Metformin-associated lactic acidosis reported to the United Kingdom National Poisons Information Service (NPIS) between 2010 and 2019: a ten-year retrospective analysis.

INTRODUCTION: Metformin toxicity following therapeutic use or overdose may result in metabolic acidosis with hyperlactatemia. This study aims to assess the relationship between serum lactate concentration, arterial pH, and ingested dose with severity of poisoning, and to identify if serum lactate concentration is a useful marker of severity in metformin toxicity. METHODS: A retrospective study of telephone enquiries relating to metformin exposures to the National Poisons Information Service between 2010 and 2019 from hospitals in the United Kingdom. RESULTS: Six-hundred and thirty-seven cases were identified; 117 involved metformin only and 520 involved metformin with other drugs. The majority of cases involved acute (87%) and intentional (69%) exposures. There was a statistically significant difference in doses between the Poisoning Severity Scores, as well as between intentional and unintentional or therapeutic error doses (P < 0.0001). The distribution of cases for each Poisoning Severity Score differed between the metformin only and metformin with other drugs cases (P < 0.0001). Lactic acidosis was reported in 232 cases. Serum lactate concentration and arterial pH differed across Poisoning Severity Scores. Arterial pH inversely correlated with ingested dose (r=-0.3, P = 0.003), and serum lactate concentration positively correlated with ingested dose (r = 0.37, P < 0.0001). Serum lactate concentration and arterial pH did not correlate with each other. Twenty-five deaths were recorded, all following intentional overdoses. DISCUSSION: The dataset focuses mostly on acute, intentional overdoses. Increasing ingested metformin dose, a higher serum lactate concentration and worsening arterial pH were all associated with an unfavourable Poisoning Severity Score in patients in both metformin only and metformin with other drugs groups. As serum lactate concentration did not correlate with arterial pH, it represents an independent marker of poisoning severity. CONCLUSIONS: Data from the present study suggest that serum lactate concentration can be used to assess severity of poisoning in patients who have reportedly ingested metformin.

Potential cyanide poisoning reported to the UK national poisons information service: 2008-2019.

INTRODUCTION: Cyanide is a prevalent, lethal chemical. Possible sources of exposure include products of combustion, plant material, industry, chemical warfare and terrorism. METHODS: Retrospective review of UK Poisons Information Database of telephone enquiries to the National Poisons Information Service between 1st January 2008 and 31st December 2019 where cyanide poisoning was considered a possibility. Data extracted included demographics, exposure source, clinical features, Poisoning Severity Score, lactate concentration and antidotes given. RESULTS: A total of 1,252 cases of suspected cyanide poisoning were identified, 239 (19%) involved children under 10 years. The commonest sources of exposure were ingestion of plant material (437 cases; 35%) and smoke inhalation (399; 32%). Smoke inhalation caused the majority of severe and fatal cases (139; 71%). Clinical features associated with fatal outcomes were cardiac arrest (OR 36.4; 95% CI 14.4-92.2), hypotension (15.8; 7.0-35.9), coma (10.8; 5.6-21.0) and lactic acidosis (7.8; 4.1-14.8). 110 patients (9%) were given an antidote and 40 patients (3%) died.Lactate concentrations correlate with Poisoning Severity Score category (r = 0.6, p < 0.0001). Serum lactate <2.0 mmol/L was associated with Poisoning Severity Score None or Minor (sensitivity 76%; specificity 86%) and >11.0 mmol/L was associated with fatal outcome (sensitivity 74%; specificity 80%). 61 cases (5%) had severe carboxyhaemoglobin toxicity (COHb >30%). This was associated with a fatal outcome (OR 7.0; 95% CI 1.5-33.7) and there was positive correlation between carboxyhaemoglobin and Poisoning Severity Score, r = 0.57, p < 0.0001. CONCLUSIONS: Most cases of ingestion of plant material involved children under five years and resulted in no or mild symptoms. In adults smoke inhalation was associated with the most severe poisoning. The lactate cut-off values associated with each severity score calculated in this study are lower than the values used by NPIS on TOXBASE. Analytical conformation of cyanide exposure was unavailable in the majority of case, limiting the strength of these conclusions.

Safety and Efficacy of the SNAP 12-hour Acetylcysteine Regimen for the Treatment of Paracetamol Overdose.

BACKGROUND: Acetylcysteine (NAC) is effective at preventing liver injury after paracetamol overdose. The Scottish and Newcastle Anti-emetic Pre-treatment for Paracetamol Poisoning (SNAP) Study demonstrated that a 12 h NAC regimen was associated with fewer adverse drug reactions compared with the standard 21 h regimen. Here, we describe the clinical effectiveness of the SNAP NAC regimen. METHODS: The SNAP regimen, consisting of intravenous NAC 100 mg/kg over 2 h then 200 mg/kg over 10 h, was introduced to treat all paracetamol overdose patients at the Royal Infirmary of Edinburgh, the Royal Victoria Infirmary, Newcastle and St Thomas' Hospital, London. Patient data were prospectively and systematically collected before and after the change in treatment (total patients N = 3340, 21 h N = 1488, SNAP N = 1852). Health record linkage was used to determine patient outcome after hospital discharge. FINDINGS: There was no difference in liver injury or liver synthetic dysfunction between regimens. Hepatotoxicity (peak ALT > 1000 U/L) occurred in 64 (4.3%) and 67 (3.6%) patients, respectively, in the 21 h and SNAP groups (absolute difference - 0.7%, 95% CI - 2.1 to 0.6). Multivariable logistic regression did not identify treatment regimen as an outcome-associated factor. No patients were readmitted to hospital with, or died from, liver failure within 30 days of discharge. Anti-histamine treatment (for NAC anaphylactoid drug reactions) was prescribed for 163 (11.0%) patients with the 21 h regimen and 37 (2.0%) patients with the SNAP regimen (absolute difference 9.0% (95% CI 7.3 to 10.7)). INTERPRETATION: In clinical use the SNAP regimen has similar efficacy as standard therapy for preventing liver injury and produces fewer adverse reactions.

Management of poisoning with ethylene glycol and methanol in the UK: a prospective study conducted by the National Poisons Information Service (NPIS).

BACKGROUND: Poisoning with methanol and ethylene glycol can cause serious morbidity and mortality. Specific treatment involves the use of antidotes (fomepizole or ethanol) with or without extracorporeal elimination techniques. METHODS: A prospective audit of patients with methanol or ethylene glycol poisoning reported by telephone to the National Poisons Information Service (NPIS) in the UK was conducted during the 2010 calendar year and repeated during the 2012 calendar year. The study was conducted to determine the frequency of clinically significant systemic toxicity and requirement for antidote use and to compare outcomes and rates of adverse reaction and other problems in use between ethanol and fomepizole. RESULTS: The NPIS received 1315 enquiries involving methanol or ethylene glycol, relating to 1070 individual exposures over the 2-year period. Of the 548 enquiries originating from hospitals, 329 involved systemic exposures (enteral or parenteral as opposed to topical exposure), of which 216 (66%) received an antidote (204 for ethylene glycol and 12 for methanol), and 90 (27%) extracorporeal treatment (86 for ethylene glycol and 4 for methanol). Comparing ethanol with fomepizole, adverse reactions (16/131 vs. 2/125, p < 0.001) and administration errors, lack of monitoring, or inappropriate use (45/131 vs. 6/125, p < 0.0001) were reported more commonly, whereas non-availability and inadequate stocks were reported less commonly (6/125 vs. 33/131, p < 0.0001). Eight fatalities and complications or sequelae occurred in 21 patients. Poor outcome (death, complications, or sequelae) was significantly associated with older age, higher poisoning severity scores, and lower pH on admission (p < 0.001). CONCLUSIONS: Systemic poisoning with ethylene glycol or methanol results in hospitalisation at least 2-3 times per week on average in the UK. No difference in outcome was detected between ethanol and fomepizole-treated patients, but ethanol was associated with more frequent adverse reactions.

Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital.

UNLABELLED: Acetaminophen overdose is a common reason for hospital admission and the most frequent cause of hepatotoxicity in the Western world. Early identification would facilitate patient-individualized treatment strategies. We investigated the potential of a panel of novel biomarkers (with enhanced liver expression or linked to the mechanisms of toxicity) to identify patients with acetaminophen-induced acute liver injury (ALI) at first presentation to the hospital when currently used markers are within the normal range. In the first hospital presentation plasma sample from patients (n = 129), we measured microRNA-122 (miR-122; high liver specificity), high mobility group box-1 (HMGB1; marker of necrosis), full-length and caspase-cleaved keratin-18 (K18; markers of necrosis and apoptosis), and glutamate dehydrogenase (GLDH; marker of mitochondrial dysfunction). Receiver operator characteristic curve analysis and positive/negative predictive values were used to compare sensitivity to report liver injury versus alanine transaminase (ALT) and International Normalized Ratio (INR). In all patients, biomarkers at first presentation significantly correlated with peak ALT or INR. In patients presenting with normal ALT or INR, miR-122, HMGB1, and necrosis K18 identified the development of liver injury (n = 15) or not (n = 84) with a high degree of accuracy and significantly outperformed ALT, INR, and plasma acetaminophen concentration for the prediction of subsequent ALI (n = 11) compared with no ALI (n = 52) in patients presenting within 8 hours of overdose. CONCLUSION: Elevations in plasma miR-122, HMGB1, and necrosis K18 identified subsequent ALI development in patients on admission to the hospital, soon after acetaminophen overdose, and in patients with ALTs in the normal range. The application of such a biomarker panel could improve the speed of clinical decision-making, both in the treatment of ALI and the design/execution of patient-individualized treatment strategies.

National audit of antidote stocking in acute hospitals in the UK.

BACKGROUND: Inadequate stocking of essential antidotes in hospitals for the treatment of poisoned patients has been reported worldwide. Joint National Poisons Information Service (NPIS)/College of Emergency Medicine (CEM) guidelines for antidote stocking in UK emergency departments and acute hospitals were published in 2008. AIM: To determine the impact of these guidelines by surveying the availability of antidotes in acute hospitals in the UK. METHODS: A two-page questionnaire consisting of antidote stocking information was distributed in 2010 to the Chief Pharmacist in all acute hospitals in the UK. The availability of 28 antidotes in the NPIS/CEM antidote guidelines as well as that of Intralipid was surveyed. RESULTS: Surveys were completed for 196 of the 224 (87.5%) hospitals. Over 90% of hospitals had acetylcysteine, activated charcoal, dantrolene, desferrioxamine, naloxone, flumazenil and vitamin K available within the recommended time period. Pralidoxime was reported to be held in only 33% of hospitals, though pralidoxime is supplied by the Department of Health to 95 hospitals in the UK that act as holding centres. Cyproheptadine and viper venom antiserum were held in around 50% of acute hospitals. For the treatment of cyanide and toxic alcohol poisoning, more than one antidote is available. For cyanide poisoning, most hospitals held at least one antidote (usually dicobalt edetate) but 9 (5%) held none of the four antidotes. For toxic alcohol and glycol poisoning, most hospitals held ethanol for intravenous use but not fomepizole and 30 (15%) did not stock any antidote for toxic alcohol poisoning. CONCLUSION: Stocking of less commonly used antidotes is inconsistent. This is likely to result in delayed access to treatment and worse patient outcomes.

Extracorporeal elimination in acute valproic acid poisoning.

INTRODUCTION: Valproic acid (VPA) is an antiepileptic drug that is now used for a variety of neurological and psychiatric indications. Clinical manifestations of severe VPA poisoning include central nervous system depression, hypotension, electrolyte and acid-base disturbances, and hyperammonemia. Although extracorporeal methods have been used to enhance VPA elimination, the indications for and effectiveness of these methods have not been fully characterized. METHODS: A systematic literature search was performed, which identified 31 reports of the use of extracorporeal elimination in VPA poisoning. RESULTS: VPA has a low molecular weight of 144 Da and a low volume of distribution, but at therapeutic concentrations, it is highly protein bound (85-95%). Protein-binding studies during hemodialysis demonstrate that at high VPA concentrations protein binding is saturated, allowing substantial clearance of the free VPA fraction. Case reports consistently show that during hemodialysis the elimination half-life of VPA can be reduced to around 2 h and the enhanced VPA clearance is often associated with improvement clinically. Hemoperfusion also enhances VPA elimination, but its effectiveness may be limited by column saturation. "In-series" hemodialysis and hemoperfusion have been used, but the combination offers little benefit over hemodialysis alone. Continuous renal replacement techniques are increasingly being used although continuous venovenous hemofiltration and continuous venovenous hemodiafiltration do not appear to be as effective as hemodialysis. No controlled trials are available comparing clinical outcomes with or without extracorporeal elimination in VPA poisoning. Novel techniques such as slow low-efficiency dialysis with filtration and supplementation of the dialysate with albumin are being evaluated. INDICATIONS: Extracorporeal methods of elimination should be considered in patients with features of severe VPA poisoning (coma or hemodynamic compromise) and plasma VPA concentration >850 mg/L (coma is more likely to be present at concentrations >850 mg/L), particularly if severe hyperammonemia and electrolyte and acid-base disturbances are present. CONCLUSIONS: Based on limited anecdotal evidence, hemodialysis appears to be the extracorporeal method of choice to enhance VPA elimination in acute poisoning. Controlled, randomized trials are required to better characterize the effect of extracorporeal treatment on clinical outcome.