Fomepizole versus ethanol in the treatment of acute methanol poisoning

Clinical Toxicology (2015), Early Online: 1–10 Copyright © 2015 Informa Healthcare USA, Inc. ISSN: 1556-3650 print / 1556-9519 online DOI: 10.3109/15563650.2015.1059946

ORIGINAL ARTICLE

Fomepizole versus ethanol in the treatment of acute methanol poisoning: Comparison of clinical effectiveness in a mass poisoning outbreak

Clinical Toxicology Downloaded from informahealthcare.com by Charles University on 06/24/15 For personal use only.

Sergey Zakharov,1 Daniela Pelclova,1 Tomas Navratil,1,2 Jaromir Belacek,3 Martin Komarc,3 Michael Eddleston,4 and Knut Erik Hovda5 1Department

of Occupational Medicine, Toxicological Information Center, First Faculty of Medicine, Charles University in Prague and General University Hospital, Na Bojisti, Prague, Czech Republic 2Department of Biomimetic Electrochemistry, J. Heyrovsky Institute of Physical Chemistry of AS CR, v.v.i, Dolejskova, Prague, Czech Republic 3Institute of Biophysics and Informatics, First Faculty of Medicine of Charles University in Prague, General University Hospital, Salmovska, Prague, Czech Republic 4Pharmacology, Toxicology, & Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK 5Department of Acute Medicine, The Norwegian CBRNe Centre of Medicine, Oslo University Hospital, Ullevaal, Nydalen, Oslo, Norway

Context. Mass or cluster methanol poisonings are frequently reported from around the world. The comparative effectiveness of ethanol and fomepizole as antidotes for methanol poisoning is unknown due to the difficulty of performing a randomized controlled trial. Objective. During an outbreak of mass poisonings in the Czech Republic in 2012–2014, we compared the effects of antidotes on the frequency of health sequelae and mortality. Methods. The study was designed as a cross-sectional case series and quasi-case–control study. Patients with a diagnosis of methanol poisoning on admission to hospitals were identified for the study. Diagnosis was established when (i) a history of recent ingestion of illicit spirits was available and serum methanol was higher than 6.2 mmol/L (20 mg/dL), or (ii) there was a history/clinical suspicion of methanol poisoning, and serum methanol was above the limit of detection with at least two of the following: pH  7.3, serum bicarbonate  20 mmol/L, and anion gap or AG  20 mmol/L. Fomepizole was given as a bolus dose of 15 mg/kg i.v. diluted in isotonic saline, followed by 10 mg/kg every 12 h (every 4 h during hemodialysis); ethanol was administered both intravenously as a 10% solution in 5% glucose, and per os in boluses of 20% solution. Multivariate regression was applied to determine the effect of antidote on outcome. Additionally, for a retrospective quasi-case–control study, a control group of patients treated with ethanol, matched carefully on severity of poisoning and other key parameters, was selected. Results. Data were obtained from 100 hospitalized patients with confirmed poisoning: 25 patients treated with fomepizole were compared with 68 patients receiving ethanol (seven patients did not receive any antidote). More severely acidotic (p  0.001) and late-presenting (12 h; p  0.028) patients received fomepizole more often than ethanol, as reflected in the higher number of fomepizole-treated patients being intubated (p  0.009). No association was found between the type of antidote and the survival in either the case series (p  0.205) or the quasi-control groups (p  0.705) in which patients were very closely matched to minimize confounding by allocation. In the multivariate analysis, positive serum ethanol (odds ratio [OR], 10.8; 95% confidence interval [CI], 2.9–39.9) and arterial blood pH (OR, 3.7; 95% CI, 1.3–10.5) on admission were the only independent variables for the survival. The median intensive care unit length of stay was 6 (range, 2–22) days in the fomepizole group and 4 (range, 1–33) days in the ethanol group (p  0.131). There were no differences in the use of elimination techniques between the two groups (neither in the full material (n  100), nor the case–control groups (n  50)). Conclusions. This study on antidotes for methanol poisoning did not show any evidence of different clinical effectiveness. Although ethanol is generally associated with a higher incidence of complications, this study suggests that both antidotes are similarly effective and that ethanol should not be avoided on grounds of effectiveness. Keywords Clinical effectiveness; Hospital treatment; Antidote administration; Treatment outcome; Sequelae of poisoning

Received 31 March 2015; accepted 03 June 2015.

Introduction

Address correspondence to Sergey Zakharov, M.D., PhD. Department of Occupational Medicine, Toxicological Information Center, First Faculty of Medicine, Charles University in Prague and General University Hospital, Na Bojisti 1, 120 00, Prague 2, Czech Republic, Tel.:  420 224 964 155; E-mail: [email protected]

Mass or cluster methanol poisonings as a result of its use as a cheap substitute for ethanol occur frequently worldwide.1–6 Treatment includes the use of antidotes, fomepizole or ethanol, to prevent the formation of the 1


2 S. Zakharov et al. toxic metabolites, formic acid or formate anions.7,8 These metabolites have a strong cytotoxic effect by inhibition of mitochondrial respiration.9,10 Accumulation of formic acid results in a metabolic acidosis with lactacidemia, visual impairment, and damage of basal ganglia. Clinical symptoms, such as visual disturbances, dyspnea, and others, seem to occur when its concentration rises above 9 mmol/L.11–13 The mortality of methanol poisonings remains high; on admission, the degree of metabolic acidosis (low serum bicarbonate, high anion gap, serum lactate, and formate concentrations), negative serum ethanol, lack of respiratory compensation when severely acidotic, and coma are known risk factors predicting poor outcome.3,14–16 The time from intake to diagnosis is highly relevant, yet clearly defined by the state of the patient on admission. There is no consistent correlation between serum methanol concentration on admission and mortality,1–3 but despite the absence of correlation between serum methanol and serum formate, patients with poor outcome often have a higher serum methanol concentration.3,15,17 Finally, stress-induced hyperglycemia seen in critically ill patients has been proposed as a poor prognostic factor.3,18 Ethanol is a well-established antidote in the treatment of acute methanol poisoning.19,20 It has approximately ten times greater affinity for alcohol dehydrogenase (ADH) than methanol, effectively blocking the conversion of methanol to formaldehyde when its concentration in blood serum is above approximately 22 mmol/L.8,21 Fomepizole (4-methylpyrazole) is another effective antidote with affinity to ADH several thousand times higher than that of methanol.22–25 Fomepizole was recently (2013) added to the WHO Essential Medicines List, but its availability is still limited.26 Potential benefits of fomepizole versus ethanol include sober patients with no CNS-depressive effect of fomepizole, an easier administration with a pre-defined dosing regimen, no need for measuring of the serum level of the antidote, and a lower likelihood of underdosing during dialysis.27–30 However, except for the large retrospective study by Paasma et al looking at the prognosis in hospital, no studies comparing short- and long-term outcomes have been performed.16 This is due to the great difficulty of performing a randomized controlled trial (RCT) during a methanol epidemic.2,28,30 A recent comprehensive systematic assessment of the data on antidote effectiveness urged further research into the relative benefits of ethanol and fomepizole in the management of toxic alcohol ingestions.31 During an outbreak of mass poisonings in the Czech Republic in 2012–2014, we compared the effects of both antidotes on the frequency of health sequelae and mortality. The epidemiological description of the outbreak has been presented elsewhere.3 During the epidemic, the availability of fomepizole was limited; although the more severely ill patients were more likely to receive fomepizole than less sick patients, many sick patients only received ethanol.

Materials and methods Patients and procedures The study was designed as a cross-sectional case series and quasi-case–control study. Case series data set A total of 137 cases of methanol poisonings occurred between September 3rd, 2012 and August 31st, 2014; 106 patients were treated in hospitals. A detailed history of the poisoning, and of the onset and dynamics of ocular and systemic toxicity, was obtained in a prospective manner directly from the patients or from relatives of critically ill patients upon admission to the secondary hospital. Detailed neurological and ophthalmological examinations were performed during hospitalization and on discharge. At this point, the discharge reports of all hospitalized patients with a confirmed diagnosis were collected and analyzed in the Czech Toxicological Information Center or TIC. Laboratory analyses were performed on admission. The patients with established diagnosis of methanol poisoning on admission to hospitals were identified for the study. Diagnosis was established when (i) a history of recent ingestion of illicit spirits was available and serum methanol was higher than 6.2 mmol/L (20 mg/dL), or (ii) there was a history/clinical suspicion of methanol poisoning, and serum methanol was above the limit of detection with at least two of the following: pH  7.3, serum bicarbonate  20 mmol/L, and anion gap (AG)  20 mmol/L. The patients were considered to have visual sequelae of acute methanol poisoning if the symptoms of toxic neuropathy of the optic nerve were documented on admission or during hospitalization, with pathologic findings on visual acuity, visual fields, color vision, and contrast sensitivity, together with persisting lesions on fundoscopy and other symptoms of visual damage being detectable on hospital discharge. The patients were considered as having CNS sequelae of poisoning if symmetrical necrosis and hemorrhages of basal ganglia were present on CT or MRI of the brain. Quasi-control data set To minimize the differences between patients receiving fomepizole or ethanol, we also performed a quasi-control study. From the total number of patients treated in hospitals with ethanol as an antidote, the smaller group was selected retrospectively to make a highly matched quasi-control group for the fomepizole-treated patients from the more severely poisoned patients treated with ethanol. The patients were matched in pairs (“case–control”) following all known demographic, toxicological, biochemical, clinical, and therapeutic factors with possible influence on the outcome of poisoning including age, gender, dose ingested, time from ingestion, poisoning severity score (PSS),32 Glasgow Coma Scale (GCS), mean arterial pressure (MAP), arterial blood pH, bicarbonate, pCO2, base deficit, AG, serum methanol, ethanol, formate (where available), lactate, glucose, Clinical Toxicology Early Online 2015

Fomepizole vs. Ethanol in acute methanol poisonings 3


creatinine, and treatment modalities (alkalization, hemodialysis, and folate substitution), to minimize confounding in this non-randomized study. Treatment All patients were treated in accordance with the American Academy of Clinical Toxicology/European Association of Poisons. Centres and Clinical Toxicologists (AACT/ EAPCCT) practice guidelines on the treatment of methanol poisoning.7 Bicarbonate 8.4% or 4.2% solution was given intravenously as a buffer to the patients with metabolic acidosis. Ethanol was administered intravenously as 10% solution in 5% glucose according to the following scheme: the loading dose of approximately 7.5–8.0 ml/kg during 1 hour, followed by the maintenance dose 1.0–2.0 ml/kg/h or 2.5–3.0 ml/kg/h during the hemodialysis. If ethanol was administered per os, 0.7–1.0 ml/kg/h of 20% solution was generally applied in boluses each 3 h. In these cases, the intravenous administration of ethanol was followed by the oral administration after the patients had been dialyzed, with the serum methanol level under 6.2 mmol/L (20 mg/dL) and the metabolic acidosis corrected at the moment of change of the route of ethanol administration. The serum ethanol concentration was monitored every 2–4 h during this period according to the AACT/EAPCCT practice guidelines, and the results of each measurement were used to calculate the dose of ethanol in the further bolus.7 Treatment with ethanol continued until the serum methanol concentration was under the detection limit and the patient was asymptomatic with normal arterial pH. Fomepizole (Fomepizole EUSA, EUSA Pharma, France) was given as a bolus dose of 15 mg/kg i.v. diluted in isotonic saline, followed by 10 mg/kg every 12 h (every 4 h during hemodialysis). Since there was a limited availability of fomepizole, the following antidote-saving approach was used: (a) if fomepizole was not available immediately, an initial bolus of ethanol was administered to rapidly achieve a protective serum concentration of 100–150 mg/dL (21.7– 32.6 mmol/L); (b) when available, fomepizole treatment was prioritized in patients with serum methanol higher than 50 mg/dL (15.6 mmol/L) (or formate higher than 40 mg/dL (8.9 mmol/L)) and pH  7.0, or methanol higher than 30 mg/dL (9.4 mmol/L) and pH  7.0 in patients unable to hyperventilate (pCO2  3.07 kPa or 23.0 mmHg); c) treatment with fomepizole was stopped and followed by ethanol administration when methanol concentration decreased below 30 mg/dL (9.4 mmol/L) given a normal pH, or 20 mg/dL (6.2 mmol/L) if metabolic acidosis was not yet corrected. The rationale for this approach is given elsewhere.3,25 Hemodialysis was performed if the patients met any of the following criteria: serum methanol higher than 50 mg/ dL (15.6 mmol/L), metabolic acidosis with a pH  7.30, or visual disturbances.7 The mode of dialysis, intermittent hemodialysis (IHD), extended daily dialysis (EDD), or continuous veno-venous hemofiltration/hemodialysis/ hemodiafiltration (CVVH/HD/HDF) was based on several factors, such as the hemodynamic stability of a patient on Copyright © Informa Healthcare USA, Inc. 2015

admission, or the severity of poisoning, and availability of dialysis equipment. Folates were administered to supplement the endogenous pool of folate: folinic acid (Calcium Folinate Hospira, amp. 20 ml, 10 mg/mL Hospira UK Limited, Great Britain, and folic acid (Acidum folicum Léčiva, tbl. 10 mg, Zentiva, Czech Republic).11 The dose of folinic acid was 50 mg, administered intravenously, every 4–6 h until methanol and formate were eliminated. If folinic acid was not available, 50 mg of folic acid in tablets were administered orally every 3–4 h. Corticosteroids were not administered to the patients with visual disturbances. Laboratory investigations Methanol was measured using gas chromatography with flame ionization detection and a direct injection with internal standard (Gas Chromatograph Chrom 5, Laboratory Instruments Prague, Czech Republic), limit of detection of 1.9 mmol/L (6 mg/dL), and day-to-day coefficient of variation 2.5–5.4%. Calibrators and controls were made by dilution of methanol p.a. (Penta, Czech Republic). Formate was measured enzymatically on a Hitachi analyzer (Hitachi 912, Hitachi Science Systems Ltd., Japan) using formate dehydrogenase (Roche, France) and nicotinamide adenine dinucleotide (NAD) (Roche, France), according to a previously published method.17 Serum ethanol was analyzed by gas chromatography with flame ionization detection and a direct injection with internal standard (Gas Chromatograph Chrom 5, Laboratory Instruments Prague, Czech Republic). Limit of detection was 0.9 mmol/L (4 mg/dL) and day-to-day coefficient of variation 3.8–7.1%. Osmolality was measured by freezing point depression method on a Fiske one-ten osmometer. Reference range for the osmolal gap was –9 to 19 mOsm/kg H2O. The osmolal contribution from ethanol was subtracted from the measured osmolality. Calculations and data analysis The laboratory and clinical data were compared using Two-Sample Assuming Unequal Variances (Equal Means), Two-sample F-Test for Variances, bias test, and two-sample Kolmogorov–Smirnov test. The normality of data distribution was characterized using skewness and kurtosis tests. Data are expressed as medians and arithmetic means with either range or standard deviation, or confidence interval (significance level a  0.05), as appropriate. Spearman’s rank correlation, exploratory factor analysis, and Chi-square tests were used to analyze the association between different variables (laboratory parameters, clinical features, and treatment modalities), and the outcomes of treatment. Statistically significant parameters were subsequently used in univariate, bivariate, and multivariate linear regression models of ordinal multinomic logistic regression based on likelihood ratio estimation. All statistical calculations were carried out on level of significance a  0.05. Statistical analysis was performed using Excel (Microsoft, USA), and the formal calculations were produced in QC

4 S. Zakharov et al. Expert software 3.1 (Trilobyte, Pardubice, Czech Republic) and in IBM SPSS (version. 17.0, SPSS Inc., Chicago, IL, USA) and Statistica SW ver. 10.0, Dell Inc., Round Rock, Texas, USA. Ethics The study was approved by the General University Hospital Ethics Committee in Prague, Czech Republic.


Results Of 106 hospitalized patients, laboratory and clinical data were incomplete in six cases. Since these data were a key issue for the study and were necessary for the multivariate regression analysis, these six patients were excluded from the study. Seventy-nine patients treated in hospitals survived the poisoning. A follow-up clinical examination was carried out 3–8 months after discharge in 50/79 (63.3%) survivors to identify sequelae of poisoning. In 29 survivors, a follow-up could not be carried out; for these patients, information on treatment outcome and sequelae was extracted from the discharge reports. Among the 100 hospitalized patients who were included in the study (median age: 52 (range, 16–79) years), 25 patients were treated with fomepizole, while 68 patients received ethanol; seven patients did not receive any antidote (Figure 1). Regarding the time of presentation, where known, the median time to presentation was 41 (interquartile range or IQR, 24–48) h; only 12% were admitted within 12 h of the methanol ingestion, 61% within 13–48 h, and 13% later than 48 h. In 14% of the cases, it was not possible to identify the time between the consumption of toxic spirits and admission to a hospital. Thirty patients received pre-hospital ethanol either directly from ambulance crews or from medical or paramedical staff at ‘Collecting Points’ (smaller local hospitals without toxicological laboratories able to measure methanol and without dialysis facilities) as a “first aid antidote.” The

remaining 70 patients did not receive pre-hospital ethanol from paramedical or medical staff. Twelve of these patients self-administered ethanol in the community, shortly before the first contact with paramedic/medical staff. An analysis of the effect of this pre-hospital treatment is being published elsewhere (Zakharov et al, unpublished). An initial bolus of ethanol was administered before fomepizole in 16/25 (64%) of the fomepizole cases, and administration of ethanol followed the treatment with fomepizole after the decrease of methanol concentration under 30 mg/dL (9.4 mmol/L) and correction of metabolic acidosis in 2/25 (8%) fomepizole cases. All these cases were included in the fomepizole group. Admission laboratory data The laboratory data on admission in 100 patients allocated to groups according to the antidote given is shown in Table 1. Patients treated with fomepizole were more acidotic on admission with lower arterial blood pH and bicarbonate, higher base deficit, and AG. They also had higher serum concentration of creatinine. The patients with more severe acidosis on admission received fomepizole more often (r2  0.137, n  100; p  0.001). Patients presenting late, after 12 and more hours, were administered fomepizole more often than ethanol (r2  0.059, n  100; p  0.028). To minimize the effect of this differential allocation of patients to antidote based on severity, we performed a quasi-case–control study closely matching on a pairwise basis 25 of the most severely ill ethanol-treated patients with the 25 fomepizole-treated patients. The laboratory data for these 50 patients separated by allocation with similar key parameters is shown in Table 2 and Appendix 1 to be found online at http://informahealthcare. com/doi/abs/10.3109/15563650.2015.1059946. In this sample, there were no statistically significant differences in any of the laboratory parameters.

Fig. 1. Flow chart of the patients in the study. Clinical Toxicology Early Online 2015

Copyright © Informa Healthcare USA, Inc. 2015

0.791

54 (16–79)

55 (59–65)

53 (23–79)

50 (16–73)

Age

0.72

21F

1F

14F

6F

G

0.115

41 (8–72)

36 (24–72)

35 (8–72)

48 (11–72)

0.164

400 (100–1200)

ND

300 (100–800)

450 (100–1200)

mL

92.0 6.0–730.8 0.408

17.0 6.0–160.0 28.7 (1.9–228.0)

92.0 8.7–730.8 5.3 (1.9–49.9)

138.1 (32.4–394.9) 28.7 (2.7–228.0)

43.1 (10.1–123.2)

(mg/dL)

0.0 0.0–446.1 0.018

0.0 0.0–25.8 0.0 (0.0–96.8)

0.0 0.0–446.1 0.0 (0.0–5.6)

0.0 0.0–118.0 0.0 (0.0–96.8)

0.0 (0.0–25.6)

(mg/dL)

63.5 0.0–140.0 0.612

ND 13.8 (0.0–30.4)

64.0 0.0–140.0 ND

62.1 4.6–91.6 13.9 (0.0–30.4)

13.5 (1.0–19.9)

(mg/dL)

mmol/L

(h)

EtOH mmol/L

0.440

3.5 (0.5–19.4)

5.9 (1.5–10.2)

2.8 (0.5–19.4)

6.0 (1.1–16.3)

Lactate mmol/l

0.007

7.18 (6.57–7.46)

7.03 (6.58–7.45)

7.24 (6.57–7.46)

6.99 (6.65–7.39)

pH

0.707

4.2 (1.0–11.5)

3.3 (1.2–5.1)

4.4 (1.7–11.5)

3.4 (1.0–7.9)

pCO2 kPa

0.002

10.0 (2.0–27.2)

7.9 (2.2–24.2)

12.0 (2.1–27.2)

5.2 (2.0–20.9)

HCO3 mmol/l

49 28–67

0.785

Ethanol

P Fom/Eth

0.877

48 0–56

48 (11–72)

0.700

400 200–1500

500 100–1200

Dose ingested mL 43.1 10.1–123.2 138.1 (32.4–394.9) 44.0 6.2–228.1 141.0 19.9–731.1 0.301

MetOH mmol/L (mg/dL) 0.0 0.0–25.6 0.0 0.0–118.0 0.0 0.0–96.8 0.0 0.0–446.1 0.336

EtOH mmol/L (mg/dL) 13.5 1.0–19.9 62.1 4.6–91.6) 14.8 0.0–25.2 68.1 0.0–116.0 0.475

Formate mmol/L (mg/ dL)

0.702

6.1 0.5–15.6

6.0 1.1–16.3

Lactate mmol/l

0.719

7.02 6.63–7.44

6.99 6.65–7.39

pH

0.571

3.8 1.8–9.5

3.4 1.0–7.9

pCO2 kPa

0.596

5.7 2.1–23.7

5.2 2.0–20.9

HCO3 mmol/l

0.703

 25.2–0.6–25.2

 26.4–3.5– 38.1

BD mmol/l

0.001

17.8 (0.1–38.1)

22.5 (0.3–22.9)

12.8 (0.1–36.0)

26.4 (3.5–38.1)

BD mmol/l

0.947

33.0 11.0–50.0

32.2 18.1–54.8

AG mmol/l

0.009

28.3 (11.1–54.8)

32.9 (18.0–39.2)

25.9 (11.1–50.1)

32.2 (18.1–54.8)

AG mmol/l

0.808

7.8 2.9–24.5

9.4 (5.5–9.8)

Glucose mmol/L

0.053

7.3 (2.9–24.5)

9.0 (5.7–12.7)

6.9 (2.9–24.5)

9.4 (5.5–9.8)

Glucose mmol/L

0.082

93 45–175

110 (58–119)

Creatinine mmol/L

0.002

87 (44–199)

88 (62–129)

79 (44–199)

110 (58–119)

mmol/L

Creatinine

EtOH, serum ethanol on admission; MetOH, serum methanol on admission; AG, anion gap; BD, base deficit. To convert from mg/L to mmol/L divide the concentration in mg/L on the following conversion factors: methanol – 32.05; ethanol – 46.08; formate – 46.03; lactate – 90.09; glucose – 180.18. To convert bicarbonate and base deficit from mmol/L to mEq/L use the conversion factor 1.0. To convert kPa to mmHg (torr) use the conversion factor 7.501.

50 (16–73)

Age

Fomepizole

Group

Time to treatment (h)

Table 2. Demographics and laboratory data on admission in 25 patients treated with Fomepizole vs. 25′ patients treated with Ethanol – the quasi-control group (medians with ranges).

G, gender; F, female; MetOH, serum methanol on admission; EtOH, serum ethanol on admission; BD, base deficit; AG, anion gap.

P (F/E)

(n  100)

Total

(n  7)

No antidote

(n  68)

Ethanol

(n  25)

Fomepizole

Group

MetOH mmol/L

Formate Dose ingested

Time to

treatment

Table 1. Demographics and laboratory data on admission in 100 patients with acute methanol poisoning (medians with ranges).


Fomepizole vs. Ethanol in acute methanol poisonings 5

SS 1/2/3, Poisoning severity score (1 – minor severity grade; 2 – moderate severity grade; and 3 – severe severity grade); VD, visual disturbances; GI, gastrointestinal disturbances; D, dyspnea; C, coma; “First aid P ethanol” – pre-hospital administration of ethanol by paramedics/medical staff; VP/IN, vasopressors and inotropes administration; CVVHD/HDF, continuous veno-venous hemodialysis/hemodiafiltration; IHD, intermittent hemodialysis; EDD, extended daily dialysis; ICU LOS, intensive care unit length of stay.

0.201 0.207 0.030 0.131 0.211 0.422 0.830 0.059 0.083 0.009 0.809 0.106 0.044 0.326 0.109 0.012

0.032

21 (21%) 30 (30%) 49 (49%) 4 (1–22) 35 (35%) 44 (44%) 75 (75%) 64 (64%) 39 (39%) 43 (43%) 30 (30%) 32 (32%) 35 (35%) 51 (51%) 23 (23%) 38/18/44

43 (43%)

3 (43%) 2 (29%) 2 (29%) 1 (1–21) 00 2 (29%) 2 (29%) 4 (57%) 4 (57%) 4 (57%) 2 (29%) 3 (43%) 2 (29%) 3 (43%) 4 (57%) 1 (14%) 2/1/4

11 (17%) 18 (26%) 39 (57%) 4 (1–33) 23 (34%) 29 (43%) 53 (78%) 40 (59%) 22 (32%) 23 (34%) 20 (29%) 18 (26%) 20 (29%) 33 (49%) 19 (28%) 31/14/23

24 (35%)

7 (28%) 10 (40%) 8 (32%) 6 (2–22) 12 (48%) 13 (52%) 20 (80%) 20 (80%) 13 (52%) 16 (64%) 8 (32%) 11 (44%) 13 (52%) 15 (60%) 15 (60%) 3 (12%) 5/3/17

Fomepizole (n  25) Ethanol (n  68) No antidote (n  7) Total (n  100) P (F/E)

Death Sequelae C

First aid ethanol

Intubation

VP/IN

Alkalization

Folate

CVVHD/ HDF

IHD/EDD

ICU LOS (days)

No sequelae

Outcomes Treatment

D GI VD No symptoms PSS 1/2/3

Outcomes in quasi-case–control group In this group of 50 patients, 11/50 (22%) patients died and 39/50 (78%) survived. The case fatality did not differ from that seen in the total study population (p  0.888). All patients who died were comatose on admission. Among the

Group

Outcome in the whole population Among all patients, 21 (21%) died and 79 (79%) survived. From these 79 survivors, 49 patients survived without sequelae, and 30 survived with visual and/or CNS sequelae. No significant correlation was found between the type of antidote applied and the case fatality in the studied population (r2  0.018, n  100; p  0.205). Table 5 shows the results of the multivariate regression analysis on the factors associated with survival. Positive serum ethanol and arterial blood pH on admission were the only independent variables for the survival of the patients. The probability of death depending on arterial blood pH on admission did not differ between the groups of patients treated with ethanol versus fomepizole in hospitals (Figure 2).

Clinical features

Clinical features and treatment Corresponding to the data presented in Table 1, the fomepizole patients (n  25) had more symptoms in general on admission compared with the ethanol group (n  68), but the difference was only significant for the visual disturbances (p  0.032) and dyspnea (p  0.044). There was also a significantly higher proportion of intubated patients in the fomepizole group (p  0.009). These differences were not present in the quasi-case–control study (see below). Initial bolus of ethanol was administered on admission before fomepizole application in 16/25 (64%) of fomepizole cases to prevent any delay with antidote administration when fomepizole was not available immediately. In 2/25 (8%) cases, administration of ethanol followed the treatment with fomepizole after the decrease in methanol concentration under 6.2 mmol/L (20 mg/dL) and correction of metabolic acidosis. In seven patients, who did not receive any antidote in hospitals, two patients received pre-hospital ethanol, alkalization was applied in all patients with arterial blood pH under 7.2, and hemodialysis and folate therapy was applied in two cases. There were no differences between the intensive care unit (ICU) length of stay, the number of survivors with or without sequelae, or the number of fatalities in the case–control study (Table 3). The clinical features on admission, treatment measures and outcomes in 50 patients selected for quasi-case–control study and divided on separate pairs “fomepizole versus ethanol” are shown in Table 4 and Appendix 2 to be found online at http://informahealthcare.com/doi/abs/10.3109/ 15563650.2015.1059946. There were no significant differences in the clinical parameters, the treatment (except the antidote given), the length of stay in the ICU, or the outcome.

Table 3. Clinical features on admission, treatment, length of ICU stay, and outcomes in 100 patients with acute methanol poisoning.


6 S. Zakharov et al.

Clinical Toxicology Early Online 2015

0.440 0.733 0.564

No-3 Yes-22 No-6 Yes-19 No-11 Yes-14

0.729 P Fom/Eth

0.980

0.255

1.00

No-16 Yes-8 ND-1 0.921 No-13 Yes-12 100 (63–130) 11 (3–15) 4/3/18 Ethanol


SS, Poisoning Severity Score; GCS, Glasgow Coma Scale; MAP, mean arterial pressure; VP/IN, vasopressors/inotropes administration; Alkalization – administration of 8.4% or 4.2% bicarbonate i.v. to correct metaP bolic acidosis; IHD, intermittent hemodialysis; EDD, extended daily hemodialysis; CVVHD, continuous veno-venous hemodialysis; CVVHDF, continuous veno-venous hemodiafiltration; ICU LOS, intensive care unit length of stay; VS, long-term visual sequelae; CS, long-term CNS sequelae.

0.951  0.001

–

5.0 (2.0–33.0)

NONE-9 VS/CS-10 DIED-6 NONE-10 VS/CS-10 DIED-5 0.705 6.0 (2.0–22.0) 2.0 (1.0–9.0)

IHD-9 CVVHD/ F-14 EDD-5 IHD-7 CVVHD/ F-17 0.471 No-5 Yes-20 No-9 Yes-16 No-17 Yes-8 No-13 Yes-12 85 (43–127) 5/3/17 Fomepizole

12 (3–15)

VP/IN MAP Group

GCS

No-5 Yes-20

Outcome of poisoning ICU LOS (days) Folate Alkalization Intubation

Hemodialysis

Total Fomepizole dose (g) Pre-hospital ethanol PSS 1/2/3

Table 4. Clinical features on admission, treatment, length of ICU stay, and outcomes in 25 patients treated with Fomepizole vs. 25´ patients treated with Ethanol – the quasi-control groups (medians with ranges).


Fomepizole vs. Ethanol in acute methanol poisonings 7 Table 5. Univariate and multivariate logistic regression of parameters on admission significant for the survival in the patients with acute methanol poisoning. Unadjusted Variable pH S-EtOH S-MetOH Antidote

Adjusted

OR

95% CI

OR

95% CI

9.5 13.1 2.6 2.9

4.2–21.3 4.9–35.3 1.5–4.4 1.1–7.5

3.7 10.8 1.7 2.5

1.3–10.5 2.9–39.9 0.6–4.2 0.5–12.5

OR, odds ratio; 95% CI, 95% confidence interval; pH, arterial blood pH on admission; S-EtOH, serum ethanol concentration; S-MetOH, serum methanol concentration; Antidote, type of antidote (fomepizole or ethanol) administered in hospitals.

39 survivors, 19 survived without sequelae and 20 survived with visual and/or CNS sequelae. The differences in the numbers of patients treated with fomepizole versus the numbers of patients treated with ethanol who died, survived with and without sequelae were not significant (Table 4). The patients treated with fomepizole who survived with visual/CNS injury had a median pH of 6.92 (range, 6.65–7.25; n  10), and the patients who died had a median pH of 6.75 (range, 6.65–6.93; n  6); the patients treated with ethanol who survived with visual/CNS injury had a median pH of 6.93 (range, 6.77–7.32; n  10), and the patients who died had a median pH of 6.75 (range, 6.63–6.90; n  5); the difference between both groups was not significant (all p  0.05). Adverse reactions and complications during the treatment with antidotes In the group of patients treated with fomepizole, no cases of seizures, hypoglycemia, and pancreatitis were observed. During the extended daily dialysis, one case of ventricular tachycardia/ventricular fibrillation or VT/VF requiring two sets of defibrillation with a subsequent elevation of cardiomarkers was seen. One case of delirium tremens occurred in a patient with the history of chronic alcohol abuse. One case of rebound of metabolic acidosis occurred after the discontinuation of CVVH due to bleeding. Complications during treatment were observed in 7/25 (28%) of fomepizole cases including aspiration pneumonia (4 cases), sepsis (2 cases), and bleeding due to systemic anticoagulation with heparin during the hemodialysis (2 cases). In the ethanol group, no cases of hypoglycemia, or severe CNS or respiratory depression due to ethanol were observed. No patients needed intubation due to ethanol administration; all the patients with intubation were either admitted to hospitals in coma or they were sedated due to other severe condition on admission (agitation, severe dyspnea, and confusion). Complications during the treatment were observed in 15/68 (22%, p  0.55) cases including aspiration pneumonia (8 cases), delirium tremens after the discontinuation of ethanol administration in chronic alcohol abusers (6 cases), bleeding due to thrombocytopenia or heparinization during hemodialysis sessions (3 cases), agitation after start of ethanol infusion requiring sedation (2 cases), acute pancreatitis


8 S. Zakharov et al.

Fig. 2. Risk of death versus arterial blood pH and the antidote administered in hospitals. Total: n  93: died (n  17)  survived (n  76).

(2 cases), sepsis (2 cases), and rebound of acidosis after discontinuation of continuous veno-venous hemodialysis (CVVHD) due to the set clotting (1 case). In one case oral administration of ethanol was discontinued due to intolerance, requiring intravenous administration to be restarted.

Discussion In this study, we did not find any difference in outcome, length of ICU stay, or dialysis between patients treated with fomepizole or ethanol. This was true for analysis of both the case series and the quasi-case–control study in which confounding by antidote allocation was reduced as much as possible by very close pairwise matching on known risk factors. At present, there are no data supporting the superiority of fomepizole over ethanol as treatment for methanol poisoning.31 RCTs to formally compare the antidotes are very unlikely to be performed for a variety of reasons, including infrequent poisonings and lack of availability of fomepizole where the large outbreaks occur. Also, most of the outbreaks are limited in size and time, making the planning of a RCT a challenging task. Further, due to the lack of follow-up clinical examinations in general, and in particular with more advanced diagnostic methods (such as MRI, ocular coherence tomography, visual evoked potentials, and electromyography), an underestimation of long-term health sequelae is likely.33 Fomepizole is the preferred antidote over ethanol because its pharmacokinetics are more predictable than ethanol, it has a safer side effect profile, it can be used in children, it shortens ICU and hospital stays, and it can decrease the need for hemodialysis.28,29,34 There are, however, also some reports on bradycardia and hypotension, headache, nausea, dizziness, and nystagmus.35,36

In our study, we did not find any difference in the effectiveness between the two antidotes with respect to the hospital mortality or ICU stay. The probability of death depended on arterial blood pH on admission and pre-hospital ethanol administration, not the antidote received (Figure 2). The hospital case fatality in the mass methanol outbreak in Norway in 2002–2004, where fomepizole was used predominantly as an antidote, did not differ from the hospital mortality rate in our study (7/36, 19% vs. 6/25, 24%; p  0.669).2 No other data from mass methanol outbreaks where fomepizole was used are available at present. Both the patients who died and the patients who survived with sequelae were significantly more acidotic on admission than those who survived without sequelae; no shift toward better outcome in fomepizole group was observed, as has been reported from other studies.2,16 Based on the results of our study, outcome does not depend on the type of antidote used in hospitals during mass poisoning outbreaks as long as the patients are treated in hospitals where there are sufficient ICU resources and other facilities (such as hemodialysis) to care for them. Unlike ethanol, fomepizole does not have any inebriating effects or CNS-depressive effects. Unlike Paasma et al,1,16 we did not see any patients losing their consciousness after treatment with ethanol. One reason for this could be a better availability of serum ethanol level monitoring during administration in the present study. Also, many severely poisoned patients were sedated during transportation to hospital or shortly after admission due to complications from the poisoning (severe dyspnea, agitation, lack of cooperation, etc.), potentially influencing our findings. Finally, we did not find any significant differences in the ICU length of stay, or the use of enhanced elimination methods between the two antidote groups. However, there was no need for monitoring of the serum ethanol level in the Clinical Toxicology Early Online 2015

Fomepizole vs. Ethanol in acute methanol poisonings 9 fomepizole group, and the patients were less drunk and thus easier to handle for the ICU doctors and nurses.3,25


Strengths and limitations The study had some principal limitations, the most important one being the lack of randomization, leaving a head-tohead comparison as the best alternative. The numbers of the patients in both groups were relatively small, and most of the patients in both groups were severely poisoned “late-presenters” (patients admitted to hospitals later than 12 h after stop of toxic spirits ingestion): The fomepizole group was more severely poisoned; therefore a very closely matched quasi-control group of ethanol-treated patients were picked to match them. This does however represent the most important group to study, since late presentation is associated with poor outcome. The scope of this study was to compare the clinical effectiveness of hospital treatment with two antidotes. Several patients in both groups received pre-hospital ethanol. Nevertheless, the effect of pre-hospital ethanol, as well as the effect of other pre-hospital variables is clearly defined by the condition of the patients on admission to hospital, and we compared the outcomes in the patients admitted in the same clinical condition. Several patients in the fomepizole group received an initial bolus of ethanol in hospitals before fomepizole administration, and the treatment with fomepizole during the critical phase of poisoning (see “Methods” section) was followed by ethanol administration after the decrease of serum methanol under 30 mg/dL (9.4 mmol/L) and normalization of arterial blood pH. Finally, the follow-up examination was performed in approximately 2/3 of all survivors, so the data on longterm sequelae in both groups could be an underestimate. Despite the limitations and confounders, this is the first study performed during a mass poisoning outbreak comparing the short- and long-term outcomes of treatment with two different antidotes, fomepizole and ethanol, representing the most comprehensive data ever generated. During the Estonian mass poisoning outbreak in 2001, fomepizole was not applied.1,16,33 The total number of cases during Norwegian mass outbreak analyzed in the study of Hovda et al was only half the number of patients, and no follow-up examination of survivors was carried out.2,17 The essential clinical and laboratory data were collected during the Czech mass outbreak using standardized forms; the follow-up examination was carried out in one medical facility using a uniform investigation protocol. The patients in the quasi-case–control pairs were very closely matched with more than 20 independent variables and the groups had similar demographic, toxicological, biochemical, clinical, and therapeutic parameters.

Acknowledgements Supported by the Projects of the Charles University in Prague PRVOUK – P25/1LF/2, P26/1LF/2, and P28/1LF/6, the Project of the Ministry of Health of the Czech Republic 9/15/NAP, and EU Project “Material - technical Research Copyright © Informa Healthcare USA, Inc. 2015

Base for the Diagnostics and Treatment of Environmentally-caused and Oncological Disorders and their Risks, in the General University Hospital in Prague” (reg. No. CZ.2.16/3.1.00/24.12).

Declaration of interests The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

References 1. Paasma R, Hovda KE, Tikkerberi A, Jacobsen D. Methanol mass poisoning in Estonia: outbreak in 154 patients. Clin Toxicol 2007; 45:152–157. 2. Hovda KE, Hunderi OH, Tafjord AB, Dunlop O, Rudberg N, Jacobsen D. Methanol outbreak in Norway 2002–2004: epidemiology, clinical features and prognostic signs. J Intern Med 2005; 258:181–190. 3. Zakharov S, Pelclova D, Urban P, Navratil T, Diblik P, Kuthan P, et al. Czech mass methanol outbreak 2012: epidemiology, challenges and clinical features. Clin Toxicol 2014; 52:1013–1024. 4. Hassanian-Moghaddam H, Nikfarjam A, Mirafzal A, Saberinia A, Nasehi AA, Masoumi Asl H, Memaryan N. Methanol mass poisoning in Iran: role of case finding in outbreak management. J Public Health (Oxf) 2014; 37:354–359. doi: 10.1093/pubmed/fdu038. Epub 2014/06/20. 5. Levy P, Hexdall A, Gordon P, Boeriu C, Heller M, Nelson L. Methanol contamination of Romanian home-distilled alcohol. J Toxicol Clin Toxicol 2003; 41:23–28. 6. Ahmad K. Methanol-laced moonshine kills 140 in Kenya. The Lancet 2000; 356:1911. 7. Barceloux DG, Bond GR, Krenzelok EP, Cooper H, Vale JA. American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning. J Toxicol-Clin Toxicol 2002; 40:415–446. 8. Megarbane B, Borron SW, Baud FJ. Current recommendations for treatment of severe toxic alcohol poisonings. Intensive Care Med 2005; 31:189–195. 9. Liesivuori J, Savolainen H. Methanol and formic-acid toxicity biochemical mechanisms. Pharmacol Toxicol 1991; 69:157–163. 10. Sejersted OM, Jacobsen D, Ovrebo S, Jansen H. Formate concentrations in plasma from patients poisoned with methanol. Acta Med Scand 1983; 213:105–110. 11. Zakharov S, Nurieva O, Navratil T, Diblik P, Kuthan P, Pelclova D. Acute methanol poisonings: folates administration and visual sequelae. J Appl Biomed 2014; 12:309–316. 12. Bezdicek O, Klempir J, Liskova I, Michalec J, Vaneckova M, Seidl Z,. Sequelae of methanol poisoning for cognition. Cesk Slov Neurol N 2014; 77/110:320–325. 13. Zakharov S, Kurcova I, Navratil T, Salek T, Pelclova D. Is the measurement of serum formate concentration useful in the diagnostics of acute methanol poisoning? A prospective study of 38 patients. Basic Clin Pharmacol Toxicol 2015; 116:445–451. doi: 10.1111/bcpt.12338. 14. Coulter CV, Farquhar CE, McCherry CM, Isbister GK, Dufful SB. Methanol and ethylene glycol acute poisonings – predictors of mortality. Clin Toxicol 2011; 49:900–906. 15. Liu JJ, Daya MR, Carrasquillo O, Kales SN. Prognostic factors in patients with methanol poisoning. J Toxicol Clin Toxicol 1998; 36:175–181. 16. Paasma R, Hovda KE, Hassanian-Moghaddam H, Brahmi N, Afshari R, Sandvik L, Jacobsen D. Risk factors related to poor outcome after methanol poisoning and the relation between outcome and antidotes -- a multicenter study. Clin Toxicol 2012; 50:823–831. 17. Hovda KE, Urdal P, Jacobsen D. Increased serum formate in the diagnosis of methanol poisoning. J Anal Toxicol 2005; 29:586–588. 18. Sanaei-Zadeh H, Esfeh SK, Zamani N, Jamshidi F, Shadnia S. Hyperglycemia is a strong prognostic factor of lethality in methanol poisoning. J Med Toxicol 2011; 7:189–194.


10 S. Zakharov et al. 19. Bergeron R, Cardinal J, Geadah D. Prevention of methanol toxicity by ethanol therapy. N Engl J Med 1982; 307:1528. 20. Hantson P, Wittebole X, Haufroid V. Ethanol therapy for methanol poisoning: duration and problems. Eur J Emerg Med 2002; 9:278–279. 21. Jacobsen D, Jansen H, Wiik-Larsen E, Bredesen JE, Halvorsen S. Studies on methanol poisoning. Acta Med Scand 1982; 212:5–10. 22. Burns MJ, Graudins A, Aaron CK, McMartin K, Brent J. Treatment of methanol poisoning with intravenous 4-methylpyrazole. Ann Emerg Med 1997; 30:829–832. 23. Bekka R, Borron SW, Astier A, Sandouk P, Bismuth C, Baud FJ. Treatment of methanol and isopropanol poisoning with intravenous fomepizole. J Toxicol, Clin Toxicol 2001; 39:59–67. 24. Brent J, McMartin K, Phillips S, Aaron C, Kulig K. Fomepizole for the treatment of methanol poisoning. N Engl J Med 2001; 344:424–429. 25. Zakharov S, Navratil T, Pelclova D. Fomepizole in the treatment of acute methanol poisonings: experience from the Czech mass methanol outbreak 2012–2013. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2014; 158:641–649. 26. WHO. 18th Model List of Essential Medicines 2013; 2014. Available from: http://www.who.int/medicines/publications/essential medicines/18th_EML_Final_web_8Jul13.pdf?ua  1. (Last accessed on February 20, 2014) 27. Brent J. Fomepizole for ethylene glycol and methanol poisoning. N Engl J Med 2009; 360:2216–2223. 28. Brent J. Fomepizole for the treatment of pediatric ethylene and diethylene glycol, butoxyethanol, and methanol poisonings. Clin Toxicol 2010; 48:401–406.

29. Hovda KE, Jacobsen D. Expert opinion: fomepizole may ameliorate the need for hemodialysis in methanol poisoning. Hum Exp Toxicol 2008; 27:539–546. 30. Megarbane B, Borron SW, Trout H, Hantson P, Jaeger A, Krencker E, et al. Treatment of acute methanol poisoning with fomepizole. Intensive Care Med 2001; 27:1370–1378. 31. Beatty L, Green R, Magee K, Zed P. A systematic review of ethanol and fomepizole use in toxic alcohol ingestions. Emergen Med Int 2013; 2013:14. 32. Persson H, Sjöberg G, Haines J, Pronczuk de Garbino J. Poisoning severity score: grading of acute poisoning. J Toxicol - Clin Toxicol 1998; 36:205–213. 33. Paasma R, Hovda KE, Jacobsen D. Methanol poisoning and long term sequelae - a six years follow-up after a large methanol outbreak. BMC Clin Pharmacol 2009; 9:5. 34. Lepik KJ, Levy AR, Sobolev BG, Purssell RA, DeWitt CR, Erhardt GD, et al. Adverse drug events associated with the antidotes for methanol and ethylene glycol poisoning: a comparison of ethanol and fomepizole. Ann Emerg Med 2009; 53:439–450. 35. Lepik KJ, Brubacher JR, Dewitt CR, Lam GS, Lawson EJ, Erhardt GD, et al. Bradycardia and hypotension associated with fomepizole infusion during hemodialysis. Clin Toxicol 2008; 46: 570–573. 36. Benitez JG, Swanson-Bierman B, Krenzelok EP. Nystagmus secondary to fomepizole administration in a pediatric patient. Clin Toxicol 2000; 38:795–798.

Supplementary material available online Supplementary Appendix 1–2


Age

37 37 30 38 38 41 46 48 66 62 46 48 60 65 40 42 54 53 58 52 73 67 60 58 43 46 67 66 50 42 48 57 61 66 36 37 62 58 16 28 56 67 32 35 63 60 50 49

No.

1. 1′. 2. 2′. 3. 3′. 4. 4′. 5. 5′. 6. 6′. 7. 7′. 8. 8′. 9. 9′. 10. 10′. 11. 11′. 12. 12′. 13. 13′. 14. 14′. 15. 15′. 16. 16′. 17. 17′. 18. 18′. 19. 19′. 20. 20′. 21. 21′. 22. 22′. 23. 23′. 24. 24′.

M M M M M M M M F F M M M M M M M M F F M M M M F F M M M M F F M M M M M M F F F F F F M M M M

G

48–72 48 48–72 48–72 48–72 56 24 48 11 14 18 12 60 48 30 32 36 ND 48 48 24 48 48 ND ND 24 52 41 26 31 ND 24 48 48 24 48 48–72 ND 48 24 ND 48 30 48 48 ND 48 24

(h)

treatment

Time to

ND 500 1000 ND 100 ND 350 200 100 300 600 360 ND 280 700 500 500 500 100 400 400 ND ND ND ND 300 250 500 750 500 ND ND 250 200 1200 1500 ND ND 750 500 ND ND 500 ND ND ND ND 300

mL

Dose ingested

Yes Yes No No No ND Yes Yes No No No No No No No Yes No No No Yes ND Yes ND ND No No No No Yes No ND ND Yes Yes No Yes ND ND No No ND No No No ND ND No No

EtOH

Coing.

12.5 14.9 86.7 148.9 43.1 218.5 93.6 82.4 22.5 54.9 108.6 62.1 22.5 24.0 49.3 14.0 47.8 34.3 105.4 109.2 30.9 53.1 75.5 60.9 56.2 54.6 13.1 6.2 27.2 12.5 56.5 32.6 21.8 30.6 51.8 228.1 41.5 112.4 11.5 44.0 67.4 36.5 10.1 32.8 123.3 55.2 20.3 37.0

mmol/L

MetOH

0.0 0.0 0.0 0.0 0.0 0.0 10.9 28.4 1.7 11.1 5.0* 0.0 0.0 2.2 0.0 0.0 25.6 96.8 5.2* 3.0 17.4* 17.4 0.0 0.0 0.0 0.0 3.0 ND 11.7* 0.0 0.0 0.0 0.0 0.0 0.0 2.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 21.5

mmol/L

EtOH

14.4 10.6 19.9 25.2 ND ND ND ND 16.6 17.0 ND 19.6 12.5 21.2 ND 0.9 ND ND 17.8 ND 13.5 ND 12.2 14.3 16.4 ND 4.9 ND 8.9 7.0 9.6 ND 1.0 ND 3.8 22.5 15.6 ND 13.4 ND ND ND 14.7 14.8 ND ND ND ND

mmol/L

Formate

1.1 1.8 11.4 8.1 8.2 5.9 1.5 1.1 ND 0.9 7.8 7.6 3.5 7.3 3.0 1.9 ND 1.7 2.1 1.1 1.7 6.2 9.3 12.8 8.0 9.5 3.7 0.5 2.6 1.5 9.5 15.6 ND 2.5 4.0 1.2 12.4 7.6 7.1 2.9 5.6 12.1 6.4 8.3 ND 6.5 ND ND

Lactate mmol/l 7.25 7.25 6.71 6.79 6.69 6.77 7.37 7.44 7.06 7.08 6.86 6.82 7.02 7.00 7.05 7.09 7.39 7.32 7.11 7.09 7.16 7.16 6.65 6.67 6.93 6.69 7.18 7.17 7.34** 7.29 6.65 6.63 7.37 7.24 6.98 7.02 6.65 6.79 6.70 6.80 6.79 6.75 6.99 6.80 6.85 6.87 7.25 7.28

pH ND 3.6 ND ND 3.2 4.4 4.9 4.1 1.5 2.7 2.6 2.8 1.3 5.2 1.0 2.0 3.9 5.1 3.4 1.8 4.0 5.9 7.8 3.8 4.9 9.5 3.0 1.9 4.7 5.0 3.2 4.6 4.2 2.4 1.5 2.0 4.3 2.8 4.1 1.9 5.3 4.0 3.0 4.0 3.5 3.7 2.7 3.5

pCO2. kPa

Supplementary Appendix 1. Demographics and laboratory data on admission in 25 patients treated with Fomepizole vs. 25´ patients treated with Ethanol – the quasi-control group.

13.8 11.9 4.3 4.4 2.7 4.8 20.9 23.7 3.2 5.7 3.5 3.2 2.5 10.2 2 4.6 17.2 19.8 7.8 4.0 11.4 11.6 6.3 3.8 7.6 8.6 10.8 5.1 18.7** 17.8 3.6 3.4 18 7.6 3.4 6.8 3.2 4.4 3.9 2.1 6 4.1 5.2 8.6 4.6 5.1 8.8 12.0

mmol/l

HCO3

 13.9  14.0  38.1  34.5  29.1  30.0  3.5  0.6  24.7  23.8  30.0  27.5  26.4  19.1  26.2  25.2  6.3  5.3  21.0  25.6  17.0  12.8  31.9  27.5  26.9  30.0  18.1  20.7  6.1  7.5  35.7  36.0  6.0  17.2  27.2  25.4  28.9  31.2  33.6  33.9  31.0  31.0  25.8  19.3  28.5  27.0  16.7  12.8

BD mmol/l 24 22 55 47 33 40 24 11 36 18 28 36 32 17 36 32 20 25 24 32 29 41 33 33 ND 34 ND 31 20 18 43 38 18 32 40 35 45 50 25 46 50 49 25 27 45 37 28 26

AG mmol/l 6.1 7.3 18.4 8.0 19.8 9.6 6 6.3 5.9 5.6 12.7 13.0 11.9 19.7 9.3 6.8 6.6 8.3 7.0 5.5 7.7 7.8 11.2 16.9 15.8 16.1 5.7 8.8 5.5 6.4 15.0 2.9 6.1 11.5 6.5 6.1 15 5.6 12.5 5.1 11.1 18.9 9.4 24.5 13.4 6.9 6.4 6.0

mmol/L

Glucose


(Continued)

109 96 175 143 154 120 84 74 58 79 87 167 127 154 115 102 101 45 71 53 81 70 188 81 105 111 120 110 84 73 102 78 85 95 112 74 178 175 191 93 121 96 110 77 118 79 109 82

Creatinine mmol/L

Supplementary material for Zakharov S, et al. Fomepizole versus ethanol in the treatment of acute methanol poisoning: Comparison of clinical effectiveness in a mass poisoning outbreak, Clinical Toxicology, 2015; doi: 10.3109/15563650.2015.1059946.

1

49 28–67

0.785

(range) Md Ethanol

(range) P Fom/Eth

M M 

G

0.877

48 0–56

48 ND 48 (11–72)

(h)

0.700

400 200–1500

ND ND 500 100–1200

mL

Dose ingested

ND ND 

EtOH

Coing.

MetOH

0.301

44.0 6.2–228.1

28.9 29.0 43.1 10.1–123.2

mmol/L

EtOH

0.336

0.0 0.0–96.8

0.0 0.0 0.0 0.0–25.6

mmol/L

0.475

14.8 0.0–25.2

15.4 ND 13.5 1.0–19.9

mmol/L

Formate

0.702

6.1 0.5–15.6

16.3 13.2 6.0 1.1–16.3

Lactate mmol/l

0.719

7.02 6.63–7.44

6.72 6.90 6.99 6.65–7.39

pH

0.571

3.8 1.8–9.5

3.2 4.6 3.4 1.0–7.9

pCO2. kPa

0.596

5.7 2.1–23.7

2.9 8.8 5.2 2.0–20.9

mmol/l

HCO3

0.703

 25.2 -0.6– 25.2

 34.6  22.4  26.4  3.5– 38.1

BD mmol/l

0.947

33.0 11.0–50.0

49 46 32.2 18.1–54.8

AG mmol/l

0.808

7.8 2.9–24.5

19.5 21.5 9.4 (5.5–9.8)

mmol/L

Glucose

0.082

93 45–175

199 171 110 (58–119)

Creatinine mmol/L

G, gender; M, male; F, female; Fom, fomepizole; EtOH, serum ethanol on admission; MetOH, serum methanol on admission; AG, anion gap; BD, base deficit; Md, median; R, range; ND, not determined; Coing. EtOH, coingestion of ethanol in other alcoholic beverages; *, ethanol was administered before the first measurement; **, bicarbonate was administered before the measurement. To convert from mg/L to mmol/L divide the concentration in mg/L on the following conversion factors: methanol – 32.05; ethanol – 46.08; formate – 46.03; lactate – 90.09; glucose – 180.18. To convert bicarbonate and base deficit from mmol/L to mEq/L use the conversion factor 1.0. To convert kPa to mmHg (torr) use the conversion factor 7.501. The lines numbered with apostrophe (1´ - 25´) indicate the patients treated with ethanol; the lines numbered without apostrophe (1–25) indicate the patients treated with fomepizole.

33 29 50 (16–73)

Age

25. 25′. Md Fom

No.

treatment

Time to

Supplementary Appendix 1. (Continued)

2


2′ 3. 3′ 4. 4′ 5. 5′ 6. 6′ 7. 7′ 8. 8′ 9. 9′ 10. 10′ 11. 11′ 12. 12′ 13. 13′ 14. 14′ 15. 15′ 16. 16′ 17. 17′ 18. 18′ 19. 19′

1. 1′ 2.

No.

1 1 3

3 3 3 1 1 3 3 3 3 3 3 3 3 1 1 3 3 2 2 3 3 3 3 2 3 1 1 3 3 1 2 3 3 3 3

VD.D.GI.C. GI.D.F.C GI.D.C.RA. Inebriation Inebriation GI.VD.D HA.F GI.VD.C D.CP.C. CP.D.GI.VD VD.CP.D. D.GI.VD D.GI.VD. Inebriation Inebriation VD.GI VD.GI VD.D Inebriation CP.D.RA.C.S GI.D.C. CP.D.GI.VD.C GI.VD.C. D.GI.VD. VD GI.D HA.F D.GI.VD.C GI.D.VD.CP.C. GI VD.HA. CP.GI.VD GI.VD.D.F. C.CP.D.VD C

PSS

GI.VD GI.HA VD.D.C

Clinical features

3 3 3 15 15 15 14 5 3 15 11 15 15 15 15 15 15 15 15 3 3 3 3 13 15 12 15 3 6 15 15 12 12 3 5

15 15 3

GCS

96 83 107 93 100 88 120 78 70 47 93 98 130 113 67 117 103 113 78 70 127 84 100 43 105 92 103 104 100 85 118 127 118 57 103

85 92 79

MAP

No Yes Yes Yes No No No No Yes No Yes No No No Yes No No No No Yes Yes Yes Yes Yes No Yes No No No No No No Yes Yes Yes

No No No

VP/IN

No No No Yes Yes Yes Yes Yes No No Yes No No Yes Yes Yes Yes Yes Yes No No No No Yes ND Yes No No No No No No Yes No No

No No No

Prehospital ethanol

Yes Yes Yes No No No No Yes Yes Yes Yes No No No No No No No No Yes Yes Yes Yes Yes No Yes No Yes Yes No No Yes Yes Yes Yes

No No Yes

Intubation

Yes Yes Yes No No Yes Yes Yes Yes Yes Yes Yes No No No Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes No Yes Yes No Yes Yes Yes Yes Yes

No No Yes

Alkalization

No Yes Yes Yes Yes Yes No No Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes No Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes

No Yes Yes

Folate EDD  EDD  CVVHD CVVHD IHD  CVVHD CVVHD CVVHD CVVHD CVVHDF IHD CVVHDF CVVHDF CVVHD CVVHD IHD CVVHD IHD CVVHDF IHD IHD IHD IHD IHD  CVVHD CVVHDF EDD CVVHD CVVHD IHD IHD IHD CVVHD CVVHDF IHD CVVHDF EDD CVVHD CVVHD IHD

Hemodialysis

– 2* – 5* – 3* – 4.5* – 6 – 1 – 2 – 3** – 2,5* – 2,8* – 6 – 2* – 2* – 1* – 1 – 4,5* – 9* –

2  5**

Total Fomepizole dose (g)

3 10 33 6 4 4 6 22 23 15 11 2 3 3 2 3 2 3 2 2 8 15 3 14 5 12 8 17 16 2 2 7 7 6 9

2 5 7

ICU LOS (days)


(Continued)

DIED VS, CS VS, CS NONE NONE NONE CS VS, CS VS, CS NONE VS, CS VS*** NONE NONE CS NONE VS, CS VS NONE DIED NONE DIED DIED NONE NONE NONE NONE CS, VS DIED NONE NONE CS VS, CS DIED VS, CS

VS, CS NONE VS, CS

Outcome of poisoning

Supplementary Appendix 2. Clinical features on admission, treatment, length of ICU-stay and outcomes in 25 patients treated with Fomepizole vs. 25´ patients treated with Ethanol – the quasi-control groups.

3

C GI.D.C. C C GI.VD.D GI.D.C. C.RA GI.VD Inebriation GI.HA GI.VD.C GI.HA.CA.C. Total F (n  25)

20. 20′ 21. 21′ 22. 22′ 23. 23′ 24. 24′ 25. 25′

0.729

3 3 3 3 3 3 3 3 2 2 3 3 1–5 2–3 3–17 1–4 2–3 3–18

PSS

12 3–15 11 3–15 0.980

3 6 3 3 8 4 3 10 15 15 5 3

GCS

85 43–127 100 63–130 0.255

80 91 98 78 85 63 97 93 127 120 73 70

MAP

0.921

No-16 Yes-8 ND-1

No-13 Yes-12

1.00

No No No No No No No No No Yes No No No-17 Yes-8

Yes No Yes Yes Yes Yes Yes Yes No No Yes Yes No-13 Yes-12

VP/IN

Prehospital ethanol

0.564

No-11 Yes-14

Yes Yes Yes Yes Yes Yes Yes Yes No No Yes Yes No-9 Yes-16

Intubation

0.733

No-6 Yes-19

Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes No-5 Yes-20

Alkalization

0.440

No-3 Yes-22

Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes No-5 Yes-20

Folate

0.471

CVVH CVVHDF CVVH CVVHD EDD CVVHDF CVVHD CVVHD IHD IHD CVVHDF CVVHD IHD-9 CVVHD/F-14 EDD-5 IHD-7 CVVHD/F-17

Hemodialysis

2.0 1.0–9.0 0  0.001

3,5 – 2* – 1* – 2* – 1* – 2* –

Total Fomepizole dose (g)

6.0 2.0–22.0 5.0 2.0–33.0 0.951

8 11 17 2 3 5 5 15 4 5 15 11

ICU LOS (days)

0.705

DIED VS, CS DIED DIED CS NONE DIED VS, CS NONE NONE VS, CS DIED NONE-9 VS/CS-10 DIED-6 NONE-10 VS/CS-10 DIED-5

Outcome of poisoning

VD, visual disturbances; GI, gastrointestinal symptoms; D, dyspnea; CP, chest pain; C, coma; RA, respiratory arrest; PSS, Poisoning Severity Score; GCS, Glasgow coma scale; MAP, mean arterial pressure; VP/IN, vasopressors/inotropes administration; Alkalization, administration of 8.4% or 4.2% bicarbonate i.v. to correct metabolic acidosis; AF, acidum folicum; Leuc, Leucovorine (acidum folinicum i.v.); HD, hemodialysis; IHD, intermittent hemodialysis; EDD, extended daily hemodialysis; CVVHD, continuous veno-venous hemodialysis; CVVHDF, continuous veno-venous hemodiafiltration; CVVH, continuous veno-venous hemofiltration; SIRS, systemic inflammatory response syndrome; MODS, multiple organ dysfunction syndrome; ICU LOS, intensive care unit length of stay; Fom, fomepizole; Control examination, examination 3–6 months after discharge from hospitals; VS, long-term visual sequelae; CS, long-term CNS sequelae; *, initial dose of ethanol was administered before fomepizole application; **, ethanol administration followed the treatment with fomepizole after methanol concentration decreased below 30 mg/dL (9.4 mmol/L); ***, symptoms of regressing pseudopapillitis on discharge. The lines numbered with apostrophe (1´ - 25´) indicate the patients treated with ethanol; the lines numbered without apostrophe (1–25) indicate the patients treated with fomepizole.

Md F (range) Md E (range) P Fom/Eth

Total E (n  25)

Clinical features

No.

Supplementary Appendix 2. (Continued)

4
