Poisoning induced by alcohols (methanol, ethanol, or ethylene glycol) may cause severe metabolic acidosis with high anion and/or osmolal gaps, neurological changes ranging from confusion to deep coma, amaurosis, and death. Some patients may also develop acute renal failure.1-3 Despite intensive treatment, morbidity and mortality of these poisonings continue to be very high, mainly because of the delay in diagnosis and start of treatment.4,5 If there is no history of methanol, ethanol, or ethylene glycol intake, initial diagnosis is difficult. Measurement of serum levels  of  toxic alcohol is helpful, but is not always readily available on hospital admission. Diagnosis is often based on an obvious epidemiological context, and above all on the finding of metabolic acidosis with an elevated anion gap and/or osmolal gap.1-3 In some cases, osmolal gap may overestimate the amount of alcohols  present  in  serum,6,7 but a good linear correlation usually exists between them, and in the absence of toxic alcohol levels, osmolal gap allows for  a quite approximate indirect estimation.8,9 Depending on the time elapsed since toxic exposure, both biochemical changes may be present to a greater or lesser extent. In the earliest phase of poisoning, the osmolal gap is greater and the anion gap is lower, while as the alcohol  is  metabolised  the  osmolal  and  anion  gaps  approximate  to  each  other  (both  being  elevated),  and  in  the  latest phase the osmolal gap tends to normalise and the anion gap continues to increase.3,8,9 While less commonly, poisoning by other alcohols such as diethylene glycol and propylene glycol may also cause metabolic acidosis with elevation of the anion and/or osmolal gap, whereas isopropanol only causes elevation of osmolality.3



Methanol  poisoning may  result  from  a  suicidal  attempt, accidental intake, or consumption instead of ethanol in chronic drinkers. Methanol  is  a  small molecule  (32 Da)  that  is not bound to protein. Its distribution volume is therefore relatively small (0.6-0.7 L/kg), which allows for a particularly effective  removal by haemodialysis  (HD). Development of toxicity is related to plasma levels of methanol and its metabolites.10 Its  lethal  dose  is  50  to  100  mL,  but  smaller amounts may induce permanent amaurosis1 and in some patients necrosis of basal ganglia, more specifically  the putamen, or bleeding.11-13 However,  there are  reports of patients surviving with no organic damage to much higher methanol intakes.11 Among subjects who experienced seizures, coma, or  an  initial  pH  <  7, mortality was  higher  than  80%.14 By contrast, in the absence of these findings, the mortality rate was  less  than  6%.  In  another  series,  morbidity  was  also high,  and  mortality  occurred  in  up  to  44%  and  48%  of

cases.4,5 The mortality rates in three large series recently reported were 18%, 19%, and 44%  respectively. Methanol  is metabolised  by  the  enzyme  alcohol  dehydrogenase  (ADH) to yield  formic acid,  responsible  for metabolic acidosis.18,19 Management  of  severe methanol  poisoning  includes  administration of ethanol or fomepizole and early start of HD.11,20,22 Indications  for  ethanol  administration  include  methanol levels > 20 mg/dL or  an osmolal gap > 10 mosm/L in  the event of recent intake or when poisoning is strongly suspected. General indications of HD include high serum methanol levels  (>  50  mg/dL),  metabolic  acidosis,  and  visual  and mental  changes.3 In  addition,  in methanol  poisoning  folic acid  is  effective  for  accelerating  formate metabolism  into carbon dioxide and water.11,22



Ethylene  glycol  is  a  component  of  antifreezes  and  solvents. Poisoning is usually due to accidental intake. Ethylene glycol  is a small molecule  (62 Da)  that  is not bound  to protein  and  has  a  distribution  volume  of  0.5-0.8 L/kg.  Its lethal dose  is approximately 100 mL. Earliest  findings  include neurological changes ranging from confusion to deep coma. If untreated, these findings may be followed by cardiopulmonary symptoms (tachypnoea and pulmonary oedema) and acute renal failure, that may be associated to marked  crystalluria  in  urinary  sediment  (oxalate  crystals).23 Acid-base changes and clinical symptoms are due to accumulation  of  toxic metabolites,  rather  than  to  the  original toxic compound.1-3 Ethylene glycol is metabolised by ADH to  a  variety  of  toxic  compounds  including  glycolic  acid (that may be  toxic  for  renal  tubules)  and oxalic  acid  (that may  precipitate  in  the  tubules).23,24 The  mortality  rate  of ethylene  glycol  poisoning  is  variable,  ranging  from  1%-22%.25 The highest mortality is found in patients with most severe  metabolic  acidosis  and  longer  delay  in  treatment start. Management of severe ethylene glycol poisoning  includes  administration  of  ethanol  or  fomepizole  and  early start of HD.3,24,26,27 General  indications  for HD  include high ethylene glycol plasma levels (over 20 mg/dL), severe metabolic  acidosis  and/or  an  osmolal  gap  also  elevated.  In ethylene glycol poisoning, vitamins thiamine and pyridoxine may  be  effective  for  promoting  conversion  of  glycolic acid into  -hydroxy- -ketoadipate and glyoxylate into metabolites less toxic than oxalate, such as glycine.27,28 Moreover, during ethylene glycol poisoning,  forced diuresis may preserve  kidney  function  by minimising  tubular  blockade

by oxalate crystals.



Ethanol has a molecular weight of 46 Da and a distribution  volume  of  0.5  L/kg.1-3 Ethanol  exerts  its  actions  through several mechanisms. Thus, it is directly bound to the gamma-aminobutyric  acid  (GABA)  receptor  in  the  CNS and  causes  sedative  effects  similar  to  benzodiazepines, which  bind  to  the  same  GABA receptor.  Ethanol  levels peak  30-60 min  after  intake.  Ethanol  absorption  starts  at the oral mucosa  and  continues  in  the  stomach  and bowel. Ethanol  is mainly metabolised  in  the  liver. Approximately 90% of an ethanol overload is metabolized in the liver, and the remaining 10% is eliminated by the kidneys and lungs. In the liver, ethanol is converted by the action of ADH into acetaldehyde, which  is  then metabolised  to  acetic  acid by acetaldehyde dehydrogenase. Acetic acid enters  the Krebs cycle  and  is  finally  converted  into  carbon  dioxide  and water.  Clinical  findings with  different  ethanol  concentrations  may  be  classified  as  follows:  poisoning  100-150 mg/dL, loss of muscle coordination 150-200 mg/dL, decreased  level  of  consciousness  200-300  mg/dL,  and  death 300-500  mg/dL. Alcoholic  ketoacidosis  syndrome  is  uncommon and usually occurs  in patients with chronic ethanol ingestion and hepatic disease.29-32 The syndrome occurs during periods of high ethanol intake and low food intake. It  is  therefore  common  to  find metabolic  acidosis with  a high anion gap and sometimes with an also elevated osmolal gap. HD is able to efficiently clear ethanol from blood, but  should not be  routinely used because  it  is an  invasive procedure. In addition, HD has only been used in some isolated  cases  of  acute  ethanol  intoxication  in  pregnant women.



Alcohol  absorption  from  the  gastrointestinal  tract  is rapid. Thus,  gastric  lavage,  vomiting  induction,  or  use  of activated charcoal should be started in 30-60 minutes to be beneficial. Treatment of metabolic acidosis with bicarbonate  is a priority  that also allows  for  increasing  renal excretion  of  formic  cid  and  glycolate.15,33-35 Bicarbonate may  be administered by  the  intravenous  route or HD. Administration of ethanol or fomepizole to delay metabolism of alcohols, methanol  and  ethylene  glycol,  is  an  integral  part  of therapy. Though it has never been approved by the FDA, ethanol has been used for the treatment of poisoning by methanol  and  ethylene  glycol  for  many  years.11,20,28,36 Ethanol has a 10 to 20-fold greater affinity for ADH as compared to

other  alcohols,  and  completely  inhibits ADH  at  a  serum concentration of 100 mg/dL.3 Fomepizole (4-methylpyrazole, Antizol;  Jazz  Pharmaceuticals,  Palo Alto, CA)  has  approximately a 500 to 1,000-fold greater affinity for ADH as compared  to ethanol and may completely  inhibit  the enzyme  at  a  much  lower  serum  concentration.11,37 Fomepizole has a distribution volume of 0.6 to 1 L/kg and a low protein biding,  and  is  eliminated  by metabolism  in  the  liver  and renal  excretion. Studies  in  humans  have  confirmed  its  effectiveness  for  preventing  metabolism  of  methanol  and ethylene glycol to its toxic products. Fomepizole is therefore approved by the US FDA for the treatment of both poisonings. Fomepizole  is  removed by HD, and  its dose should therefore  be  increased  during  the  dialysis  procedure. The problems  for  use  of  fomepizole  are  its  unavailability  in many  countries  and  its high price  (approximately 7800 e per treatment).15 In addition, a recent study conducted on 20 patients  treated with  fomepizole  and/or  ethanol  could  not elucidate  in practice  the  superiority of one over  the other, and controversy therefore continues.37



Ethanol is dialysable, and when HD is required the dose of ethanol to be administered should be adjusted. Reduction

in  ethanol  levels  during HD may  be  prevented  by  increasing infusion rate or by adding ethanol directly to the dialysis bath.10,38,39 Efficacy of ethanol administration  for  inhibiting ADH  is  higher when  plasma  ethanol  levels  are  from 100  to 200 mg/dL. These  levels may be  reached by administering ethanol IV at the following dosage regimen: a loading dose of 0.6 g/kg body weight, plus an hourly maintenance  dose  of  66  mg/kg  in  non-drinkers,  154  mg/kg  in drinkers, and 240 mg/kg when HD is started.3 Regardless of how ethanol  is administered, ethanol plasma  levels should be  monitored  whenever  possible,  because  many  patients will  require  dose  adjustments.  Ethanol  infusion  and  HD should be continued until  the serum  levels of  the  toxic are

sufficiently low or have completely disappeared. When poisoning by these toxic alcohols is clinically suspected, even

before pharmacological confirmation is obtained, treatment with ethanol and HD should be started as soon as possible. Conventional  HD  may  rapidly  decrease  plasma  levels  of these alcohols, and also of their toxic metabolites, simultaneously  correcting  electrolyte  and  acid-base  disorders. Continuous  procedures  have  been  used  in  some  isolated cases,40 but results superior to those reported with HD have not been shown to date.



Randomised, controlled studies would be useful to provide evidence-based guidelines for the treatment of the different  phases  of  alcohol-induced  poisoning. While  no  such controlled  studies  allowing  for  assessing  the  value  of  the different therapies are available, the study published in this issue  of NEFROLOGIA41 demonstrates  that  early  start  of HD  techniques  using  a  bicarbonate  bath  enriched  with phosphorus  and  potassium39,41,42 and  high  efficiency  dialysers  achieves  an  excellent  removal  of  methanol,  ethanol, and ethylene glycol, as well as their toxic metabolites, producing  at  the  same  time  a  rapid  correction of water,  electrolyte, and acid-base disturbances. Measures implemented in  this  study  represent  a  combination  of  relatively  simple

and safe procedures  that decrease morbidity and mortality, allowing  for  a  shorter  hospital  stay.  However,  our  study was  limited  by  its  relatively  small  number  of  patients, though  this was  the  largest  series  (of  cases  from  a  single centre)  reported  to date  in Spain. Taking  into account  that there  has  been  in  recent  years  in  the Madrid Autonomous Community an increase in the number of cases of methanol poisoning among  immigrants who massively drank methanol during social events and who were referred to different hospitals, it would be appropriate for centres to coordinate their action protocols, and to share databases in order to be able to conduct cooperative studies.