for hemodialysis (HD), and bicarbonate via multiple boluses and continuous infusion. The ethanol drip was stopped. The nephrology service had been alerted to this patient’s arrival and condition; hemodialysis via a standard heparinized circuit was initiated immediately after her arrival, which produced a marked improvement in the patient’s acid-base status. Her serum methanol concentration subsequently returned at > 200 mg/dL. After 12 hours and 2 sessions of hemodialysis, the patient remained unresponsive despite minimal sedation. Anisocoria was noted on exam. Computed tomography of the brain demonstrated a large hematoma in the left basal ganglia that extended into the left frontal and parietal white matter accompanied by intraventricular extension, midline shift, loss of grey-white differentiation throughout, suggesting tonsillar herniation (Figure 1). Forty-eight hours after presentation, radionuclide imaging of the brain revealed no intracranial blood flow; heart, lungs, liver, kidneys, and pancreas were subsequently harvested for transplantation.     

Toxicity of sodium iodide in the rabbit: effects on hydrogen ion homeostasis, hepatic and renal function.

The effect of parenteral sodium iodide on hepatic and renal function and acid-base balance was studied in New Zeland white rabbits. Four groups of rabbits were infused intravenously with either 0.15 m NaCl or NaI in different concentrations, 0.03–0.15 m. Renal function as measured by blood-urea-nitrogen and urine protein excretion, hepatic cellular integrity, reflected in the serum activity of glutamic oxaloacetic transaminase, and acid-base balance determined by arterial pH and pCO₂, were the parameters chosen for study. The groups receiving the largest amount of iodide manifested severe hepatic changes, moderate renal changes, and metabolic acidosis. Histologic examination showed marked hepatic vacuolization and necrosis at the highest iodide dose. Renal tubular cells were vacuolated and occasionally necrotic. The genesis of the acidosis is obscure and may be augmented by an inadequate renal compensation for systemic acidosis. It is concluded that, in the rabbit, iodide is toxic to the liver and kidney and produces metabolic acidosis.     

Gas chromatographic analysis of methyl formate and application in methanol poisoning cases

A modified headspace gas chromatographic method for analysis of formate in biological fluids is described. Serum or whole blood specimens were methylated in the presence of concentrated sulfuric acid and sodium propionate (internal standard) dissolved in methanol. Derivatization was performed at 35 degrees C for 30 min before injection (0.5 mL headspace) onto a Hallcomid-Carbowax packed GLC column. Using serum or aqueous standards, the method was linear from 5 to 100 mg/dL. The limit of detection was 2.5 mg/dL. Day-to-day precision was less than 5% (CV) at 54 mg/dL formate. Formate and methanol were analyzed in 3 methanol poisonings, two of which were fatal. Formate analysis is considered important in any patient with suspected methanol poisoning who presents for medical assistance with metabolic acidosis. The extent of ocular toxicity correlates better with formate concentration than with methanol concentration.     

Human skeletal muscle lactate dehydrogenase activity in the presence of some alcohol dehydrogenase inhibitors

Methanol, ethylene glycol and other alcohol intoxications are complicated by severe acidosis which could be caused by formation of metabolic acids and additionally lactic acid production. An increasing nicotinamide adenine dinucleotide reduced/nicotinamide adenine dinucleotide oxidized (NADH/NAD) ratio during alcohol biotransformation is responsible for the induction of lactic acidosis. The main purpose of the present paper was to evaluate the effect of 4-methylpyrazole, cimetidine, ethylenediaminetetraacetic acid disodium salt, ethanol and methanol on lactate dehydrogenase (E.C. 1.1.1.27) activity and to discuss this issue. The activity of the enzyme was determined spectrophotometrically, in vitro using human enzyme skeletal muscle homogenates. 4-Methylpyrazole, cimetidine and ethylenediaminetetraacetic acid disodium salt at concentrations 0.01, 0.1, 1.0 mM and 12.5, 25.0, 50.0 mM of ethanol and methanol were studied. Our results showed that cimetidine increased lactate dehydrogenase activity as compared to the control at all tested concentrations. Such activity was noted for 4-methylpyrazole at 0.1 mM and higher concentration. By contrast, no significant effect on lactate dehydrogenase activity in the presence of ethylenediaminetetraacetic acid disodium salt, methanol and ethanol was observed.     

Fomepizole (4-methylpyrazole) in fatal methanol poisoning with early CT scan cerebral lesions

BACKGROUND: Methanol poisoning, potentially fatal, is generally treated with the combination of ethanol as antidote, and hemodialysis. Fomepizole, a competitive inhibitor of alcohol dehydrogenase, has more recently been used, and is capable of blocking the toxic metabolism of methanol. To our knowledge, its use has never been reported as an antidote in severe methanol poisoning requiring hemodialysis. CASE REPORT: We report a case of fatal methanol poisoning (1.9 g/L on admission) suspected due to the combined presence of coma and severe metabolic acidosis with normokalaemia. CONCLUSION: The fomepizole treatment protocol (10 mg/kg by i.v. infusion over 1 hour before dialysis, repeated 12 hours later in combination with 1.5 mg/kg/h during dialysis) was simple to use and appeared effective in eliminating methanol in combination with hemodialysis. The case is also unusual in terms of severity and the early onset of cerebral lesions demonstrated by computed tomography (CT) scan.     

Brain biogenic amine levels after methanol administration: possible mechanism of action on central monoaminergic neurons in discrete areas of brain in Wistar rat

Alterations in the steady state level of rat brain biogenic amines - dopamine, nor-epinephrine, epinephrine, serotonin and 5-hydroxy indole acetic acid, in response to intraperitoneal administration of methanol (3g/kg b.w.) were studied in discrete areas of the rat brain. The monoamine changes induced by methanol were quite different from those induced by ethanol consumption. They were also region-specific; hypothalamus being more vulnerable for methanol-induced monoamine changes. The effects produced by methanol were correlated with the blood and brain level of methanol at the given time, suggesting that the effects were dependent upon the local concentration of methanol in different brain regions. Acidosis induced by ammonium chloride and sodium formate administration did not alter the monoamine levels and therefore, the effects of methanol were not possibly due to acidosis. Blocking or delaying the metabolism of methanol either by 4-Methyl Pyrazole and 3-Amino 1,2,4-Triazole or by simultaneous administration of ethanol resulted in the potentiation of methanol effect. Therefore, it was concluded that methanol induced changes in brain biogenic amines were due to methanol per se and not due to metabolic end products viz. formaldehyde or formic acid.     

Decreased frontal white-matter volume in chronic substance abuse

There is quite a body of work assessing functional brain changes in chronic substance abuse, much less is known about structural brain abnormalities in this patient population. In this study we used magnetic resonance imaging (MRI) to determine if structural brain differences exist in patients abusing illicit drugs compared to healthy controls. Sixteen substance abusers who abused heroin, cocaine and cannabis but not alcohol and 16 age-, sex- and race-matched controls were imaged on a MRI scanner. Contiguous, 5-mm-thick axial slices were acquired with simultaneous T2 and proton density sequences. Volumes were estimated for total grey and white matter, frontal grey and white matter, ventricles, and CSF using two different methods: a conventional segmentation and a stereological method based on the Cavalieri principle. Overall brain volume differences were corrected for by expressing the volumes of interest as a percentage of total brain volume. Volume measures obtained with the two methods were highly correlated (r=0.65, p<0.001). Substance abusers had significantly less frontal white-matter volume percentage than controls. There were no significant differences in any of the other brain volumes measured. This difference in frontal lobe white matter might be explained by a direct neurotoxic effect of drug use on white matter, a pre-existing abnormality in the development of the frontal lobe or a combination of both effects. This last explanation might be compelling based on the fact that newer concepts on shared aspects of some neuropsychiatric disorders focus on the promotion and inhibition of the process of myelination throughout brain development and subsequent degeneration.