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'Massive' metformin overdose.

ABSTRACT: Massive metformin overdose can cause metabolic acidosis with hyperlactatemia. A 55-year-old woman presented 5 h after multidrug overdose, including 132 g extended-release metformin. Continuous venovenous haemodiafiltration (CVVHDF) and noradrenaline were commenced due to metabolic acidosis (pH 7.0, lactate 17 mmol l-1 ) and shock. Despite 3 h of CVVHDF, her acidosis worsened (pH 6.83, lactate 24 mmol l-1 ). Intermittent haemodialysis (IHD) improved acidosis (pH 7.13, lactate 26 mmol l-1 ) but again worsened (pH 6.91, lactate 30 mmol l-1 ) with CVVHDF recommencement. IHD (12 h), CVVHDF (26 h) and vasopressor support for 7 days resulted in survival. Measured metformin concentrations were extremely high with a peak of 292 ?g ml-1 at 8 h postingestion. IHD, but not CVVHDF in this case, was associated with improvement in metabolic acidosis and hyperlactataemia. Pharmacokinetic analysis of metformin concentrations found a reduced apparent oral clearance of 8.2 l h-1 and a half-life of approximately 30 h. During IHD, the apparent oral clearance increased to 22.2 l h-1 with an approximate half-life of 10 h. The impact of prolonged oral absorption from a pharmacobezoar and redistribution of metformin from peripheral sites (including erythrocytes) on the pharmacokinetic profile cannot be determined from the data available.

SUBMITTER: Chiew AL

PROVIDER: S-EPMC6256011 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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'Massive' metformin overdose.

Chiew Angela L AL Wright Daniel F B DFB Dobos Nicola M NM McArdle Kylie K Mostafa Ahmed A AA Newth Annemarie A Roberts Michael S MS Isbister Geoffrey K GK

British journal of clinical pharmacology 20180417 12

Massive metformin overdose can cause metabolic acidosis with hyperlactatemia. A 55-year-old woman presented 5 h after multidrug overdose, including 132 g extended-release metformin. Continuous venovenous haemodiafiltration (CVVHDF) and noradrenaline were commenced due to metabolic acidosis (pH 7.0, lactate 17 mmol l<sup>-1</sup> ) and shock. Despite 3 h of CVVHDF, her acidosis worsened (pH 6.83, lactate 24 mmol l<sup>-1</sup> ). Intermittent haemodialysis (IHD) improved acidosis (pH 7.13, lactat ...[more]

PMID: 29534338

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Project description:IntroductionHepatic mitochondrial dysfunction may play a critical role in the pathogenesis of metformin-induced lactic acidosis. However, patients with severe metformin intoxication may have a 30 to 60% decrease in their global oxygen consumption, as for generalized inhibition of mitochondrial respiration. We developed a pig model of severe metformin intoxication to validate this clinical finding and assess mitochondrial function in liver and other tissues.MethodsTwenty healthy pigs were sedated and mechanically ventilated. Ten were infused with a large dose of metformin (4 to 8 g) and five were not (sham controls). Five others were infused with lactic acid to clarify whether lactic acidosis per se diminishes global oxygen use. Arterial pH, lactatemia, global oxygen consumption (VO2) (metabolic module) and delivery (DO2) (cardiac output by thermodilution) were monitored for nine hours. Oxygen extraction was computed as VO2/DO2. Activities of the main components of the mitochondrial respiratory chain (complex I, II and III, and IV) were measured with spectrophotometry (and expressed relative to citrate synthase activity) in heart, kidney, liver, skeletal muscle and platelets taken at the end of the study.ResultsPigs infused with metformin (6 ± 2 g; final serum drug level 77 ± 45 mg/L) progressively developed lactic acidosis (final arterial pH 6.93 ± 0.24 and lactate 18 ± 7 mmol/L, P < 0.001 for both). Their VO2 declined over time (from 115 ± 34 to 71 ± 30 ml/min, P < 0.001) despite grossly preserved DO2 (from 269 ± 68 to 239 ± 51 ml/min, P = 0.58). Oxygen extraction accordingly fell from 43 ± 10 to 30 ± 10% (P = 0.008). None of these changes occurred in either sham controls or pigs infused with lactic acid (final arterial pH 6.86 ± 0.16 and lactate 22 ± 3 mmol/L). Metformin intoxication was associated with inhibition of complex I in the liver (P < 0.001), heart (P < 0.001), kidney (P = 0.003), skeletal muscle (P = 0.012) and platelets (P = 0.053). The activity of complex II and III diminished in the liver (P < 0.001), heart (P < 0.001) and kidney (P < 0.005) while that of complex IV declined in the heart (P < 0.001).ConclusionsMetformin intoxication induces lactic acidosis, inhibits global oxygen consumption and causes mitochondrial dysfunction in liver and other tissues. Lactic acidosis per se does not decrease whole-body respiration.

Project description:BackgroundOpioid overdose is a preventable injury leading to high morbidity and premature mortality in communities across the United States. Overdoses take place where people use drugs, including commercial and public locations like community pharmacies, and necessitate swift detection and response to avoid harm and, even more seriously, death. The presence of emergency and safety protocols improves occupational health and safety for all in the workplace. The aim of this study was to assess the prevalence of experience with on-site pharmacy overdose and to explore pharmacist and site characteristics associated with having a known protocol for responding to on-site overdose emergencies.Methods: An anonymous, online survey about naloxone provision and opioid safety was delivered by email, through professional pharmacy associations and continuing education attendance lists, to 3,100 pharmacists in Massachusetts and Rhode Island between October 2017 and January 2018. Survey items gauged socio-demographics, practice site characteristics, safer opioid dispensing and naloxone provision. Summary statistics and bivariate analyses were conducted to describe characteristics associated with items pertaining to on-site overdose policy awareness.Results: Of the 357 respondents (11.5% response rate), 154 (5.0%) answered the questions of interest: 17.5% reported having at least one suspected overdose on-site at their practice location, while 42.9% reported that they were knowledgeable about and could locate at their practice location an on-site overdose protocol detailing how to respond to an overdose. Pharmacists who were knowledgeable about protocols were also more likely to offer naloxone to patients (p = 0.02) and did not practice at a chain pharmacy (p = 0.01).Conclusions: Community pharmacies that stock and distribute naloxone are key parts of community efforts to address the opioid crisis. Pharmacies and other healthcare settings should develop and implement on-site overdose response protocols and cultivate a norm of naloxone provision to patients.

Project description:BackgroundThe overdose crisis continues across Canada which calls for novel harm reduction strategies. Previous research indicates that a majority of eHealth solutions are cost-effective however current literature on the cost-benefit of eHealth for harm reduction is sparse. The National Overdose Response Service (NORS) is a Canada-wide telephone-based harm reduction service. Service users can call the phone number and connect to a peer who can virtually monitor the substance use session and dispatch appropriate interventions in the case of overdose.Objectives of the research/projectWe aim to assess the cost-benefit of NORS by comparing the estimated cost-savings from prevented overdose mortality to the operating costs of the program, alongside healthcare costs associated with its operation.MethodsData around systems costs and operational costs were gathered for our calculations. Our primary outcome was cost-benefit ratios, derived from estimates and models of mortality rates in current literature and value of life lost. We presented our main results across a range of values for costs and the probability of death following an unwitnessed overdose. These values were utilized to calculate cost-benefit ratios and value per dollar spent on service provision by NORS over the length of the program's operation (December 2020-2022).ResultsOver the total funded lifespan of the program, and using a Monte Carlo estimate, the benefit-to-cost ratio of the NORS program was 8.59 (1.53-15.28) per dollar spent, depending on estimated mortality rates following unwitnessed overdose and program operation costs. Further, we conservatively estimate that early community-based naloxone intervention results in healthcare system savings of $4470.82 per overdose response.ConclusionsWe found the NORS program to have a positive benefit-to-cost ratio when the probability of death following an unwitnessed overdose was greater than 5%. NORS and potentially other virtual overdose monitoring services have the potential to be cost-effective solutions for managing the drug poisoning crisis.

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'Massive' metformin overdose.

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'Massive' metformin overdose.

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