Bs @, ALOOHOLS AND GLYG: resulting in lactic acidosis. Almost all propylene glycol is ‘metabolized within 24h of ingestion, Diagnosis and treatment (Clinical signs depend on the quantity ingested and may include depression, ataxia, muscle fasciculations, hypo- tension, osmotic diuresis, respiratory arrest, and circula tory collapse, Clinical signs in ruminants are similar to those seen in other species and include ataxia, depres sion, and recumbency (Pintchuck eal, 1993). Laboratory findings include metabolic acidosis, increased anion gap, and hyperosmolality of the plasma and the presence of Heinz bodies in cats and horses. Diagnosis is usually based on history of exposure and can be confirmed by measuring propylene glycol concentrations in urine and serum by gas chromatography. Treatment forall species is supportive and includes correction of hydration and acid-base abnormalities, Butylene glycol toxicosis, Butylene glycol (12, 13, and 14-butanediol) has the structural formula C\H,O; and a molecular weight of 90 Da, Butylene glycol is used as antifreeze, as an ind trial cleaner, and in cosmetics. It is also a component of polyurethane and is used to make Spandex. Although no published reports of butylene glycol toxicosis in domestic Animals were found in the literature, there are numerous reports of human intoxications from butylene glycol or the metabolite gamma-hydroxybutyrate (Dyer, 1991; Mack, 1983). Butylene glycol and the metabolite gamma-hydroxy- butyrate ate used as “recreational” drugs and were once ‘marketed by health food stores asa food additive for body- builders anc to treat depression and insomnia, 1,3-Butanediol has been used as an antidote for exper: mental EG toxicosis in dogs because itis a competitive substrate for ADH (Taal eal, 1982; Murphy et al, 1984 Cox etal, 1992) Although it was found to be a more effec tive antidote than ethanol, in that more unmetabolized FG was excreted in the urine in patients treated with 1 a-butanediol, CNS depression was as severe of more severe than that induced by ethanol therapy, and plasma hyperosmolality and metabolic acidosis were more severe than with ethanol therapy (Thrall ¢ al, 1982) Toxicokinetics Butylene glyco! is metabolized by ADH to acetoacetate and -gamma-hydroxybutyrate, the so-called “date rape” drug, Mechanism of action Butylene glycol is @ CNS depressant much like ethanol, due to the effect of the gamma-hydroxybutyrate on the NS, and in large quantities can result in seizures and. respiratory arrest Treatment ‘Therapy for butylene glycol toxicosis in humans is sup. portive, similar to therapy for ethanol toxicosis. yylene glycol toxicosis EG has the structural formula C,H,0; and a molecular weight of 62 Da. EG is used primarily as an antifreeze and windshield devicing agent. Its small molecular weight makes it very effective in lowering the freezing point of water. EG is also used as a cryoprotectant for embryo preservation; in the manufacture of polyester compounds; a8 a solvent in the paint and plastic indus tries; and as an ingredient in photographie developing. solutions, hydraulic brake fluid and motor oil, and inks and wood stains (Davis et al, 1997). The most readily available source of EG in the home is antifreeze solu tions, which consist of approximately 95% EC. Texicokineties Unlike the other alcohols (with the exception of metha- nol in primates) and glycols, the metabolites of EG are very toxic. EG is initially oxidized to glycoaldehyde by ADH, and glycoaldenyde is then oxidized to glycolic acid and then to glyoxylie acid. Glyoxylie acid is prima rily converted to oxalie acid but may follow several met- abolic pathways; end produets may also include glycine, formic acid, hippuric acid, oxalomalie acid, and benzoic acid. Calcium is bound t© oxalic acid, resulting in cal- cium oxalate crystal formation, Calcium oxalate crystal deposition is widespread but is most severe in the kid- ney, and crystalluria is a consistent finding in animals producing urine (Grauer eal, 1984; Thrall et al, 1984) Mechanism of action EG per se has no major effects other than GI irrita- tion and increased serum. osmolality. Glycoaldehyde, the first metabolite, is thought to be primarily respon- sible for CNS dysfunction; respiration, glucose, and serotonin metabolism are depressed; and CNS amine concentrations are altered (Parry and Wallach, 1974; Gordon and Hunter, 1982). Hypocaleemia secondary to caleium oxalate deposition may contribute to CNS signs, although the concurrent metabolic acidosis shifts calcism to the ionized active state, reducing the chances of hypocaleemia-associated clinical signs. Acidosis is also thought to lead to altered levels of conscious ness and cerebral damage. Most of the metabolites are very eytotoxie to renal tubular epithelium, and some‘GLYCOL TOMIOOSES| 739 renal epithelial and interstitial damage may be associ ated with caleium oxalate crystal formation within the renal tubules (de Water eal, 1999). Renal epithelial cell, death appears to be due primarily to destruction of cyto- plasmic organelles, especially mitochondria (Bachman and Goldberg, 1971). Metabolic acidosis is often severe and has a deleterious effect on multiple organ systems Glycolic acid accumulation is the primary cause of the metabolic acidosis associated with EG intoxication acobsen ef al, 1984), although other acid metabolites also contribute. Glycolic acid accumulates because the lactic dehydrogenase enzyme that metabolizes glycolic to glyoxylic acid becomes saturated Toxicity Before it is metabolized, EG is no more toxic than etha- nol, although FG is a more potent CNS depressant than ethanol (Berger and Ayyar, 1981). However, EG is biotransformed to highly toxic metabolites that result in severe metabolic acidosis and acute renal failure, hall marks of EG poisoning (Thrall etal, 1984b; Dial etal, 1994a,b; Davis ef al, 1997). The minimum lethal dose of undiluted EG is 6 mL/kg in the dog (Kersting and Nielson, 1956) and 1.51aL./kg in the cat (Milles, 1946) Clinical signs Clinical signs ate dose dependent and can be divided into those caused by unmetabolized EG and those caused by its toxic metabolites, The onset of clinical signe is almost always acute. Early clinical signs are usually observed 30min after ingestion and often last until approximately Dh after ingestion; they are primarily associated with EG-induced gastric irritation and high EG blood con- centrations. These signs commonly include nausea and vomiting, CNS depression, ataxia and knuckling, muscle fasciculations, decteased withdrawal reflexes and righting. ability, Aypothermia, and osmotic diuresis with resultant polyuria and polydipsia (Grauer etal, 1984; Thrall etal, 198db; Connally etal, 1996). As CNS depression increases in severity, dogs drink less but osmotic diuresis persists, resulting in dehydration. In dogs, CNS signs abate after approximately 12h, and patients may briefly appear to have recovered, Cats usually remain markedly depressed and do not exhibit polydipsia, Animals may be severely hypothermic, particularly if housed outside during the winter months. Clinical signs associated with the toxic metabolites are primarily related to oliguric renal failure, Which is evident by 35-72h following ingestion in dogs and by 12-26h following ingestion in cats. Clinical signe may include severe lethargy or coma, seizures, anorexia, vomiting, oral uleers and salivation, and oliguria with iso sthenuria, Anuria often develops 72-96h after ingestion The kidneys are often swollen and painful, particularly incats Early laboratory abnormalities Abnormal laboratory findings can also be divided into those associated with early EG intoxication, which may bbe related to the presence of EG per se oF to its toxic metabolites, and those associated with late EG intox!- cation, most of which are related to renal failure. Early abnormalities are primarily due to the presence of acid metabolites of EG in the serum that result in metabolic acidosis and inchide decreased plasma bicarbonate concentration and increased anion gap. In addition, hyperphosphatemia may occur due to ingestion of a. phosphate rust inhibitor present in some commercial antifreeze products (Grauer «tal, 1984; Connally et al, 1996). The decreased plasma bicarbonate (HCO) con centration can be seen as early as 1h following EG inges- tion. Metabolites of EG significantly increase the pool of tunmeasured anions and cause an increased anion gap. The anion gap is increased by Sh after ingestion, peaks at 6h after EG concentration, which peaks 1-6h follow ing ingestion, and EG is usually no longer detectable in the serum or urine 48-72h after ingestion (Thrall etal, 1982; Grauer ef al, 1984; Dial ef al, 1994a,b). Kits (eg. Ethylene Glycol Test Kit, PRN Pharmacol, Pensacola, FL) are available that accurately estimate blood EG. concentrations with a minimum detection limit of 50mg/dl, and the results correlate well with other established methods of measuring EG concentrations such as gat chromatography (Dasgupta eal, 1995), although the presence of propylene glycol or glycerol in the blood may cause a false-positive test reaction, Ethanol and methanol do not result in a false-positive test result. Cats may be intoxicated with a lethal dose of EG that is below the 50mg/dL. detectable level of the EG test kt. Therefore, if the test kit is negative and historical findings as well as clinical signs are compatible with EG. ingestion, the recommendation isto initiate appropriate therapy for EG intoxication as well as submit a serum, sample to a reference laboratory capable of determining. a quantitative concentration Determination of serum osmolality is also useful for diagnosing early EG toxicosis, although other osmoti- cally active, low-molecular-weight alcohols and glycols also increase serum osmolality (Ammar and Heckerling, 1996), Seram osmolality is increased by 1h alter inges- tion of EG, increasing in parallel with serum E centrations (Dial et al, 1994a,b). When measured serum. osmolality (by osmometzy) is compared to calculated. serum osmolality, the difference is referred to as the fosmole or osmolal gap. If calculated osmolality is not provided on the biochemical profile printout, osmolal ity in mOsm/kg may be calculated using the following, formula 1.85 (Na” +K°) + glucose /18 + BUN/28 ~740 @, ALOOHOLS AND GLYG: Normal serum osmolality is 280-S10mOsm/kg, and the normal osmole gap is less than 10mOsm/kg, Serum osmo Inlity as high as 450mOsm/kg. and an esmole gap as high a5 150mOsm kg may be seen 3h aftr ingestion, depen! ing on the quantity of antifreeze ingested (Jacobsen # al, 1982b; Grauer eal, 198). Both the gap and the measured osmolality may remain signiicanly high for approx mately 18h after ingestion. Multiplication of the osmole zap by 5 yields an approximate serum FC concentration in sg/Al. (@urkhart and Kulig, 19%), Fach 100mg/l incre rent increase in EG concentration contributes approx: rately 16mOsm/kg 1,0 to the serum osmolality (Eder ctl, 1988), Simultaneous or sequental increases in esmole and anion gaps are very suggestive of BG intoxication AAs EG is metabolized, its contribution to the osmole gap diminishes because the accumulating negatively charged retabolites do not contribute to the osmole gap (Eder tal, 1998) Two types of instruments are used to measure cosmolalty ~ feering point cemometers and vapor pres sure osmometers. Because BG ie nonvolatile (boing point, 197°), tis detected by either the freezing point or vapor pressure methods. However, methanol, ethanal, and other ‘Volatile compounds although conteibuting to serum osmo Inlity may go undetected if assayed by the vapor pressure method. Most clinical laboratories use the freezing point method (Kruse and Cadnapaphorncha, 199). Osmolality can be measured using serum or plain; if the latter is ‘used, heparin isthe preferred anticoagulant. Other antico agulants, such as EDTA, can markedly increase osmolal- sty and can result im spurious increases in the osmole gp (Krse and Cadnapaphornchai, 1991), Dogs are issthenuri (urine specific gravity of 1.008 1.012) by 3 following ingestion of EG due to osmotic diuresis and serum hyperosmolality-induced polydipsio (Grauer al, 1984; Dale al, 1994). The urine specific gravity in cats is also decreased by 3h after ingestion but ‘may be above the isosthenutic range (Dial e al, 19946; Fogazz, 1996). Calcium oxalate crystalluria is 3 com ‘mon finding and may be observed as early as 3 and 6h after ingestion inthe eat and dog, respectively, 35 2 result of oxalic acid combining with calcium (Dial al, 19943,5) Calcium oxalate monohydrate erystals ae vari ably sized, clea, sb-sided prisms (Figure 601) (Seully fa, 1979; Godolphin eal, 1980; Teeinsky etal, 1981; Jacobsen ef al, 19828; Kramer etal, 1984; Foi eal, 1985; Thrall al, 1985; Steinhart, 1990). In animals and people poisoned with EG, the monohydrate form is observed rote frequently than the dihydrate form, which appears a5 an envelope or Maltese cross (Connally eta, 1996; dere al, 1998). Dumbbell or sheafshaped crystals are cbserved infrequently. The detection of calcium oxalate cryatalluria, particularly the monohydrate form, pro: vides strong Supporting evidence for the diagnosis of EG poisoning (Fogszzi, 1995). Urinary pH consistently decreases following EG ingestion, FIGURE 60.1 Calcium oxste monchye ined light) fom 3 dog with EG toxiosie te cystals (pola Another diagnostic procedure that may be helpful in detecting early EG intoxication is examination ofthe oral cavity, face, paws, vomitus, and urine with a Wood's lamp to determine whether they appear fluorescent Many antifreeze solutions manufactured today contain sodium fluorescein, a fluorescent dye that aids in the detection of leaks in vehicle coolant systems. The dye is excreted in the urine for up to 6h following ingestion of the antifreeze (Winter ef al, 1990). A negative test does not eliminate the possibility of EG ingestion because not all antifreeze solutions contain the dye Late laboratory abnormalities With the onset of renal damage and subsequent decreased glomerular filtration, serum creatinine and blood urea nitrogen (BUN) concentrations increase. In the dog, these increases begin to occur between 24 and 48h following EG ingestion. In the cat, BUN and creati- nine begin to increase approximately 12h after ingestion; however, because cats do not develop polydipsia, this may be in part due to dehydration, Serum phosphorus concentrations increase at this time due to decreased glomerular filtration. Hyperkalemia develops with the onset of oliguria and anuria. Serum calcium concen- tration is decreased in approximately half of patients (Thrall etal, 1984b; Connally et al, 1996) and is due to formation of insoluble calcium oxalate. Clinical signs fof hypocalcemia are infrequently observed because acidosis results in a shift to the ionized, physiologi- cally active form of caleium, Serum glucose concentra tion is increased in approximately 50% of dogs and cats (Thrall ef al, 1984; Connally ef al, 1996) and is attrib uted to inhibition of glucose metabolism by aldehydes, increased epinephrine and endogenous corticosteroids, and uremia, Animals presenting with late EG poison- ing are likely to have little or no osmole gap inerease but will have an increased osmolality (whether calculated or‘GLYOOL TOXIGOSES v4 measured) because of the azotemia and hyperglycemia, Animals remain isosthenuric in the later stages of toxico- sis due to renal dysfunction and impaired ability to con- centrate urine, Calcium oxalate crystalluria persists for as long as animals are producing urine. Urine abnormali- ties associated with renal damage may include hematu- ria, proteinuria, and glucosuria. Granular and cellular casts, white blood cells, red blood cells, and renal epi- thelial cells may be observed in the sediment of some patients (Thrall etal, 1984b; Connally etal, 1996), Treatment ‘Therapy for EG poisoning is aimed at preventing absorption, increasing excretion, and preventing metab- olism of EG. Supportive care to correct fluid, acid-base, and electrolyte imbalances is also helpful, Although ther: apeutic recommendations have traditionally included Induetion of vomiting, gastric lavage, and administra- tion of activated charcoal (Thrall eta, 1995, 1998), i is likely that these procedures are not beneficial because of the rapidity with which EG is absorbed (Davis etal, 1997), The most critical aspect of therapy is based fon prevention of EG oxidation by ADI, the enzyme responsible for the initial reaction in the EG metabolic pathway (Parry and Wallach, 1974), Typically, dogs must be treated within 8h following ingestion and cats must be treated within 3h for teatment to be successful (Dial al, 1994a,6). However, this is somewhat dependent on. the amount of EG ingested. Historically, teating EG toxi- cosis has been directed toward inhibiting BC: metabolism with ethanol, 2 competitive substrate that has a higher affinity for ADH than EG (Penumarthy and Oehme, 1975; Bostrom and Li, 1980), Ethanol has numerous dis advantages because it enhances many of the metabolic effects of EG, Both ethanol and EG are CNS depressants, and its the compounded CNS depression that most lim- its the usefulness of ethanol as an antidote. Additional disadvantages of ethanol treatment include its metabo- lism to acetaldehyde, which impairs glucose metabo- lism and is a cerebral iritant. Ethanol also contributes to ‘metabolic acidosis by enhancing the formation of lactic acid from pyruvate and may potentiate hypocalcemia (Money et al, 1989). Moreover, ethanol compounds the effects of EG induced osmotic diuresis and serum hyper osmolality (Kruse and Cadnapaphornchai, 1994), “{Methylpyrazole (fomepizole) has become the pre: ferred antidote in dogs (Grauet etal, 1987; Dial eta, 1989; Connally e a, 1996) and cats (Thrall etal, 2008; Connally «tal, 2010). Fomepizole is an ADH inhibitor, not a competi- tive substrate, and it does not induce CNS depression (in dogs), diuresis, or hyperosmolality at the recommended dosage. The recommended dose of fomepizole for dogs is 20mg/kg body weight ix initially, followed by 15mg/kg, iv. at 12 and 24h and Smg/kg iv. at 36h (Grover eal, 1987; Connally e al, 1996; Tal etal, 2006), Cats must be given a much higher dose of fomepizole than dogs because feline ADH is less effectively inhibited by fomepizole than, is canine ADH (Connally etal, 2000, 2010). Cats are ini- tially treated with 125mg/kg fomepizole iv. fllowed by 31.25mq/kg ix: fomepizole at 12, 24, and 36h. The only adverse clinical sign that the authors have observed is CNS depression that appears to be fomepizole related (Connally etal, 2010). If ingestion of a large dose of EG is suspected, repeating serum quantification tests can be performed to determine whether contiauation of therapy beyond 36h is necessary: Alternatively, additional doses of fomepizole can be administered empirically. Fomepizole is commercially available as Antizol-Vet (Orphan Medical, Minnetonka, MN), which can be conveniently reconsti- tuted. Appropriate therapy also consist of iv lids to cor- rect dehyération, increase tissue perfusion, and promote diuresis. ‘The fluid volume administered should be based ‘on the maintenance, deficit, and continuing loss needs of the patent. Frequent measurement of urine production, serum urea nitrogen and creatinine, and blood pH, bisarbo- nate, ionized calcium, and electrolytes daily oF twice daily, will help guide fd and electrolyte therapy (Graver, 1958) Bicarbonate should be given slowly ix: to core the meta~ bolic acidosis. Hypothermia can be controlled with blan- kets or the use ofa pad with circulating warm water. Im animals that are azotemic and in oligutie renal fail- ure on presentation, almost all of the EG has been metab- ‘lized, and treatment to inhibit ADIT is likely to be of little benefit. However, ADH inhibitors should be given up to 36h following ingestion to prevent the metabolism. of any residual EG. Fluid, electrolyte, and acid-base dis- orders should be corrected and diuresis established, if possible, Diuretics, particularly mannitol, may be help ful. The tubular damage caused by EG may be revers- ible, but tubular repair can take weeks to months ‘Animals may take up to 1 year following EG toxicosis to regain concentrating ability, and some remain isosthenu- ric. Supportive care to maintain the patient during the Bev f renal bul regeneton nen, nd neal dialysis may be useful (Shahar and Holmberg, 1985; Fox etal, 1987, Crisp eta, 1989). Hemodialysis has been attempted in dogs with EG induced renal fil- lure (DiBartola ea, 1985) and has been shown to have a relatively good success rate in cats with acute renal fil- ture (Langston eta, 1997). Renal transplantation has also, ‘been used with variable success in cats with renal failure (Gregory et al, 1992; Mathews and Gregory, 1997) and thas been described in dogs (Nemeth etal, 1997). Prognosis EG has 2 very high potential for a lethal outcome, but ‘vith early recognition of the syndrome and timely insti- tution of therapy, animals ean be saved. The quantity ofa (@. ALCOHOLS AND GLYCOLS IEG ingested, rate of absorption, and time interval prior to institution of therapy are variables that affect the prognosis. The prognosis is excellent in dogs treated ‘with fomepizole within 5h of ingesting EG. In a retro- spective study of dogs with confirmed EG poisoning, all of the dogs that were azotemic when initially treated died. OF the dogs that did not have azotemia when ini- tially treated, approximately 90% survived (Connally tal, 1996). The prognosis for cats is reasonably good if treatment is instituted within 3h following ingestion (Dial etal, 19845) In contrast, the prognosis in humans who survive the initial syndrome of severe acidosis is, very good. Terminal renal fuilure in humans is raze, and ‘most human patients regain renal function by 2 months following EG poisoning (Davis «f al, 1997) likely due to the effectiveness of hemodialysis therapy in humans (Cheristiansson etal, 1993), CONCLUSIONS Ethanol, methanol, isopropanel, propylene glycol, buty- Tene glycol, and marijuana toxicosis can produce ataxia and other CNS signs similar to those seen in acute EG poisoning but are much less common than EG texico- sis (Godbold ea, 1979; Hurd-Kuenzi, 1983; Theall etal, 19849; Suter, 1992). These disorders can be differenti- ated by the diagnostic laboratory tests discussed previ- ously, Other causes of an increased anion gap include diabetic ketoacidosis and lactic acidosis; these disorders can also be differentiated by appropriate laboratory tests. Other causes of increased osmolality include ethanol, isopropanol, methanol, and propylene glycol toxicosis. Ethanol, like EG, can also produce hypocalcemia (Money. al, 1989), Other differentials for acute renal failure include leptospitosis, ibuprofen and other nonsteroidal antiinflammatory drug toxicosis, aminoglycoside anti- biotics, hemolyticuremic syndrome, cholecalciferol toxi- cosis, grape and raisin toxicosis in dogs, and ingestion of coxalate-containing plants such as philodendron and lily toxicosis in eats (Brown eta, 1985, 1996; Spyridakis eal, 1985; Gunther ef al, 1988; Peterson etal, 1991; Holloway ft al, 1993; Rivers et al, 1996; Vaden et ah, 19973; Poortinga and Hungerford, 1998; Forrester and Troy, 1999; Adin and Cowgill, 2000; Hovda, 2000; Rumbeiha et al, 2000; Singleton, 2001; Langston, 2002; Tefft, 2001). The majority of dogs with grape and raisin toxicosis are hyper- calcemic, a5 are animals with cholecaliferol toxicosis (ooshee and Forrester, 190; Gwaltney-Brant etal, 2001); hypercalcemia is not associated with EG toxicosis (Thrall al, 1984b; Connally tal, 1996). Acute renal failure must be differentiated from acutely decompensated chronic renal failure, Carbamylated hemoglobin concentration has been shown to be useful in making this differentia: tion (Vaden et al, 1997b; Helene et al, 2001) In addition, animals with ehronic renal failure may be anemic and in poor body condition, history of the duration of clinical signs is also helpful. Continuing to increase the awareness ofthe toxicity of EG, as well as other alcohols and glycols, will aid in preventing exposure and result in earlier pres- entation of animals. REFERENCES ‘Adin CA, Cowgill LD 2000) Treatment and outcome of dogs with Teptosprsis: 36 cases (990-1998) | Aw Vet Mol Assoc 216 sna, ‘Ammar KA, Heckerlng PS (1986) Ethylene glyeol poisoning with 2 normal ation gap eaused by concurrent ethanol ingestion: Importance ofthe csmolal gap. 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