Ethylene glycol poisoning treated by intravenous 4-methylpyrazole
Received: 25 August 1997 Accepted: 9 April 1998
P. Hantson ( ~ ) Department of Intensive Care, Cliniques Universitaires St-Luc, Avenue Hippocrate, 10, B-1200 Brussels, Belgium Tel.: + 32-2-7642743; Fax: + 32-2-7648928 email: [email protected]
E Hantson. R Mahieu Laboratory of Toxicology, Cliniques Universitaires St-Luc, Brussels, Belgium
Abstract A 19-year-old woman was admitted 45 min after ethylene gly- col (EG) ingestion. The initiai se- rum E G concentrat ion was 1.34 g/1 (21.6 mmol/1), the anion gap 14.5, and the osmolal gap 24. Renal func- tion was preserved (serum creati- nine 75.1 ~tmol/1). As the patient was seen soon after poisoning, before the development of metabolic aci- dosis, therapy with 4-methylpyraz- ole (4-MP) was proposed as an anti- dote. 4-MP was administered via the intravenous route (7 mg/kg as load- ing dose, followed by 3.6, 1.2, 0.6, and 0.6 mg/kg at intervals of 12 h). 4-MP alone was effective in pre-
venting E G biotransformation to toxic metabolites (absence of meta- bolic acidosis and renal injury). Ethanol therapy, hemodialysis, and sodium bicarbonate administration were not required. The half-life of E G during 4-MP therapy was 11 h, with a mean E G renal clearance of 26.9 ml/min, and a total of 65.3 g E G was eliminated unchanged in the ur- ine. 4-MP therapy was also well tol- erated.
Key words Ethylene glycol. Poisoning. Antidotal therapy . 4-Methylpyrazole
Introduction
The diagnosis of ethylene glycol (EG) poisoning may be difficult in some cases. When patients have been t reated after a delay, significant biotransformation of E G into more toxic metabolites has occurred. Effective anti- dotes exist, but they need to be given early [1]. Ethanol is considered as the reference antidote for both E G and methanol poisoning. Another strong inhibitor of alcohol dehydrogenase, 4-methylpyrazole (4-MP), is being in- vestigated in a large clinical trial in the United States. It could offer several advantages over ethanol therapy. We report a case of E G poisoning observed soon after ingestion of E G and t reated successfully by intravenous 4-MP only.
Case report
A 19-year-old woman (weight 62 kg, height 165 cm) without a past medical history was referred to the emergency department (day 1, 11:30 a.m.) 45 min after the ingestion of about 300 ml of an anti- freeze solution containing 45 % EG. She admitted having also ab- sorbed 600 mg chlormezanone, 0.5 mg alprazolam, and 1 mg lora- zepam; she had vomited before reaching the hospital. On admis- sion, she was conscious, but drowsy. Her vital signs were: arterial blood pressure 140/70 mm/Hg, heart rate 120/rain, respiratory rate 12/min, temperature 36.6 °C. The fingers and the lips showed cyanosis. Cardiopulmonary auscultation was normal, while diffuse tenderness was noted on abdominal palpation. No anomalies were seen on the electrocardiogram and chest X-ray. The first arte- rial blood gas analysis revealed: pH 7.54, partial pressure of oxy- gen, 12.5 kPa, partial pressure of carbon dioxide 4.7 kPa, total bi- carbonate 23 mmol/1, base excess -1, 02 saturation (calculated) 98%, oxyhemoglobin (measured) 85.9%, hemoglobin 12.3 g/dl, carboxyhemoglobin 4.8%, methemoglobin 7.1%, lactate 3.9 mmol/1. The methemoglobin concentration was controlled a few minutes later at 12.1%. Cyanosis disappeared after the intra- venous administration of 50 mg methylene blue ( < 1 mg/kg). The patient's father remembered that the antifreeze solution had been
Fig.1 Evolution of serum ethylene glycol EG concentration, ox- aluria, anion gap, arterial pH, serum creatinine crea, and arterial lactate concentrations during 4-MP therapy
diluted with well water and a high nitrite concentration was pre- sent in the solution. We were unable to detect another contaminant in the antifreeze solution. Though low doses (1 mg/kg) of methyl- ene blue are usually well tolerated in patients who are not glu- cose-6-phosphate dehydrogenase-deficient, its use should be re- served for symptomatic patients whose methemoglobin levels ex- ceed 20 to 30 %.
The serum EG concentration on admission was 1.34g/l (21.6 mmol/1) and rose to 1.6 g/1 (25.8 mmol/1) 1 h later; ethanol was not detected (Fig. 1). Other relevant biological data were: measured serum osmolality 323 mOsm/kg H20, calculated serum osmolality 299 mOsm/kg H20 (using the formula 2 x Na + + blood urea nitrogen/2.8 + glucose/18), osmolal gap 24, anion gap 14.5 [with the formula (Na + + K+)--(CI-+ HCOf), usual range 10-16 mmol/1], serum creatinine 75.1 ~tmol/1, calcium 2.43 mmol/1.
The patient had persisting nausea and vomiting, and a nasogas- tric tube could not be inserted for gastric lavage or activated char- coal administration. As the patient was admitted soon after EG in- gestion and did not present acid-base disorders, and also had pre- served diuresis and renal function, we decided to treat her with 4- MP as antidotal therapy. The substance was provided by the Phar- macie Centrale des H6pitaux de Paris (20-ml vial containing 100 mg 4-methylpyrazole as an isotonic, nonpyrogenic solution). Intravenous administration was preferred because the patient was still vomiting, but also in order to inhibit rapidly EG metabolism. Each dose was diluted in 250 ml of isotonic sodium chloride solu- tion and infused over a period of 30 min. The dosage regimen was: initial dose (12:30 a.m.) of 570 mg (9.5 mg/kg) followed by ad- ministration every 12 h of, respectively, 420 mg (7 mg/kg), 220 mg (3.6 mg/kg), 70 mg (1.2 mg/kg), 35 mg (0.6 mg/kg), and a last dose of 35 mg (0.6 mg/kg) 60 h after the initiation of therapy. Arterial
blood gas analysis, anion gap, serum creatinine concentration, blood EG concentration, and oxaluria data are summarized in Fig. 1. The amount of nonmetabolized EG excreted in the urine was determined (Fig.2). A total amount of 65.3 g EG was recov- ered in the urine. The theoretical amount of EG ingested was 135 grams, but the patient had vomited and the EG solution had been diluted. EG was no longer detected in the blood 60 h after poisoning. The half-life (T1/2) of EG calculated during 4-MP ad- ministration was 11h. The calculated total body clearance (C1T = 0.693 x V D × body weight/T1/2) of EG with an apparent vol- ume of distribution (VD) of 700 ml/kg, was 45.6 ml/min. The mean renal clearance of EG during 4-MP therapy was 26.9ml/min (39.4 ml/min during the first day with a creatinine clearance of 83 ml/min). Oxaluria was moderately increased (reference val- ue: < 32 mg/g creatinine) on the first day but returned to normal on the second day. Only a slight increase in the anion gap was ob- served (in the absence of sodium bicarbonate administration).
Hemodialysis was not performed. Neurological status im- proved rapidly and the clinical course was uneventful. 4-MP thera- py was well tolerated: bloodcell counts and liver function tests re- mained within normal limits. The patient was discharged from the intensive care department on the fourth day.
Discussion
Afte r an ini t ial cent ra l ne rvous system (CNS) depres- s ion mimick ing the ac t ion of e thanol , E G poisoning m a y cause severe me tabo l i c acidosis. O t he r compl ica- t ions inc lude cardiac fai lure, acute oliguric rena l failure, seizures, secondary CNS depress ion, and coma.
The toxicity of E G results f rom its b io t r ans fo rma t ion by alcohol dehydrogenase ( A D H ) in to glycolic acid, which is fur ther me t a bo l i z e d to glyoxylic acid. Metabo l - ic acidosis is the c onse que nc e of glycolic acid fo rma t ion
Fig.2 Urine ethylene glycol EG excretion and calculation of EG renal clearance during 4-MP therapy
[2]. Various pathways exist for the transformation of glyoxalate, but the major route in terms of toxicity is the conversion to oxalate. The role of oxalate deposi- tion in the kidneys, as calcium oxalate crystals, is a com- monly accepted but not demonstrated mechanism of re- nal toxicity.
In many clinical situations, specific analyses for EG or its metabolites are not immediately available to the clinician. The calculation of the anion and osmolal gaps may have a diagnostic value. However, the calculation of the gaps has to be repeated. In comparison with methanol, EG has a higher molecular weight and thus a smaller molar contribution (EG: 1 g/1 = 16 mmol/1). In the late stage of EG poisoning, there is a pronounced metabolic acidosis with a high anion gap but an osmol gap that may be close to normal values (-9 to 19 mOsm/kg H20 ).
Conventional treatment of acute EG poisoning in- cludes supportive measures, ethanol as an antidotal therapy, and hemodialysis.
Among supportive measures, the maintenance of ad- equate urinary output is of primary importance as the kidney is largely involved in the removal of EG from the blood [3, 4]. Acute renal failure is often delayed, usually until 24 to 72 h after ingestion; initial aggressive management could help to prevent its development [5]. The indications for early hemodialysis are still debated [6]. Hemodialysis has been shown to be effective in re- moving EG and glycolate from the blood and to correct acid-base disorders [7]. Hemodialysis becomes the ma-
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jor route of glycol removal from the body if ethanol (or 4-MP) is given and renal failure is present. Hemodialy- sis may not be necessary at a very early stage, when the patient is observed before the development of severe metabolic acidosis and renal impairment. Several cases were treated by Baud et al. with 4-MP and bicarbonate alone [8,9]. Once hemodialysis is started, it should be continued until EG cannot be detected in the blood and acid-base disorders are corrected.
Ethanol is the commonly accepted specific antidotal therapy for both methanol and EG poisoning. The ad- ministration of pyridoxine and thiamine, as adjunct therapy, has also been proposed, but its routine use is not supported by sufficient data; pyridoxine may shunt the metabolism of EG metabolites from glyoxylic acid to glycine, and thiamine may shunt glyoxylic acid to al- pha-hydroxy-beta-ketoadipic acid. Ethanol is a compet- itive antagonist of ADH, with a higher affinity for the active site than the other alcohols. The effective ethanol blood concentration to completely block methanol or EG metabolism is about 100 mg/dl. However, there are several limitations to ethanol therapy. Large interindi- vidual variations exist for ethanol metabolism. More- over, when hemodialysis is applied, ethanol is also re- moved by this route and the maintenance ethanol infu- sion rate should be carefully adapted, with close moni- toring of ethanol blood concentrations. Finally, when large doses of ethanol are administered, the initial cen- tral nervous system depression caused by methanol or EG poisoning may be worsened by ethanol therapy.
These features led to research of other potential in- hibitors of ADH. 4-MP is a potent inhibitor of ADH, which may offer numerous advantages : possible oral administration, rapid onset of action, strong inhibition
739
of ADH, and slow rate of elimination. The efficacy of pyrazole in animal models has been demonstrated since 1978 [10,11]. Baud et al. have successfully treated pa- tients poisoned by EG with 4-MP by either the oral or the intravenous route [8,9]. The oral dose was 15 mg/kg body weight, followed by 5 mg/kg in 12 h and 10 mg/kg every 12 h thereafter until EG levels were nondetect- able. The initial intravenous dose was 9.5 mg/kg, fol- lowed by smaller doses every 12 h until EG disappeared from the blood. The calculated elimination half-life of EG was 12 h, which is very close to the value we ob- served. The renal clearance of EG was 31.5 ml/min over the first 2 days. 4-MP is still considered as an or- phan investigational drug. In a first step, tolerance and pharmacokinetics have been studied in healthy volun- teers. Jacobsen et al. [12] did not observe any serious adverse effects with a single oral dose of 10 mg/kg and 20 mg/kg. A transient elevation of aminotransferase lev- els were observed. After single doses, the elimination of 4-MP follows a two-enzyme elimination model: a dose of 10 mg/kg should be eliminated in about 25 h [13].
Large clinical studies are currently underway in the United States to evaluate the use of 4-MP to treat meth- anol and EG poisoning. A lot of questions remain unan-
swered: which is the optimum dosing regimen for 4- MP and the effective blood 4-MP level? Is there a place for combination therapy with 4-MP plus ethanol (com- petitive mechanism between the two molecules)? What about 4-MP elimination during hemodialysis[14]? Which therapy should be used in the case of EG poison- ing after a delay? The clinical experience demonstrates that most of the patients poisoned by EG are admitted with a significant delay. In these situations, current anti- dotal therapy (ethanol or 4-MP) will not necessarily be effective and hemodialysis cannot be avoided.
Our case illustrates the most beneficial situation for the use of 4-MP in EG poisoning: the patient was poorly symptomatic and had not developed metabolic disor- ders and renal impairment. CNS depression was also minimized by 4-MP therapy in comparison with ethanol. Hemodialysis was avoided and sodium bicarbonate ad- ministration was not necessary. However, as blood EG levels cannot be obtained rapidly, and due to the pro- longed elimination half-life under 4-MP therapy, a close monitoring of renal function and metabolic disorders is mandatory to assess the complete inhibition of EG me- tabolism.
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