Eric Villeneuve

Four-hour acetaminophen concentration estimation after ingested dose based on pharmacokinetic models

Abstract Introduction. The United Kingdom has recently changed the indications for N-acetylcysteine treatment for acetaminophen intoxication. Any ingestion over 75 mg/kg is now referred to the hospital. A model based on pharmacokinetic parameters was developed to predict 4-h acetaminophen concentration for this and other ingested doses. Methodology. EMBASE and Medline were searched to obtain values for volume of distribution, absorption, and elimination constants and bioavailability for acetaminophen. Four-hour concentrations were calculated for ingestion doses currently recommended for hospital referral in different countries. Calculated plasma concentrations at 4 h for several doses were plotted against the Rumack-Matthew and the United Kingdom treatment lines. Results. Six articles were used for the calculations (4 adult and 2 pediatric). In order to achieve a 4-h acetaminophen concentration of 100 mg/L, doses (mg/kg ± 99.9CI) of 180.5 ± 43.2 for adults and 396.1 ± 115.5 for children were calculated. Discussion. A dose of 75 mg/kg would likely yield a 4-h acetaminophen concentrations well below 100 mg/L. Medical toxicologists and poison information specialists are left without evidence-based guidance for which patients or which ingestion history would now warrant referral to hospital for acetaminophen concentration measurement. Larger toxicokinetic studies in acetaminophen overdose are needed to define ingestion dose for referral to hospital.

Sedating the Agitated Patient: A Moving Target?

1. Peterson DC, Martin-Gill C, Guyette FX, et al. Outcomes of medical emergencies on commercial airline flights. N Engl J Med. 2013;368:2075-2083. 2. Health Canada. Units of measurement for blood glucose meters sold in Canada. Health Canada, 2010. Available at: http://www.hc-sc.gc.ca/ dhp-mps/md-im/activit/announce-annonce/md_notice_glucose meters_im_avis_glycometres-eng.php. Accessed November 4, 2016.

Massive acetaminophen overdose: effect of hemodialysis on acetaminophen and acetylcysteine kinetics

Abstract Context: Early onset acidosis from mitochondrial toxicity can be observed in massive acetaminophen poisoning prior to the development of hepatotoxicity. In this context, the efficacy of acetylcysteine to reverse mitochondrial toxicity remains unclear and hemodialysis may offer prompt correction of acidosis. Unfortunately, toxicokinetics of acetaminophen and acetylcysteine during extracorporeal treatments hemodialysis have seldom been described. Case details: An 18-year-old woman presented to the emergency department 60 minutes after ingestion of 100 g of acetaminophen, and unknown amounts of ibuprofen and ethanol. Initial assessment revealed an agitated patient. Her mental status worsened and she required intubation for airway protection. Investigations showed metabolic acidosis with lactate peaking at 8.6 mmol/L. Liver and coagulation profiles remained normal. Acetaminophen concentration peaked at 981 μg/ml (6496 μmol/L). Pending hemodialysis, the patient received 100 g of activated charcoal and an acetylcysteine infusion at 150 mg/kg over 1 hour, followed by 12.5 mg/kg/h for 4 hours. During hemodialysis, the infusion was maintained at 12.5 mg/kg/h to compensate for expected removal before it was decreased to 6.25 mg/kg for 20 hours after hemodialysis. The patient rapidly improved during hemodialysis and was discharged 48 hours post-admission. Toxicokinetics: The acetaminophen elimination half-life was 5.2 hours prior to hemodialysis, 1.9-hours during hemodialysis and 3.6 hours post hemodialysis. The acetaminophen and acetylcysteine clearances by A-V gradient during hemodialysis were 160.4 ml/min and 190.3 ml/min, respectively. Hemodialysis removed a total of 20.6 g of acetaminophen and 17.9 g of acetylcysteine. Conclusion: This study confirms the high dialyzability of both acetaminophen and acetylcysteine. Hemodialysis appears to be a beneficial therapeutic option in cases of massive acetaminophen ingestion with coma and lactic acidosis. Additionally, these results suggest that the infusion rate of acetylcysteine must be more than double during hemodialysis to compensate for its ongoing removal and provide similar plasma concentrations to the usual acetylcysteine regimen.

Letter in reply to Levine et al. Re: hypoglycemia and lactic acidosis outperform King’s College criteria for predicting death or transplant in acetaminophen toxic patients

three-bag IV NAC was initially studied [2]. Based on these results the author report that the absence of unexpected hepatotoxicity may be due to the low risk cohort included in this study. It is important to remember that the three-bag method was designed to match the amount of NAPQI formed from APAP with the amount of glutathione provided by NAC. The author’s proposed dosing regimen would not succeed in providing the needed amount of glutathione early on in a patient more severely poisoned with APAP. Second, the authors report a lower rate of adverse reactions with the two-bag protocol compared to the three bad protocol. In Table 2, the authors list a higher incidence of anaphylactoid reactions (14% vs 5%) and higher use of antiallergy medication (11% vs 4%) in the three bag protocol compared to the two bag protocol. However the definition of anaphylactoid reaction is not stated clearly and there is a risk for bias and misreporting as the data for the three-bag control group were collected retrospectively while the data for the two-bag group was collected prospectively. More importantly, even if the rate of adverse reactions is truly lower in the two-bag protocol, this is not a sufficient reason to abandon the three-bag protocol. Anaphylactoid reactions or antiallergy medication administration rarely change care plans, length of stay or clinical outcomes. Finally, the time to reaction in Table 2 was analyzed on a log scale. Log transformation helps normalize widely spread out data. While it serves no purpose with events ranging from 1 to 4 h, the use of log analysis may be concerning for incongruent or unreported results. In conclusion, this paper is underpowered both for safety and efficacy, included patients with low risk ingestions and suffers from methodological limitations. Most importantly this paper should not be used to change practice until it can be proved to be safe for patients with acetaminophen concentrations well above the Rumack Matthew line of 993lmol/L (200mcg/mL) at 4 h post ingestion. Disclosure statement

Balancing the risks and benefits of medication organizers: reply to Wang et al.

We read with interest the article by Wang et al. that states higher odds of unintentional pediatric ingestions in households having a medication organizer [1]. Although we laud the authors’ efforts to investigate factors responsible for unintentional ingestion of pharmaceuticals, a number of methodological issues in their study shed doubt on their conclusions. One concern, as the authors rightly noted, is that the use of medication organizers is a well-proven method for increasing medication adherence, and thus improving patient outcomes [2,3]. Homes and caregivers that require a medication organizer may vary in important aspects that impact the ability of a child to accidentally ingest medication. Although the authors controlled for age, grandparents, and number of caregivers in the home, most families with children under six years of age do not require a medication organizer. Therefore, the case group may have confounding factors such as polypharmacy or cognitive impairments that were not accounted for. Indeed, the greater number of previous encounters with poison control observed in the case group may point to significant factors in overall home safety. Recall bias may have also caused caretakers in the case group to report more frequent use of medication organizers to avoid the perception of being negligent. Furthermore, various medication organizers have different levels of packaging safety. The study did not specify between blister-packs, pill-minders with child locks, or other child-proof methods. If the authors were able to differentiate a safety profile of the different pill organizers, this would provide valuable information on the risk associated with various devices. Finally, we note that only 40 (63%) of the patients in the case group actually ingested pills from the medication organizer. If the authors are inferring that ingestions were due to the medication organizer, then the ingestions from the medication organizer should be 100%, if indeed the medication organizer is the cause. Given this, it does not make sense to keep the ingestions that were not in the medication organizer in the case group. By removing the patients that did not ingest from the medication organizer, the odds ratio becomes non-significant (OR 1⁄41.22, 95%CI: 0.80–1.87). Given these shortcomings, to associate medication organizers with higher odds of unintentional pediatric ingestion is premature, and may tarnish an effective low-cost tool to increase medication compliance. We would thus encourage further exploration of other factors that may be associated with the need for a medication organizer, given the important role medication organizers play in medication adherence.

Utilization of lipid emulsion therapy in fatal overdose cases: an observational study

Abstract Objective: Although anecdotal reports suggest that intravenous lipid emulsion (ILE) therapy is effective in a large variety of overdoses, the few controlled human trials published to date yielded disappointing results. Because of potential publication biases, there are few reports concerning the failure of ILE. The primary aim of this study was to identify fatal poisoning cases in the American Association of Poison Control Centers (AAPCC) National Poison Data System (NPDS) in which ILE was administered. Methods: We obtained an approved release of data from NPDS for years 2010–2015 in which the words “lipid,” “ILE,” or “fat” appeared in the narrative. Duplicate cases were excluded as were cases in which ILE was not clearly given. Case data were extracted by one author using a predetermined tool, and the information was confirmed by a second author. The timing of ILE administration was characterized into one of four categories: cardiac arrest, first line, last resort, or part of multiple therapies given simultaneously. Response to ILE and adverse events was recorded. Results: Of the 826 cases retrieved from NPDS, 459 met final inclusion criteria. Over 50% of included cases involved either a calcium channel blocker or a beta-adrenergic antagonist. Of note, less than 25% of cases involved a substance for which the Lipid Emulsion Working Group found evidence to support its use. Most often, ILE was given along with multiple therapies (277 cases) or as a last resort (137 cases). In 127 cases, ILE was given during cardiac arrest. ILE was used as first line therapy in 34 cases. Response rates were reported as follows: no response (45%), unknown response (38%), transient/minimal response (7%), ROSC (7%), and immediate worsening (3%). Possible adverse reactions included: ARDS in 39 patients, lipemia causing a delay in laboratory evaluation in three cases, lipemia causing failure of a CRRT filter in two cases, worsening or new onset seizure in two cases, asystole immediately after administration in two cases, and fat embolism in one case. Conclusion: Within the Association of Poison Control Centers (AAPCC) National Poison Data System (NPDS), hundreds of cases exist in which ILE therapy was given and death occurred. In many of these cases, ILE was given prior to cardiovascular collapse. Although there is some suggestion of transient improvement in a small subset of cases, adverse effects are also reported. When taken in totality, the number of published cases of failed lipid emulsion therapy outnumbers the published instances of ILE success. Given all the uncertainty generated by case reports, the evaluation of the role and efficacy of ILE therapy in non-local anesthetic poisoning needs robust controlled clinical trials.

Letter in Reply to Arno et al. “Pharmacokinetics in Morbid Obesity: Influence of Two Bariatric Surgery Techniques on Paracetamol and Caffeine Metabolism”

To the Editor: We read with interest the article from Arno and colleagues [1]. In the evaluation of caffeinemetabolism, the authors accounted for various confounders among study participants, such as cytochrome P450 (CYP)-modulating medications, caffeinecontaining or xanthine-related products, and smoking status. However, we believe that by limiting the analysis to a dichotomous variable for smoking status, the authors neglected an important information needed to accurately compare study groups and interpret their results. Tobacco smoke is rich in polycyclic aromatic hydrocarbons, compounds known to be potent CYP1A2 inducers [2]. Caffeine metabolism, as measured by the paraxanthine/ caffeine ratio, is higher among smokers compared to nonsmokers. Furthermore, caffeine metabolism among smokers increases with the quantity of cigarettes consumed per day, indicating that CYP1A2 induction is proportional to the intensity of tobacco exposure. As such, assessing the quantity of cigarettes smoked per day for each study participant would help distinguish the effects of body mass index (BMI) on CYP activity. It is unclear from the reported data whether study participants identified as smokers during study enrolment were actively smoking at the time blood samples were taken and the quantity of tobacco exposure. Also as CYP1A2 induction quickly stops after smoking cessation, with a 20% reduction in caffeine clearance 2 days after interruption of smoking [3]. Any change in smoking pattern in the days prior to blood sampling likely affected the observed paraxanthine/caffeine ratio. Quantifying the smoking history and exposure more precisely might modify the results and the authors’ conclusions on the effect of obesity and bariatric surgery on drug metabolism. Future efforts to characterize CYP metabolism in obese patients may also benefit from examining the contribution of enzyme induction from weight-loss related behaviors such as vigorous physical exercise, cruciferous vegetable ingestion, and dietary grilled meat—all of which are subject to change preand post-bariatric surgery [4, 5].

Letter in response to “Lithium poisoning in the intensive care unit: predictive factors of severity and indications for extracorporeal toxin removal to improve outcome”

We read with interest the article from Vodovar and colleagues “Lithium poisoning in the intensive care unit: predictive factors of severity and indications for extracorporeal toxin removal to improve outcome.”[1] We commend the authors for using non-parametric tests and acknowledge that prospective validation of their threshold values is needed. However, we would like to raise our concerns with several aspects of their methodology and the reported results. First, the study population consisted of patients admitted to the intensive care unit and may not be representative of the larger spectrum of lithium (Li) poisonings without listing what criteria merit intensive care admission in this particular health care system. The authors themselves note that the use of the Hansen and Amdisen scale to categorize all ingestions is questionable considering that this scale was originally developed from a subject pool that consisted predominantly of patients with chronic lithium poisoning and has previously been shown to lack usefulness in acute ingestions.[2,3] The authors state that their decision to use a threshold value for creatinine of 200 lmol/L and a peak serum [Li]> 5.2mmol/L as indications for ECTR was derived from multiple logistic regression analysis. However, they do not explain why the selection of a single creatinine concentration was chosen instead of using the KDIGO criteria to determine renal function, as was reported in their Table 3. In addition to other shortcomings, use of a single creatinine concentration fails to distinguish whether the renal dysfunction is an evolving process due to the lithium intoxication or from an underlying chronic renal disease. Indeed, serum creatinine does not accurately reflect the GFR in patients in whom it is not in steady state. Use of KDIGO criteria, or at the very least successive creatinine concentrations would have facilitated the distinction. The relationship between persisting neurotoxicity and the length of time of central nervous system (CNS) exposure to toxic lithium concentrations is not discussed even though some authors have previously implied that this was the primary mechanism responsible for syndrome of irreversible lithium-effectuated neurotoxicity (SILENT).[4] While the authors’ study is notable for its detailed record of specific neurological impairments in the study population, the criteria for neurological recovery are neither listed nor discussed. Germane to the assessment of neurological recovery is each patient’s premorbid neurological function – which may be impaired despite therapeutic or subtherapeutic serum [Li] in the context of chronic toxicity and SILENT. Although the authors report in their results and discussion sections that only three chronic poisonings were included and had serum [Li] <4mmol/L and that renal failure should dictate the use of extracorporeal toxin removal (ECTR) in this population, it is not mentioned in the Abstract nor the Conclusion that the threshold value of 5.2mmol/L should only be used for acute and acute-on-chronic poisoning in patients with normal renal function. It would have been interesting to publish the receiver operator curve (ROC) analysis mentioned and see the performance of various threshold values reported in the literature including the latest EXTRIP recommendations.[5] The timing of ECTR with regards to the onset of toxicity and the length of time to return to a Li concentration under 1.0mmol/L is not mentioned. Moreover, as this study recruitment spanned two decades, treatment changes, intensive care unit (ICU) admission criteria and especially technological advances concerning ECTR techniques, membranes or availability, need to be discussed. Intermittent hemodialysis, sustained low-efficiency dialysis, and continuous renal replacement therapy all have unique toxin removal profiles and it would have been interesting if the authors reported the use and outcomes associated with specific ECTR modalities. In conclusion, while we laud the authors’ efforts to define and identify criteria for ECTR use in Li intoxications, the lack of information and precision surrounding the variables discussed make the results difficult to interpret and inform on management strategies with lithium-poisoned patients.

Letter in response to “Idarucizumab for dabigatran overdose”

We read with interest Peetermans et al.’s communication “Idarucizumab for dabigatran overdose”.[1] The report was interesting for the clinical team’s prudent use of gastric lavage, activated charcoal, and intravenous fluids to minimize absorption and maximize excretion of dabigatran and the detailed timeline of laboratory investigations. Our attention was also drawn to the indication for idarucizumab administration: central catheter insertion for emergency dialysis. While the proposed benefit of extracorporeal treatment in dabigatran overdose or bleeding is still anecdotal,[2] the risks of placing a large-bore catheter in an asymptomatic patient with dabigatran-induced coagulopathy and normal renal function – as in this published case – likely outweigh the benefits. Vlad et al. [3] had previously reported deliberate massive dabigatran overdose in two such patients. Both were managed expectantly and experienced no major bleeds, spontaneous normalization of plasma dabigatran to therapeutic concentrations by 32 to 50 h (<92 ng/ml, the median trough serum concentration based on data from the RE-LY trial [4]), and normalization of coagulation parameters shortly thereafter. Further tipping the scale towards increasing risk, five thrombotic events and eighteen deaths were reported in the 62 analyzed patients who received idarucizumab in REVERSE AD,[5] an ongoing prospective cohort study on the safety and efficacy of the drug, and several concerns have been raised regarding its true efficacy.[6] The authors refer to the case patient’s eligibility to receive idarucizumab as part of RE-VERSE AD. In reviewing that study’s published interim analysis, we note that her data were included in the results and informed those authors’ conclusion that idarucizumab safely reverses the anticoagulant activity of dabigatran. Because research into idarucizumab’s treatment effect on patient-oriented outcomes such as major bleeding, disability, and death is still in its early stages, presenting existing RE-VERSE AD data as a case report with a positive outcome may mislead readers to overestimate the evidence-base in favour of idarucizumab administration. Our most striking concern is the lack of transparency in the authors’ “Disclosure statement”. Based on previously released disclosure forms from RE-VERSE AD, five co-authors on this report have or have had financial ties to Boehringer Ingelheim, the manufacturer of both idarucizumab and dabigatran, which include direct employment, grant funding, speaking fees, and positions on the steering committee for idarucizumab. While a partial list of these associations is included under “Funding information”, these relationships constitute real conflicts of interest and potential commercial bias and warrant disclosure in the appropriate section as well. Readers must account for potential industry influence in this report before drawing their own conclusions on the use of idarucizumab in dabigatran overdose.

Intraosseous administration of antidotes – a systematic review

Abstract Context: Intraosseous (IO) access is an established route of administration in resuscitation situations. Patients with serious poisoning presenting to the emergency department may require urgent antidote therapy. However, intravenous (IV) access is not always readily available. Objective: This study reviews the current evidence for IO administration of antidotes that could be used in poisoning. The primary outcome was mortality as a surrogate of efficacy. Secondary outcomes included hemodynamic variables, electrocardiographic variables, neurological status, pharmacokinetics outcomes, and adverse effects as defined by each article. Methods: A medical librarian created a systematic search strategy for Medline, subsequently translated to Embase, BIOSIS, PubMed, Web of Science, Cochrane, Database of Abstracts of Reviews of Effects (DARE), and the CENTRAL clinical trial register, all of which we searched from inception to 30 June 2016. Interventions included IO administration of selected antidotes. Articles included volunteer studies, poisoning, or other resuscitation contexts such as cardiac arrest, burns, dehydration, seizure, hemorrhagic shock, or undifferentiated shock. We considered all human studies and animal experiments to the exception of in vitro studies. Two reviewers independently selected studies, and a third adjudicated in case of disagreement. Three reviewers extracted all relevant data. Three reviewers evaluated the risk of bias and quality of the articles using specific scales according to each type of study design. Results: A total of 47 publications (46 articles and one abstract) met our inclusion criteria and described IO administration of 13 different antidotes. These included one case series and 21 case reports describing 26 patients, and 25 animal experiments. Of those, seven human case reports and four animal experiments specifically reported the use of antidotes in poisoning. Human case reports suggested favorable outcomes with IO use of atropine, diazepam, hydroxocobalamin, insulin, lipid emulsion, methylene blue, phentolamine, prothrombin complex concentrate, and sodium bicarbonate. Clinical outcomes varied according to the antidote used. The only reported adverse event was ventricular tachycardia following IO naloxone. Regarding the animal experiments, IO administration of lipid emulsion and of hydroxocobalamin showed improved survival in bupivacaine-poisoned rats and in cyanide-intoxicated swine, respectively. Animal data also suggested an equivalent bio-availability between IO and IV administration for atropine, calcium chloride, dextrose 50%, diazepam, methylene blue, pralidoxime, and sodium bicarbonate. Adverse effect reporting of fat emboli after IO administration of sodium bicarbonate, for example, was conflicting due to the significant heterogeneity in the timing of lung examination across studies. Conclusion: The evidence supporting the use of IO route for the administration of antidotes in a context of poisoning is scarce. The majority of the evidence consists of case reports and animal experiments. Common antidotes such as acetylcysteine, fomepizole, and digoxin-specific antibody fragments have not been studied or reported with the use of the IO route. Despite the low-quality evidence available, IO access is a potential option for antidotal treatments in toxicological resuscitation when IV access is unavailable.