Pavel Kuthan

Czech mass methanol outbreak 2012: Epidemiology, challenges and clinical features

Abstract Objectives. Methanol poisonings occur frequently globally, but reports of larger outbreaks where complete clinical and laboratory data are reported remain scarce. The objective of the present study was to report the data from the mass methanol poisoning in the Czech Republic in 2012 addressing the general epidemiology, treatment, and outcomes, and to present a protocol for the use of fomepizole ensuring that the antidote was provided to the most severely poisoned patients in the critical phase. Methods. A combined prospective and retrospective case series study of 121 patients with confirmed methanol poisoning. Results. From a total of 121 intoxicated subjects, 20 died outside the hospital and 101 were hospitalized. Among them, 60 survived without, and 20 with visual/CNS sequelae, whereas 21 patients died. The total and hospital mortality rates were 34% and 21%, respectively. Multivariate regression analysis found pH < 7.0 (OR 0.04 (0.01–0.16), p < 0.001), negative serum ethanol (OR 0.08 (0.02–0.37), p < 0.001), and coma on admission (OR 29.4 (10.2–84.6), p < 0.001) to be the only independent parameters predicting death. Continuous hemodialysis was used more often than intermittent hemodialysis, but there was no significant difference in mortality rate between the two [29% (n = 45) vs 17% (n = 30), p = 0.23]. Due to limited stockpiles of fomepizole, ethanol was administered more often; no difference in mortality rate was found between the two [16% (n = 70) vs. 24% (n = 21), p = 0.39]. The effect of folate administration both on the mortality rate and on the probability of visual sequelae was not significant (both p > 0.05). Conclusions. Severity of metabolic acidosis, state of consciousness, and serum ethanol on admission were the only significant parameters associated with mortality. The type of dialysis or antidote did not appear to affect mortality. Recommendations that were issued for hospital triage of fomepizole administration allowed conservation of valuable antidote in this massive poisoning outbreak for those patients most in need.

Long-term visual damage after acute methanol poisonings: Longitudinal cross-sectional study in 50 patients

Context. Visual disturbances due to the toxic effect of formic acid in acute methanol poisonings are generally transient. The subjective symptoms of visual toxicity may resolve within few weeks and fundoscopic signs of acute optic neuropathy subside within 1–2 months; therefore, the prevalence of long-term visual sequelae in the population of survivors of poisonings may be underestimated. Objective. To study the prevalence and character of long-term visual sequelae of acute methanol poisonings based on the data from the Czech mass methanol outbreak in 2012. Patients and methods. A total of 50 patients with confirmed methanol poisoning were included in this longitudinal cross-sectional study, median age: 48 (range, 23–73) years. The following tests were performed: optical coherence tomography or OCT with evaluation of the retinal nerve fibers layer (RNFL), visual evoked potentials (VEP), magnetic resonance imaging (MRI) of brain, complete ocular examination (visual acuity/field, color vision, contrast sensitivity, and fundus), neurological examinations, and biochemical tests. Results. Of 50 patients, 7/50 (14%) were discharged with diagnosed visual sequelae and 6/50 (12%) were discharged with both visual and central nervous system sequelae of poisoning. On the follow-up examination, 20/50 (40%) of the patients had long-term visual sequelae, with 8% of blindness. A total of 38% of the patients had abnormal (28% borderline) findings on RNFL, and 40% had abnormal (18% borderline) VEP. Among the patients discharged without detected visual sequelae, 8/37 (22%) had abnormal RNFL and VEP. Patients with visual sequelae had brain lesions more often (70% vs. 27%, p < 0.01). MRI identified optic nerve lesions in 2/20 cases with abnormal VEP only. The groups with and without visual sequelae differed in serum methanol, ethanol, HCO3-, formate, pH, anion gap, and base deficit (all p < 0.01). Visual disturbances on admission and coma were more prevalent in the patients with visual sequelae (p < 0.05). Patients with positive serum ethanol on admission were 93% less likely to have optical axonal damage (OR: 0.07 (95% CI: 0.01–0.8); p < 0.05). No association was found between visual sequelae and type of antidote administered, mode of hemodialysis, or folate substitution. Pre-hospital administration of ethanol seemed beneficial: these patients were 90% less likely to have abnormal RNFL findings (OR: 0.10 (95% CI: 0.02–0.52); p < 0.01). Conclusions. The long-term visual sequelae were clearly underestimated on discharge, suggesting a significantly higher amount of patients with long-term sequelae than earlier reported. Thorough examinations before discharge and during follow-up will likely uncover a higher morbidity also after methanol poisonings in general.

Rare Alleles within the CYP2E1 (MEOS System) Could be Associated with Better Short‐Term Health Outcome after Acute Methanol Poisoning

Genetic polymorphisms influence the metabolism of ethanol and methanol, but the potential effects of genetic predisposition on the clinical course, outcome and short‐term health sequelae of acute methanol poisoning are unknown. To evaluate the role of the MEOS system in methanol poisoning, we analysed the effect of three polymorphisms (RsaI – rs2031920; PstI – rs3813867; insertion/deletion I/D) within the CYP2E1 enzyme (MEOS system) in 50 adult survivors of methanol poisoning and compared their genotype frequencies with 460 controls. The minor allele frequencies of all three polymorphisms were below 5% in both groups. We did not detect significant differences in the genotype frequencies between survivors of methanol poisoning and controls (p = 0.34 for the RsaI variant; p = 0.59 for the PstI variant and p = 0.21 for the I/D polymorphism). The carriers of at least one minor allele in the CYP2E1 gene had less severe clinical symptoms and better short‐term outcome after acute poisoning. Variants within the CYP2E1 gene are likely not significant genetic determinants of acute methanol poisoning (if survivors are analysed), but they may influence the severity of methanol poisoning and its visual/central nervous system (CNS) outcome.

Successful Use of Hydroxocobalamin and Sodium Thiosulfate in Acute Cyanide Poisoning: A Case Report with Follow-up.

Hydroxocobalamin is an effective first‐line antidote used mainly in monotherapy of cyanide poisonings, while the opinions are different on the effects of its combination with sodium thiosulfate. A 58‐year‐old male committed a suicide attempt by ingesting of 1200–1500 mg of potassium cyanide; he was unconscious for 1–1.5 min. after ingestion with the episode of generalized seizures. On admission to the ICU, the patient was acidotic (pH 7.28; HCO3 14.0 mmol/L, base excess −12.7 mmol/L, saturation O2 0.999) with high serum lactate (12.5 mmol/L). Hydroxocobalamin was administered 1.5 hr after ingestion in two subsequent intravenous infusions at a total dose of 7.5 g. The infusion was followed by continuous intravenous administration of 1 mL/hr/kg of 10% sodium thiosulfate at a total dose of 12 g. No complications and adverse reactions were registered. Serum lactate decreased to 0.6 mmol/L the same day, and arterial blood gases became normal (pH 7.49; HCO3 27.2 mmol/L, base excess 2.2 mmol/L, saturation O2 0.994). The follow‐up examination 5 months later revealed no damage of basal ganglia and cerebellum on magnetic resonance imaging. The neurological examination revealed no pathological findings. On the ocular coherence tomography, the retinal nerve fibres layer was normal. In visual evoked potentials, there was a normal evoked complex on the left eye and minor decrease in amplitude on the right eye. Combination of hydroxocobalamin and sodium thiosulfate can have a positive effect on the survival without long‐term neurological and visual sequelae in the cases of massive cyanide poisonings due to the possibility of a potentiation or synergism of hydroxocobalamin effects by sodium thiosulfate. This synergism can be explained by the different time‐points of action of two antidotes: the initial and immediate effect of hydroxocobalamin, followed by the delayed, but more persistent effect of sodium thiosulfate.

Leukotriene-mediated neuroinflammation, toxic brain damage, and neurodegeneration in acute methanol poisoning

Abstract Context: The role of neuroinflammation in methanol-induced toxic brain damage has not been studied. Objective: We studied acute concentrations and the dynamics of leukotrienes (LT) in serum in hospitalized patients with acute methanol poisoning and in survivors. Methods: Series of acute cysteinyl-LT and LTB4 concentration measurements were performed in 28/101 hospitalized patients (mean observation time: 88 ± 20 h). In 36 survivors, control LT measurements were performed 2 years after discharge. Results: The acute maximum (Cmax) LT concentrations were higher than concentrations in survivors: Cmax for LTC4 was 80.7 ± 5.6 versus 47.9 ± 4.5 pg/mL; for LTD4, 51.0 ± 6.6 versus 23.1 ± 2.1 pg/mL; for LTE4, 64.2 ± 6.0 versus 26.2 ± 3.9 pg/mL; for LTB4, 59.8 ± 6.2 versus 27.2 ± 1.4 pg/mL (all p < 0.001). The patients who survived had higher LT concentrations than those who died (all p < 0.01). Among survivors, patients with CNS sequelae had lower LTE4 and LTB4 than did those without sequelae (both p < 0.05). The LT concentrations increased at a rate of 0.4–0.5 pg/mL/h and peaked 4–5 days after admission. The patients with better outcomes had higher cys-LTs (all p < 0.01) and LTB4 (p < 0.05). More severely poisoned patients had lower acute LT concentrations than those with minor acidemia. The follow-up LT concentrations in survivors with and without CNS sequelae did not differ (all p > 0.05). The mean decrease in LT concentration was 30.9 ± 9.0 pg/mL for LTC4, 26.3 ± 8.6 pg/mL for LTD4, 37.3 ± 6.4 pg/mL for LTE4, and 32.0 ± 8.8 pg/mL for LTB4. Conclusions: Our findings suggest that leukotriene-mediated neuroinflammation may play an important role in the mechanisms of toxic brain damage in acute methanol poisoning in humans. Acute elevation of LT concentrations was moderate, transitory, and was not followed by chronic neuroinflammation in survivors.

Role of activation of lipid peroxidation in the mechanisms of acute methanol poisoning

Abstract Context: The role of activation of lipid peroxidation in the mechanisms of acute methanol poisoning has not been studied. Objective: We measured the concentrations of lipid peroxidation markers in acutely intoxicated patients with known serum concentrations of methanol and leukotrienes. Methods: Blood serum samples were collected from 28 patients hospitalized with acute intoxication and from 36 survivors 2 years after discharge. In these samples, concentrations of 4-hydroxy-trans-2-hexenal (HHE), 4-hydroxynonenal (HNE), and malondialdehyde (MDA) were measured using the method of liquid chromatography-electrospray ionization-tandem mass spectrometry. Results: The maximum acute serum concentrations of all three lipid oxidative damage markers were higher than the follow-up serum concentrations: HNE 71.7 ± 8.0 ng/mL versus 35.4 ± 2.3 ng/mL; p < .001; HHE 40.1 ± 6.7 ng/mL versus 17.7 ± 4.1 ng/mL; p < .001; MDA 80.0 ± 7.2 ng/mL versus 40.9 ± 1.9 ng/mL; p < .001. The survivors without methanol poisoning sequelae demonstrated higher acute serum concentrations of the markers than the patients with sequelae. A correlation between measured markers and serum leukotrienes was present: HNE correlated with LTC4 (r = 0.663), LTD4 (r = 0.608), LTE4 (r = 0.771), LTB4 (r = 0.717), HHE correlated with LTC4 (r = 0.713), LTD4 (r = 0.676), LTE4 (r = 0.819), LTB4 (r = 0.746), MDA correlated with LTC4 (r = 0.785), LTD4 (r = 0.735), LTE4 (r = 0.814), LTB4 (r = 0.674); all p < .001. Lipid peroxidation markers correlated with anion gap (r= −0.428, −0.388, −0.334; p = .026, .045, .080 for HNE, HHE, MDA, respectively). The follow-up serum concentrations of lipid oxidation markers measured in survivors with and without visual/neurological sequelae 2 years after discharge did not differ. Conclusion: Our results demonstrate that lipid peroxidation plays a significant role in the mechanisms of acute methanol poisoning. The acute concentrations of three measured biomarkers were elevated in comparison with the follow-up concentrations. Neuronal membrane lipid peroxidation seems to activate leukotriene-mediated inflammation as a part of the neuroprotective mechanisms. No cases of persistent elevation were registered among the survivors 2 years after discharge.

Neuroinflammation markers and methyl alcohol induced toxic brain damage

Methyl alcohol intoxication is a global problem with high mortality and long-term visual sequelae and severe brain damage in survivors. The role of neuroinflammation in the mechanisms of methyl alcohol-induced toxic brain damage has not been well studied. We measured the acute concentrations and dynamics of lipoxins LxA4 and LxB4 and the interleukins IL-4, IL-5, IL-9, IL-10, and IL-13 in the serum of patients treated with methyl alcohol poisoning and the follow-up concentrations in survivors two years after discharge from the hospital. A series of acute measurements was performed in 28 hospitalized patients (mean age 54.2 ± 5.2 years, mean observation time 88 ± 20 h) and the follow-up measurements were performed in 36 subjects who survived poisoning (including 12/28 survivors from the acute group). Visual evoked potentials (VEP) and magnetic resonance imaging of the brain (MRI) were performed to detect long-term visual and brain sequelae of intoxication. The acute concentrations of inflammatory mediators were higher than the follow-up concentrations: LxA4, 62.0 ± 6.0 vs. 30.0 ± 5.0 pg/mL; LxB4, 64.0 ± 7.0 vs. 34.0 ± 4.0 pg/mL; IL-4, 29.0 ± 4.0 vs. 15.0 ± 1.0 pg/mL; IL-5, 30.0 ± 4.0 vs. 13.0 ± 1.0 pg/mL; IL-9, 30.0 ± 4.0 vs. 13.0 ± 1.0 pg/mL; IL-10, 38.0 ± 5.0 vs. 16.0 ± 1.0 pg/mL; IL-13, 35.0 ± 4.0 vs. 14.0 ± 1.0 pg/mL (all p < 0.001). The patients with higher follow-up IL-5 concentration had prolonged latency P1 (r = 0.413; p = 0.033) and lower amplitude N1P1 (r = -0.498; p = 0.010) of VEP. The higher follow-up IL-10 concentration was associated with MRI signs of brain necrotic damage (r = 0.533; p = 0.001) and brain hemorrhage (r = 0.396; p = 0.020). Our findings suggest that neuroinflammation plays an important role in the mechanisms of toxic brain damage in acute methyl alcohol intoxication.