Background: Acute Methanol Poisoning (MP) is rare but potentially serious.
Objectives: To study the clinical and biological characteristics of acute MP and its associated factors of mortality.
Methods: We conducted a cross-sectional study including case series of MP which took place in Kairouan. Tunisia. Cases started consulting the emergency room on a festive day (1st day of Aid el Feter) corresponding to May 24, 2021.
Results: We included 65 victims of MP, they were all males. The median age was 28.0 [21.0-35.0] years with extremes ranging from 17 to 75 years. The median time between the ingestion of methanol and the medical consultation was 48.0 [24.0-50.0s] hours.
On admission, the majority of patients described neurological (98.4%) and gastrointestinal symptoms (51.4%). Four patients remained visually impaired, and 8 patients (12.3%) had died.
The univariate analysis showed an association between mortality and age, the amount of methanol ingested, the amount diluting methanol, the co-ingestion of cannabis and the delay between ingestion and consultation, neurological distress, hemodynamic instability, seizures, hypernatremia, hypokalemia, high level of hematocrit, acute kidney failure, hyperglycemia, metabolic acidosis, plasma hyperosmolarity, high anion gap and APACHII score.
Conclusion: Acute MP remains serious not only it can be life-threatening but also is responsible of several organ damages and may lead to blindness and irreversible damage to the central nervous system. The realization of campaigns promoting awareness about MP and the enforcement of laws governing alcohol manipulation are keys for MP prevention. In addition, early identification of this intoxication and rapid management are essential to improve the prognosis.
Epidemiology, Methanol, Poisoning, Prognosis, Tunisia
Methanol (CH3OH), formerly, was known as wood alcohol because it was obtained by distillation of wood, now, is prepared by synthesis . Acute Methanol Poisoning (MP) is most often due to accidental ingestions due to distillation, fermentation errors and its use as unlisted ingredient in supposedly alcohol-based products .
The clinical presentation may mislead clinicians depending on the nature of the toxic alcohol, time of exposure, and coingestion of ethanol. The toxicity of these products is not related to the molecules ingested but to their metabolites . In Tunisia, there is no record of methanol poisoning. Epidemiological and clinical data are missing on this subject.
We aimed to describe the epidemiological, clinical and therapeutic features of the collective acute MP that took place in the governorate of Kairouan in Tunisia and to study the associated factors for mortality.
We conducted a cross-sectional study on victims of a collective acute MP which took place in Hajeb el Ayoun, Kairouan, Tunisia. This city belongs to the governorate of Kairouan which is in the center of Tunisia. Its area is 6,712 km2, populated by 581,300 inhabitants, i.e. 86.6 inhabitants/km2. This governorate suffers from several socio-economic problems. It is placed in the 22nd position on the national scale of poverty. It is known by its high rates of suicide, school dropouts, illiteracy and unemployment .
Cases started consulting the Emergency Room (ER) on a festive day (1st day of Aid el Feter) corresponding to May 24, 2021. The last case was recorded on May 27, 2021 at 6 p.m.
The Two patients who died at home before arriving in the ER and the three who escaped from hospital were not included in our study.
Socio-demographic data, including age, sex, educational level, profession, alcohol addiction, amount of methanol ingested, amount of water diluting methanol, time interval from ingestion to hospital admission, and outcome of the patients were recorded. The clinical examination included standard neurological examination and complete ocular examination with standard ophthalmologic tests. An MRI was performed to symptomatic patients. Severity was assessed by the Acute Physiology and Chronic Health Evaluation (APACHE II). We performed laboratory analyzes on admission from blood samples already drawn for treatment purposes.
All patients received appropriate treatment according to standard protocols. They received ethanol as antidote, folic acid and hemodialysis. Patients were divided into 2 groups, according to the outcome: Group I, patients who survived and group II, patients who died.
All statistical analyses were performed using SPSS Version 20.0. Qualitative data were expressed as numbers and percentages and quantitative variables as median with an interquartile range [Q25-Q75], as appropriate. For comparisons of data between groups, non-parametric tests such as Mann Whitney U test and Kruskal-Wall is test were employed to compare quantitative data. Chi-squared test and Fisher’s exact test were used to compare qualitative data. A p-value less than 0.05 was considered statistically significant.
The study population consisted of 65 patients. All the included subjects were male. The median age was 28.0 [21.0-35.0] years with extremes ranging from 17 to 75 years. The majority of patients had a primary educational level (86.1%). All of the patients were smokers and 64.6% of them were alcoholics. The median amount of methanol ingested was 1000.0 [750.0-1500] ml i.e., 972.0 [850.0-1300.0] g with a minimum of 500 ml i.e., 324 g and maximum of 3000 ml i.e., 1950 g. The median amount of water used to dilute methanol product was 1000.0 [1000.0-2000.0] ml with amounts ranging between 500 and 3000 ml.
The ingestion of methanol was associated to other substances in 46.1% of cases. The illicit substances used were cannabis (15.3%), organochlorine (3%), Parkizol (3%) and ethanol (1.5%).
The median delay between the ingestion of methanol and the medical consultation was 48.0 [24.0-50.0] hours with a minimum of 7 hours and a maximum of 72 hours (Table 1).
Table 1: Socio-demographic and methanol consumption characteristics in Kairouan, Tunisia in 2020. View Table 1
On admission, the majority of patients described neurological (98.4%) and gastrointestinal symptoms (51.4%). Headache was the most common neurological symptom (87.7%) and abdominal pain was the most gastrointestinal described sign (32.3%). Visual disturbances were present in 41.53% of cases with blurred vision (27 cases) and visual impairment (6 cases). On first examination, 12.3% of patients presented hypotension and the median Systolic Blood Pressure (SBP) was 12.0 [11.0-13.0] mmHg. The median respiratory rate was 20.0 [18.0-22.0] with a range between 16 and 30 cpm, only 36.9% of patients were polypneic and 30.8% of them presented a desaturation.
Only 20% of patients arrived in coma and 12.3% presented seizures. A mydriasis was found in 9.3% of cases. The visual acuity test was abnormal in 43.4% of cases. The fundus copy showed an optic neuritis in 12.3% of patients which was confirmed by the MRI. Half of these patients with optic neuritis had associated signs of toxic encephalopathy (6.1%) (Table 2).
Table 2: Clinical features characteristics according to MP in Kairouan, Tunisia in 2020. View Table 2
Concerning blood tests, we found an acute renal failure in 15.4% of cases. Arterial blood gas showed metabolic acidosis in 57.3% of cases. Plasma osmolarity was higher than 290 mmol in 41.5% of cases. Half of the patients had hypokalemia (52%). The anion gap was higher than 20 mmol/l in 24.6% of cases and the median anion gap was 32.0 [28.5-40.2] mmol/l with extremes ranging between 17 and 51. Acute pancreatitis was noted in 18.5% of cases and hypoglycemia in 15.4%. Methanol serum level was higher than 0.5 g/l in 16.9% of patients. The median APACHII score was 2.0 [0.0-7.0] (Table 3).
Table 3: Biological features according to MP in Kairouan Tunisia, in 2020. View Table 3
All patients received hydration with saline. The antidote which is ethanol was administered to 33 patients, i.e., 50.7%. Five patients (7.7%) received folic acid.
Hemodialysis was performed in 33 patients (50.7%). Among the eight deceased patients, 6 cases had a 2-hour hemodialysis session. Oxygen was administered to 46 patients (70.7%). Mechanical ventilation was performed to 13 patients (20%). Eight patients (12.3%) required the use of vascular drugs.
Concerning the orientation of patients, 43% of patients were transferred to an intensive care unit 18.4% were transferred to the CAMU center, 13.8% were transferred to a medical department and 18.4% were kept in the emergency room due to lack of places.
Among the 65 victims, 53 patients (81.5%) had a total recovery after therapeutic care, 4 patients (6.15%) kept a visual impairment and 8 cases died (12.3%).
The median length of stay in the ER was 24.0 [8.0-60.0] hours with extremes of 2 and 96 hours.
The mortality rate reached was 12.3%. An analysis of the predictive factors of mortal¬ity in patients with MP showed a significant association between mortality and some clinical and biological features. In the univariate analysis, we found that age (p = 0.04), the quantity of methanol ingested, the quantity of water diluting methanol, the co-ingestion of cannabis and the delay between ingestion and consultation were significantly associated with mortality.
Concerning clinical and biological features, mortality was associated with neurological distress, hemodynamic instability, seizures, hypernatremia, hypokalemia, high level of hematocrit, acute kidney failure, hyperglycemia, metabolic acidosis, plasma hyperosmolarity, high anion gap and APACHII score (Table 4).
Table 4: Associated factors with mortality in Kairouan, Tunisia, in 2020. View Table 4
MP has represented a challenge for healthcare providers. It is mainly collective, occurring during festive days . Despite improvement in care, morbidity and mortality remain high . The number of poisoned subjects recorded was 65. The median age was 28.0 [21.0-35.0] years. The median time between the ingestion of methanol and the medical consultation was 48.0 [24.0-50.0] hours. On admission, the majority of patients described neurological (98.4%) and gastrointestinal symptoms (51.4%). The mortality rate was 12.3%. We found an association between mortality and age, the amount of methanol ingested, the amount diluting methanol, the co-ingestion of cannabis and the delay between ingestion and consultation and neurological distress.
Studies reporting mass MP are scarce. The number of cases of MP reported in the literature was variable.For instance, 15 victims of MP were reported in Uganda , 26 cases in Morocco  and 121 cases in Czech Republic .
All the patients were males. Our results are congruent with results from the literature showing a masculine predominance in methanol intoxication [5-9]. This could be explained by the particularity of the Tunisian population where only a minority of women consumes alcohol due to socio-cultural norms.
Concerning sources of methanol, our outbreak was caused by drinking locally treated cologne sold by a wholesaler for drinking purposes. Cologne was also the main source of methanol in Turkey with a rate of 72.6% followed by spirits (10.6%) then antifreeze (2.7%) .
In our series, the delay between methanol ingestion and ER consultation was long and significantly associated with mortality. Similar results were found in several other studies. For instance, Brahmi and al found a delay of 36 hours (range between 6 and 48 hours) . In Canada, authors reported a delay of 38 hours ± 1.51 hours (range between 15 and 85 hours) . In China, the delay was estimated to 41.52 ± 0.72 hours . This delay could be explained by the fact that many of the patients were alcoholics and may have misinterpreted symptoms of MP as alcohol withdrawal, others might have drunk a mixture of methanol and ethanol (antidote) which would delay the onset of symptoms .
All the patients were symptomatic upon admission and the most frequent clinical features reported were neurological and gastrointestinal symptoms. In the literature, gastrointestinal disorders were reported frequently in 18 to 67% of cases [13-15]. Dyspnea was reported in 8 to 25% of cases [13-15]. Visual disturbances were present in 29 to 64% of cases [13,14] and neurological symptoms, especially coma, was reported in 10.7% to 36% of cases [5,11,16-18].
Neurological deterioration generally occurs gradually and coincides with advanced stages of intoxication . The severity of central Nervous System (CNS) damage is directly related to the degree of metabolic acidosis caused by the accumulation of formic acid [19,20]. The CNS is a main target of methanol intoxication, especially the brain and the visual pathways which are sensitive to formic acid. The neurological lesions caused by MP are characterized by the presence of a bilateral and symmetrical inflammation of the optic nerves, ischemic and hemorrhagic ranges of the grey nuclei as well as necrosis of the Putamen generally complicated of a hemorrhage with edema, a demyelination of the surrounding white matter and neuronal destruction. These lesions can also affect the cerebellum and the hypothalamus [19,20].
Systemic toxicity was also described in the literature such as hemolysis or rhabdomyolysis with secondary renal failure, pancreatitis and acute hepatitis . Formic acid causes metabolic acidosis with a high anion gap by inhibiting oxidative reactions which promotes anaerobic metabolism generating lactic acid and pyruvic acid worsening acidosis [11,16,19]. According to Nazir, et al. the triad of metabolic acidosis, plasma hyperosmolarity and a high anion gap points towards methanol intoxication [8,21-28].
Our mortality rate is considered to be high, which is consistent with results from other studies [11,19,22]. We noted a big variance in mortality rates between different studies as shown in Table 4. It ranged from 1.8% in a study in Canada  to 80% in Uganda  (Table 5).
Table 5: Comparison of mortality rate between different studies. View Table 5
Despite the improvement in treatment, morbidity and mortality following MP remain high. This may be explained by the delay in diagnosis and therapeutic management [3,6,11]. Furthermore, our analysis for associated factors for mortal¬ity concluded that the quantity of methanol ingested, the quantity of water diluting methanol, the delay of consultation, metabolic acidosis and some clinical and biological features were significantly associated with mortality. Our results are congruent with those from other studies [8,13,17,29]. Severe metabolic acidosis was the most described predictor of death. In a study conducted by Meyer, et al. the most important predictor of mortality was acidosis with blood pH of 7.0 . A study conducted in Norway also revealed that severe metabolic acidosis (pH of 6.9) was a strong predictor of death . Coulter, et al. analyzed the literature data and concluded that low pH of 7.22 was associated with increased mortality and that pH had the highest predictive value .
In Estonia, it was shown that the outcome was related to the degree of metabolic aci¬dosis . In a multicenter study of Paasma, et al. low pH (pH of 7) was also found to be among the strongest predictors of poor outcome .
Concerning the limitations of the study, it was a cross-sectional study and the number of cases was relatively small which provided insuf¬ficient data confirming the association between MP poor income and certain clinic and laboratory parameters. Furthermore, con¬centrations of other components in the alcohol-based fuels were not detected and formic acid and ethanol were not measured, due to a lack of available laboratory equipment. In addition, the hospital was unable to provide all antidotes for all patients including fomepizole which is not available in Tunisia.
In spite of these limitations, our study summarizes the clinic and biological features of MP. In accordance with previous studies, it demonstrates a large number of predictive factors for mortality after MP.
Acute MP remains serious not only it can be life-threatening but also is responsible of several organ damages and may lead to blindness and irreversible damage to the central nervous system . Early identification of this intoxication and rapid management are essential to improve the prognosis . We recommend timely intravenous administration of ethanol to victims of MP, in addition, fomepizole should be included in the list of necessary antidotes. We also recommend campaigns promoting awareness about MP and the enforcement of laws governing alcohol manipulation.
We have no conflict of interest to declare.