Intoxicación por etilenglicol, fisiopatología y enfrentamiento clínico / Ethylene glycol poisonin: an update

Toxic alcohols can produce severe poisoning with multiple organic involvement and even death. The most common form is ethylene glycol. The diagnosis can be extremely difficult if there is no history of its consumption. Its clinical presentation can simulate other conditions. Ethylene glycol poisoning is characterized by an initial rise in plasma osmolal gap that decreases during the evolution, while alcohol is metabolized to acids. This last condition causes a metabolic acidosis with elevated anion gap. The clinical manifestations are diffuse neurological involvement initially, followed by hemodynamic alterations due to myocardial damage associated with hypocalcemia and acidemia. Subsequently, severe tubular renal damage appears, which may require renal replacement therapy, and finally, focal neurological alterations. To treat this poisoning, it is necessary to inhibit the transformation of alcohol into acids, increase the metabolism of the latter or withdraw them directly with hemodialysis.

Intoxicación por etilenglicol, fisiopatología y enfrentamiento clínico.

Toxic alcohols can produce severe poisoning with multiple organic involvement and even death. The most common form is ethylene glycol. The diagnosis can be extremely difficult if there is no history of its consumption. Its clinical presentation can simulate other conditions. Ethylene glycol poisoning is characterized by an initial rise in plasma osmolal gap that decreases during the evolution, while alcohol is metabolized to acids. This last condition causes a metabolic acidosis with elevated anion gap. The clinical manifestations are diffuse neurological involvement initially, followed by hemodynamic alterations due to myocardial damage associated with hypocalcemia and acidemia. Subsequently, severe tubular renal damage appears, which may require renal replacement therapy, and finally, focal neurological alterations. To treat this poisoning, it is necessary to inhibit the transformation of alcohol into acids, increase the metabolism of the latter or withdraw them directly with hemodialysis.

Long-term renal and neurologic outcomes among survivors of diethylene glycol poisoning.

IMPORTANCE: At least 13 medication-associated diethylene glycol (DEG) mass poisonings have occurred since 1937. To our knowledge, this is the first longitudinal study characterizing long-term health outcomes among survivors beyond the acute poisoning period. OBJECTIVE: To characterize renal and neurologic outcomes among survivors of a 2006 DEG mass-poisoning event in Panama for 2 years after exposure. DESIGN, SETTING, AND PARTICIPANTS: This prospective longitudinal study used descriptive statistics and mixed-effects repeated-measures analysis to evaluate DEG-poisoned survivors at 4 consecutive 6-month intervals (0, 6, 12, and 18 months). Case patients included outbreak survivors with a history of (1) ingestion of DEG-contaminated medication, (2) hospitalization for DEG poisoning, and (3) an unexplained serum creatinine level of 1.5 mg/dL or higher (to convert to micromoles per liter, multiply by 88.4) during acute illness or unexplained exacerbation of preexisting end-stage renal disease. MAIN OUTCOMES AND MEASURES: Demographics, mortality, dialysis dependence, renal function, neurologic signs and symptoms, and nerve conduction studies. RESULTS: Of the 32 patients enrolled, 5 (15.6%) died and 1 was lost to follow-up, leaving 26 patients at 18 months. Three (9.4%) missed 1 or more evaluations. The median age was 62 years (range, 15-88 years), and 59.4% were female. Three (9.4%) patients had preexisting renal failure. Enrollment evaluations occurred at a median of 108 days (range, 65-154 days) after acute illness. The median serum creatinine level for the 22 patients who were not dialysis dependent at time 0 was 5.9 mg/dL (range, 1.8-17.1 mg/dL) during acute illness and 1.8 mg/dL (range, 0.9-5.9 mg/dL) at time 0. Among non-dialysis-dependent patients, there were no significant differences in the log of serum creatinine or estimated glomerular filtration rate over time. The number of patients with subjective generalized weakness declined significantly over time (P < .001). A similar finding was observed for any sensory loss (P = .05). The most common deficits at enrollment were bilateral lower extremity numbness in 13 patients (40.6%) and peripheral facial nerve motor deficits in 7 (21.9%). All patients with neurologic deficits at enrollment demonstrated improvement in motor function over time. Among 28 patients (90.3%) with abnormal nerve conduction study findings at enrollment, 10 (35.7%) had motor axonal involvement, the most common primary abnormality. CONCLUSIONS AND RELEVANCE: Neurologic findings of survivors tended to improve over time. Renal function generally improved among non-dialysis-dependent patients between acute illness and the first evaluation with little variability thereafter. No evidence of delayed-onset neurologic or renal disease was observed.

Clinical, laboratory, diagnostic, and histopathologic features of diethylene glycol poisoning--Panama, 2006.

STUDY OBJECTIVE: Diethylene glycol is a toxic industrial solvent responsible for more than 13 mass poisonings since 1937. Little is known about the clinical spectrum, progression, and neurotoxic potential of diethylene glycol-associated disease because of its high mortality and the absence of detailed information in published mass poisoning reports. This incident includes the largest proportion of cases with neurotoxic signs and symptoms. We characterize the features of a diethylene glycol mass poisoning resulting from a contaminated cough syrup distributed in Panama during 2006. METHODS: This was a retrospective chart review and descriptive analysis in a tertiary level, urban health care facility. A case was a person admitted to the Social Security Metropolitan Hospital in Panama City between June 1 and October 22, 2006, with unexplained acute kidney injury and a serum creatinine level of greater than or equal to 2 mg/dL, or unexplained chronic renal failure exacerbation (>2-fold increase in baseline serum creatinine level) and history of implicated cough syrup exposure. Main outcomes and measures were demographic, clinical, laboratory, diagnostic, histopathologic, and mortality data with descriptive statistics. RESULTS: Forty-six patients met inclusion criteria. Twenty-four (52%) were female patients; median age was 67 years (range 25 to 91 years). Patients were admitted with acute kidney injury or a chronic renal failure exacerbation (median serum creatinine level 10.0 mg/dL) a median of 5 days after symptom onset. Forty patients (87%; 95% confidence interval [CI] 74% to 95%) had neurologic signs, including limb (n=31; 77%; 95% CI 62% to 89%) or facial motor weakness (n=27; 68%; 95% CI 51% to 81%). Electrodiagnostics in 21 patients with objective weakness demonstrated a severe sensorimotor peripheral neuropathy (n=19; 90%; 95% CI 70% to 99%). In 14 patients without initial neurologic findings, elevated cerebrospinal fluid protein concentrations without pleocytosis were observed: almost all developed overt neurologic illness (n=13; 93%; 95% CI 66% to 100%). Despite use of intensive care and hemodialysis therapies, 27 (59%) died a median of 19 days (range 2 to 50 days) after presentation. CONCLUSION: A high proportion of patients with diethylene glycol poisoning developed progressive neurologic signs and symptoms in addition to acute kidney injury. Facial or limb weakness with unexplained acute kidney injury should prompt clinicians to consider diethylene glycol poisoning. Elevated cerebrospinal fluid protein concentrations without pleocytosis among diethylene glycol-exposed persons with acute kidney injury may be a predictor for progressive neurologic illness.

Characterizing concentrations of diethylene glycol and suspected metabolites in human serum, urine, and cerebrospinal fluid samples from the Panama DEG mass poisoning.

CONTEXT: Diethylene glycol (DEG) mass poisoning is a persistent public health problem. Unfortunately, there are no human biological data on DEG and its suspected metabolites in poisoning. If present and associated with poisoning, the evidence for use of traditional therapies such as fomepizole and/or hemodialysis would be much stronger. OBJECTIVE: To characterize DEG and its metabolites in stored serum, urine, and cerebrospinal fluid (CSF) specimens obtained from human DEG poisoning victims enrolled in a 2006 case-control study. METHODS: In the 2006 study, biological samples from persons enrolled in a case-control study (42 cases with new-onset, unexplained AKI and 140 age-, sex-, and admission date-matched controls without AKI) were collected and shipped to the Centers for Disease Control and Prevention (CDC) in Atlanta for various analyses and were then frozen in storage. For this study, when sufficient volume of the original specimen remained, the following analytes were quantitatively measured in serum, urine, and CSF: DEG, 2-hydroxyethoxyacetic acid (HEAA), diglycolic acid, ethylene glycol, glycolic acid, and oxalic acid. Analytes were measured using low resolution GC/MS, descriptive statistics calculated and case results compared with controls when appropriate. Specimens were de-identified so previously collected demographic, exposure, and health data were not available. The Wilcoxon Rank Sum test (with exact p-values) and bivariable exact logistic regression were used in SAS v9.2 for data analysis. RESULTS: The following samples were analyzed: serum, 20 case, and 20 controls; urine, 11 case and 22 controls; and CSF, 11 samples from 10 cases and no controls. Diglycolic acid was detected in all case serum samples (median, 40.7 mcg/mL; range, 22.6-75.2) and no controls, and in all case urine samples (median, 28.7 mcg/mL; range, 14-118.4) and only five (23%) controls (median, < Lower Limit of Quantitation (LLQ); range, < LLQ-43.3 mcg/mL). Significant differences and associations were identified between case status and the following: 1) serum oxalic acid and serum HEAA (both OR = 14.6; 95% C I = 2.8-100.9); 2) serum diglycolic acid and urine diglycolic acid (both OR > 999; exact p < 0.0001); and 3) urinary glycolic acid (OR = 0.057; 95% C I = 0.001-0.55). Two CSF sample results were excluded and two from the same case were averaged, yielding eight samples from eight cases. Diglycolic acid was detected in seven (88%) of case CSF samples (median, 2.03 mcg/mL; range, < LLQ, 7.47). DISCUSSION: Significantly elevated HEAA (serum) and diglycolic acid (serum and urine) concentrations were identified among cases, which is consistent with animal data. Low urinary glycolic acid concentrations in cases may have been due to concurrent AKI. Although serum glycolic concentrations among cases may have initially increased, further metabolism to oxalic acid may have occurred thereby explaining the similar glycolic acid concentrations in cases and controls. The increased serum oxalic acid concentration results in cases versus controls are consistent with this hypothesis. CONCLUSION: Diglycolic acid is associated with human DEG poisoning and may be a biomarker for poisoning. These findings add to animal data suggesting a possible role for traditional antidotal therapies. The detection of HEAA and diglycolic acid in the CSF of cases suggests a possible association with signs and symptoms of DEG-associated neurotoxicity. Further work characterizing the pathophysiology of DEG-associated neurotoxicity and the role of traditional toxic alcohol therapies such as fomepizole and hemodialysis is needed.

Medication-associated diethylene glycol mass poisoning: a review and discussion on the origin of contamination.

Diethylene glycol (DEG), an extremely toxic chemical, has been implicated as the etiologic agent in at least 12 medication-associated mass poisonings over the last 70 years. Why DEG mass poisonings occur remains unclear. Most reports do not contain detailed reports of trace-back investigations into the etiology. The authors, therefore, conducted a systematic literature review on potential etiologies of these mass poisonings. The current available evidence suggests that substitution of DEG or DEG-containing compounds for pharmaceutical ingredients results from: (1) deception as to the true nature of certain ingredients by persons at some point in the pharmaceutical manufacturing process, and (2) failure to adhere to standardized quality control procedures in manufacturing pharmaceutical products intended for consumers. We discuss existing guidelines and new recommendations for prevention of these incidents.

Outbreak of acute renal failure in Panama in 2006: a case-control study.

OBJECTIVE: In September 2006, a Panamanian physician reported an unusual number of patients with unexplained acute renal failure frequently accompanied by severe neurological dysfunction. Twelve (57%) of 21 patients had died of the illness. This paper describes the investigation into the cause of the illness and the source of the outbreak. METHODS: Case-control and laboratory investigations were implemented. Case patients (with acute renal failure of unknown etiology and serum creatinine > 2 mg/dl) were individually matched to hospitalized controls for age (+/- 5 years), sex and admission date (< 2 days before the case patient). Questionnaire and biological data were collected. The main outcome measure was the odds of ingesting prescription cough syrup in cases and controls. FINDINGS: Forty-two case patients and 140 control patients participated. The median age of cases was 68 years (range: 25-91 years); 64% were male. After controlling for pre-existing hypertension and renal disease and the use of angiotensin-converting enzyme inhibitors, a significant association was found between ingestion of prescription cough syrup and illness onset (adjusted odds ratio: 31.0, 95% confidence interval: 6.93-138). Laboratory analyses confirmed the presence of diethylene glycol (DEG) in biological samples from case patients, 8% DEG contamination in cough syrup samples and 22% contamination in the glycerin used to prepare the cough syrup. CONCLUSION: The source of the outbreak was DEG-contaminated cough syrup. This investigation led to the recall of approximately 60 000 bottles of contaminated cough syrup, widespread screening of potentially exposed consumers and treatment of over 100 affected patients.

Identification and quantification of diethylene glycol in pharmaceuticals implicated in poisoning epidemics: an historical laboratory perspective.

Over the last several decades, mass poisonings of diethylene glycol (DEG), usually ingested as an unintended component of pharmaceutical preparations, have occurred. In order to promptly halt the rise in deaths due to ingestion of these pharmaceuticals, laboratory analysis has often been employed to identify and quantify the etiologic agent after the medications have been tentatively implicated. Over the past 15 years, the Centers for Disease Control and Prevention has been involved in identifying DEG in implicated pharmaceutical products during three poisoning epidemics that occurred in Nigeria (1990), Haiti (1995), and, most recently, in Panama (2006). In each case, the timeliness of the identification was paramount in reducing the mortality involved in these mass poisonings. Using state-of-the-art analytical technology, we were able to provide initial identification of DEG within 24 h of receiving samples for each epidemic, allowing a timely public health response. However, over the past 15 years, the analytical instrumentation available and the laboratory responses undertaken have changed. In addition, the type of information and the degree of confirmation of results requested during each epidemic varied based upon the number of individuals involved and the political tenor involved with the outbreak. We describe our historical approach to identifying and quantifying DEG during each of these outbreaks. Furthermore, the reoccurrence of outbreaks has prompted us to establish standard technology to use in potential future outbreaks to allow an even more timely response. This methodology includes the development of biomarkers of DEG exposure, which would be extremely useful in instances where pharmaceuticals are not clearly implicated.

Clinical parameters, postmortem analysis and estimation of lethal dose in victims of a massive intoxication with diethylene glycol.

This work analyzes a massive intoxication that occurred in 1992 in Argentina as a result of the use of propolis syrup as a popular upper respiratory infection medicinal agent. The intoxicating agent was diethylene glycol (DEG), which caused metabolic acidosis, anuria, renal failure and death in 15 out of the 29 studied victims. DEG poisoning cases were classified in three groups according to survival time: Group 1-patients that survived up to 3 days; Group 2-patients that survived between 4 and 5 days; Group 3-patients that survived between 6 and 21 days. Patients from Group 1 showed the highest values of anion gap, the lowest measures of base excess (BE) and more severe clinical manifestations. Correlation between pH and BE was r(2) = 0.68, 0.99 and 0.55 for Groups 1, 2 and 3, respectively. A methanolic extraction was performed on the fatal victims' viscera and blood, with subsequent concentration and purification. The semi-crystalline fraction obtained retained DEG by means of co-dissolution and adsorption as demonstrated by thin lay chromatography/flame ionisation detection (TLC/FID). In 3 out of the 15 fatal cases (from Group 1), DEG was isolated from viscera and blood (femoral venous), between 48 and 72 h post ingestion. The concentration relation (DEG)viscera/(DEG)blood ranged from 1.45 to 1.55 with a coefficient correlation r(2)=0.96 (n=3). In the other victims, DEG could not be detected. The reason for this could be the long survival period of the victims after their ingestion of the syrup. Additionally, putrefying mechanisms could have been operating. Samples of the propolis syrup of each victim were studied by means of nuclear magnetic resonance (NMR) and quantified by gas chromatography/flame ionisation detection (GC/FID). Results showed that syrup samples contained 65.0% (w/v) of diethylene glycol (DEG) and 32.0% (w/v) of propylene glycol (PG). A good correlation between the amount of DEG ingested and the anion gap (r(2)=0.63) for the 15 victims studied could be observed. The lethal dose for human beings estimated in this work ranged from 0.014 to 0.170 mg DEG/kg body weight. This is a lower lethal dose than reported in a separate incident in Haiti. These results may contribute to the understanding of DEG's metabolic pathway and provides data from lethal doses in humans.

Epidemic of pediatric deaths from acute renal failure caused by diethylene glycol poisoning. Acute Renal Failure Investigation Team.

CONTEXT: Contaminated pharmaceutical products can result in substantial morbidity and mortality and should be included in the differential diagnosis of deaths of unknown origin. OBJECTIVE: To investigate an outbreak of deaths among children from acute renal failure in Haiti to determine the etiology and institute control measures. DESIGN: Case-control study, cohort study, and laboratory toxicologic evaluation. SETTING: Pediatric population of Haiti. PARTICIPANTS: Cases were defined as Haitian residents younger than 18 years with idiopathic anuria or severe oliguria for 24 hours or longer. Febrile hospitalized children without renal failure were enrolled as control subjects. MAIN OUTCOME MEASURE: The odds of exposure to suspected etiologic agents among cases and controls. RESULTS: We identified 109 cases of acute renal failure among children. The clinical syndrome included renal failure, hepatitis, pancreatitis, central nervous system impairment, coma, and death. Of 87 patients with follow-up information who remained in Haiti for treatment, 85 (98%) died; 3 (27%) of 11 patients transported to the United States for intensive care unit management died before hospital discharge. A locally manufactured acetaminophen syrup was highly associated with disease (odds ratio, 52.7; 95% confidence interval, 15.2-197.2). Diethylene glycol (DEG) was found in patients' bottles in a median concentration of 14.4%. The median estimated toxic dose of DEG was 1.34 mL/kg (range, 0.22-4.42 mL/kg). Glycerin, a raw material imported to Haiti and used in the acetaminophen formulation, was contaminated with 24% DEG. CONCLUSIONS: An epidemic of severe systemic toxicity and deaths from DEG-contaminated acetaminophen syrup occurred in Haiti. Good manufacturing practice regulations should be used by all pharmaceutical manufacturers to prevent such tragedies.

Intoxicación por contacto con óxido de etileno / Intoxication by contac with ethylene oxide

Una lactante eutrófica, durante una cirugía ortopédica tuvo contacto en su muslo derecho con una venda hemostática de látex contaminada con óxido de etileno (OE). Desarrolló una quemadura química intensa en el área expuesta y una intoxicación de efectos generalizados. Se discute el peligro al manipular objetos estrilizados con este método. Además se recomiendan pautas para evitar futuros accidentes

Intoxicación por contacto con óxido de etileno / Intoxication by contac with ethylene oxide

Una lactante eutrófica, durante una cirugía ortopédica tuvo contacto en su muslo derecho con una venda hemostática de látex contaminada con óxido de etileno (OE). Desarrolló una quemadura química intensa en el área expuesta y una intoxicación de efectos generalizados. Se discute el peligro al manipular objetos estrilizados con este método. Además se recomiendan pautas para evitar futuros accidentes (AU)

Fatalities associated with ingestion of diethylene glycol-contaminated glycerin used to manufacture acetaminophen syrup--Haiti, November 1995-June 1996.

From November 1995 through June 1996, acute anuric renal failure was diagnosed in 86 children (aged 3 months-13 years) in Haiti; most (85%) children were aged < or = 5 years. On June 14, 1996, a joint investigation was initiated by the Ministry of Health of Haiti, the University General Hospital in Port-au-Prince, the Pan American Health Organization/World Health Organization, the Caribbean Epidemiology Center, and CDC. This report summarizes the preliminary findings of this ongoing investigation, which indicate that this outbreak was associated with diethylene glycol (DEG)-contaminated glycerin used to manufacture acetaminophen syrup.

Aumento del GAP osmolal en la intoxicación con metanol / Increase the osmotic GAP in the intoxication with methanol

Se estudió un grupo de 10 pacientes que consultaron por haber ingerido vino de una marca que había sido adulterada con metanol. Fueron divididos en dos grupos: grupo I, 4 pacientes y grupo II, 6 pacientes. Los del grupo I, presentaban pH < 7,0, EB < -20 mEq/l, [CO3H-] < 6 mEq/l y GAP osmolal > 45 mosm/kg de H2O. De este grupo, los pacientes a, b y c fueron tratados con CO3H- y Etanol. El d, además fue dializado. Los pacientes a, b y c murieron a las 24 h de la internación. El paciente d, sobrevivió y fue dado de alta con ceguera irreversible. Los del grupo II no presentaron manifestaciones clínicas y el GAP osmolal fue normal. Fueron tratados con etanol por vía oral y al no presentar complicaciones se les dio el alta a las 24 h de la admisión. En los pacientes del grupo I, se analizaron 3 formas de cálculo del GAP osmolal. Se propone la utilidad de este último parámetro con fines de diagnóstico en la intoxicación con alcoholes de bajo peso molecular

Aumento del GAP osmolal en la intoxicación con metanol / Increase the osmotic GAP in the intoxication with methanol

Se estudió un grupo de 10 pacientes que consultaron por haber ingerido vino de una marca que había sido adulterada con metanol. Fueron divididos en dos grupos: grupo I, 4 pacientes y grupo II, 6 pacientes. Los del grupo I, presentaban pH < 7,0, EB < -20 mEq/l, [CO3H-] < 6 mEq/l y GAP osmolal > 45 mosm/kg de H2O. De este grupo, los pacientes a, b y c fueron tratados con CO3H- y Etanol. El d, además fue dializado. Los pacientes a, b y c murieron a las 24 h de la internación. El paciente d, sobrevivió y fue dado de alta con ceguera irreversible. Los del grupo II no presentaron manifestaciones clínicas y el GAP osmolal fue normal. Fueron tratados con etanol por vía oral y al no presentar complicaciones se les dio el alta a las 24 h de la admisión. En los pacientes del grupo I, se analizaron 3 formas de cálculo del GAP osmolal. Se propone la utilidad de este último parámetro con fines de diagnóstico en la intoxicación con alcoholes de bajo peso molecular (AU)