Anselm Wong

Simplification of the standard three-bag intravenous acetylcysteine regimen for paracetamol poisoning results in a lower incidence of adverse drug reactions.

Abstract Context: Adverse reactions to intravenous (IV) acetylcysteine treatment in paracetamol overdose, are common. Previous studies suggest the incidence and severity of non-allergic anaphylactic reactions (NAARs) are influenced by the rate of acetylcysteine infusion. Objective: We compared the incidence of adverse drug events of a two-bag IV acetylcysteine regimen with that of the traditional three-bag regimen. Materials and methods: This was a retrospective analysis of patients presenting with paracetamol overdose requiring treatment with acetylcysteine to three emergency departments. We prospectively identified all presentations where IV acetylcysteine was administered using a 20 h, two-bag regimen (200 mg/kg over 4 h followed by 100 mg/kg over 16 h) from February 2014 to June 2015. We compared this to an historical cohort treated with the 21 h three-bag IV regimen (150 mg/kg over 1 h, 50 mg/kg over 4 h and 100 mg/kg over 16 h) from October 2009 to October 2013. Medical and nursing notes were searched retrospectively for entries suggesting the presence of an adverse reaction. The primary outcome was incidence of NAARs and gastrointestinal reactions in each group. Results: 389 presentations were treated with the three-bag regimen and 210 presentations received the two-bag regimen. NAARs were recorded more commonly with the three-bag acetylcysteine regimen than the two-bag regimen (10% vs 4.3%, p = 0.02, OR 2.5, 95% CI 1.1–5.8). There was no difference in reports of gastrointestinal reactions between cohorts (three-bag 39% vs two-bag 41%, p = 0.38, OR 1.17 95% CI (0.83–1.65)). Discussion: The incidence of NAARs was significantly reduced by combining the first two bags of the traditional three-bag regimen and infusing these over 4 h at 50 mg/kg/hr. Simplifying the administration of acetylcysteine may have other benefits such as better utilisation of nursing time and reduced infusion administration errors. Conclusions: A two-bag 20 h acetylcysteine regimen was well tolerated and resulted in significantly fewer and milder NAARs than the standard three-bag regimen.

Changing epidemiology of intentional antidepressant drug overdose in Victoria, Australia

Aim: To determine the epidemiology of intentional antidepressant drug overdose (OD), over an extended time period, in Victoria, Australia. Methods: Retrospective epidemiological study of all cases reported to the Victorian Emergency Minimum Dataset (VEMD) January 1998 to December 2007 and calls to the Victorian Poisons Information Centre (VPIC) June 2005 to September 2008. Results: 5467 VEMD cases were analysed. 3169 (57.9%) cases involved selective serotonin reuptake inhibitors (SSRIs) and 1149 (21%) involved tricyclic antidepressants (TCAs). Sertraline (1252, 22.9% cases) was the most common drug. During 2001, the peak year of OD, there were 8.8 OD/100 000 population in the SSRI group and 3.8 OD/100 000 population in the TCA group. Trends over the study period showed increasing SSRI and ‘other’ newer antidepressant prescription rates and decreases for TCA and monoamine oxidase inhibitors (MAOI). However, the risks of OD in all drug classes were similar and OD/100 000 prescriptions trended downwards for all drug classes over time. 1833 VPIC calls were analysed. Calls relating to SSRIs were the most common yet SSRI OD was associated with significantly fewer symptoms (p < 0.001) and fewer patients with Poisoning Severity Score classifications of moderate or severe (p < 0.01). Conclusions: Antidepressant OD patterns are changing. Antidepressant OD incidence is following prescribing trends. The risk of OD is similar for all drug classes. Absolute numbers of OD and OD/100 000 prescriptions are decreasing for all drug classes.

External validation of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity from paracetamol overdose

Abstract Context. Risk prediction in paracetamol (acetaminophen, or APAP) poisoning treated with acetylcysteine helps guide initial patient management and disposition. The paracetamol-aminotransferase multiplication product may be a useful and less time-sensitive risk predictor. Objective. The aim of this study was to validate this multiplication product in an independent cohort of patients with paracetamol overdose. Materials and methods. Using an existing toxicology dataset of poisoned patients from two large inner-city United Kingdom teaching hospitals, we retrospectively identified by electronic search all paracetamol overdoses from February 2005 to March 2013. We assessed the diagnostic accuracy of the multiplication product (serum APAP concentration × alanine transaminase [ALT] activity), especially at the pre-specified cut-off points of 1 500 mg/L × IU/L (10 000 micromol/L × IU/L) and 10 000 mg/L × IU/L (66 000 micromol/L × IU/L). The primary outcome was hepatotoxicity defined by a peak ALT > 1000 IU/L. Results. Of 3823 total paracetamol overdose presentations, there were 2743 acute single, 452 delayed single (> 24 h post overdose), 426 staggered (ingestion over > 1 h), and 202 supratherapeutic ingestions. Altogether, 34 patients developed hepatotoxicity. Among the acute single-ingestion patients, a multiplication product > 10 000 mg/L × IU/L had a sensitivity of 80% (95% confidence interval [CI]: 44%, 96%) and specificity of 99.6% [99.3%, 99.8%], while a product > 1 500 mg/L × IU/L had a sensitivity of 100% [66%, 100%] and specificity of 92% [91%, 93%]. Overall, 16 patients with a multiplication product > 10 000 mg/L × IU/L developed hepatotoxicity (likelihood ratio: 250, 95% CI: 130, 480), and 4 patients with a multiplication product between 1 500 and 10 000 (likelihood ratio: 2.5, 95% CI: 1.0, 6.0). No patient with a product < 1 500 mg/L × IU/L who received acetylcysteine developed hepatotoxicity. Conclusions. Regardless of ingestion type, a product > 10 000 mg/L × IU/L was associated with a very high likelihood, and < 1 500 mg/L × IU/L with a very low likelihood, of developing hepatotoxicity in patients treated with acetylcysteine.

Risk prediction of hepatotoxicity in paracetamol poisoning

Abstract Context: Paracetamol (acetaminophen) poisoning is the most common cause of acute liver failure in the developed world. A paracetamol treatment nomogram has been used for over four decades to help determine whether patients will develop hepatotoxicity without acetylcysteine treatment, and thus indicates those needing treatment. Despite this, a small proportion of patients still develop hepatotoxicity. More accurate risk predictors would be useful to increase the early detection of patients with the potential to develop hepatotoxicity despite acetylcysteine treatment. Similarly, there would be benefit in early identification of those with a low likelihood of developing hepatotoxicity, as this group may be safely treated with an abbreviated acetylcysteine regimen. Aim: To review the current literature related to risk prediction tools that can be used to identify patients at increased risk of hepatotoxicity. Methods: A systematic literature review was conducted using the search terms: “paracetamol” OR “acetaminophen” AND “overdose” OR “toxicity” OR “risk prediction rules” OR “hepatotoxicity” OR “psi parameter” OR “multiplication product” OR “half-life” OR “prothrombin time” OR “AST/ALT (aspartate transaminase/alanine transaminase)” OR “dose” OR “biomarkers” OR “nomogram”. The search was limited to human studies without language restrictions, of Medline (1946 to May 2016), PubMed and EMBASE. Original articles pertaining to the theme were identified from January 1974 to May 2016. Of the 13,975 articles identified, 60 were relevant to the review. Paracetamol treatment nomograms: Paracetamol treatment nomograms have been used for decades to help decide the need for acetylcysteine, but rarely used to determine the risk of hepatotoxicity with treatment. Reported paracetamol dose and concentration: A dose ingestion >12 g or serum paracetamol concentration above the treatment thresholds on the paracetamol nomogram are associated with a greater risk of hepatotoxicity. Paracetamol elimination half-life: Patients with more severe hepatotoxicity are more likely to have a longer paracetamol elimination half-life. While median elimination half-life increases in those developing hepatotoxicity, there is wide variation in half-life, making this an insensitive parameter to use as a negative risk prediction tool. Prothrombin time (PT): An initially normal PT is associated with a lower risk of developing hepatotoxicity, but cannot be used alone to identify patients not requiring acetylcysteine treatment. Hepatic aminotransferase activity: A normal ALT activity on presentation is associated with a high negative predictive value of hepatotoxicity following paracetamol-poisoning. Psi parameter: The psi parameter takes into account the time from ingestion, the serum paracetamol concentration and the time to initiation of acetylcysteine. A hepatotoxicity risk nomogram based on this parameter may be easier to use, but is limited to acute ingestions. Paracetamol–aminotransferase multiplication product: If a hepatotoxicity risk nomogram is not available, an alternate strategy may be to use the paracetamol–aminotransferase product (<1500 low risk, 1500–10,000 low to moderate risk, >10,000 mg/L × IU/L high risk) to define liver injury risk. Serial blood tests can be performed if patients present prior to 8 h post-overdose for ultimate specificity, or a single blood test can be taken if presenting more than 8 h post-overdose. Patients receiving acetylcysteine within 8 h of their overdose, with a product less than 10,000 mg/L × IU/L have a low likelihood of developing hepatotoxicity. Any clinical trials of intensified treatment (e.g., higher dose) to prevent fulminant hepatic failure might potentially use a product of >10,000 mg/L × IU/L as a criterion for inclusion. The paracetamol–aminotransferase product <1500 mg/L × IU/L may also identify those suitable for an abbreviated acetylcysteine regimen. Newer biomarkers: These show promise in the early identification of patients with a higher risk of developing hepatic injury. Point of care devices measuring paracetamol adducts need further trials. Conclusions: Risk prediction tools can stratify those that are more likely to develop hepatotoxicity. Currently, the paracetamol–aminotransferase multiplication product may be such a tool. Novel biomarkers show promise but need further validation and greater clinical availability. These tools may help inform clinical trials on modified acetylcysteine regimens.

Oxycodone/naloxone preparation can cause acute withdrawal symptoms when misused parenterally or taken orally

Abstract Context. Oral oxycodone/naloxone preparations are designed to reduce the incidence of constipation associated with oxycodone use. The low oral bioavailability (< 2%) of naloxone makes the precipitation of the acute opioid withdrawal symptoms unlikely following oral oxycodone/naloxone exposure. The incidence of acute opioid withdrawal symptoms following both oral and intravenous administration of oxycodone/naloxone preparations has not been described. Objective. The aim of the study was to investigate the incidence and circumstances associated with oxycodone/naloxone-induced acute opioid withdrawal. Methods. An observational case series of acute opioid withdrawal following oxycodone/naloxone administration were selected from all calls received by the Victoria Poisons Information Centre from January 2012 to December 2014. Data collected included patient demographics, reported symptoms, type of caller, intentional or accidental exposure and advice given. Results. There were 107 reported exposures to oxycodone/naloxone preparations. Route of exposure was oral in 92 (86%) and intravenous injection of crushed tablets in 14 (14%) of cases, respectively. Nine callers had a history of long-standing opioid treatment and developed withdrawal symptoms with oral oxycodone/naloxone. Temporal relationship between first dose, increased dose and chewing tablets was described. There were 14 exposures to crushed oxycodone/naloxone tablets injected intravenously; all precipitated an acute withdrawal state. Discussion. The development of opioid withdrawal symptoms with intravenous injection of oxycodone/naloxone is likely a result of bypassing first-pass metabolism. Withdrawal symptoms after ingesting increased dose, first dose or chewing oxycodone/naloxone suggests that there is a systemic absorption of naloxone in opioid-dependent callers. Conclusion. Oxycodone with naloxone tablets can lead to acute opioid withdrawal symptoms if crushed and injected parentally. First dose, increased dose and chewing of these opioid–naloxone combination tablets in opioid-dependent people can also result in acute opioid withdrawal symptoms or diminished pain relief.

Anti-Xa activity in apixaban overdose: a case report.

Abstract Introduction: Apixaban is a novel oral anticoagulation agent that exerts its effect through direct factor Xa inhibition. We present a case of multi-drug overdose including apixaban with associated apixaban concentrations. Case: A 53 year-old man presented to our metropolitan hospital following a deliberate self-poisoning with 200 mg apixaban, 35 mg ramipril, 105 mg bisoprolol, 280 mg atorvastatin, 6 mg colchicine, 37.4 mg magnesium, 4 × 500 mg paracetamol/9.5 mg codeine/5 mg phenylephrine and alcohol. He developed hypotension that was treated with noradrenaline. His initial and peak apixaban concentration was 1022.6 ng/ml and was associated with only minor bleeding from his femoral central line insertion site, which improved with local compression. Vitamin K 10 mg (at 9 h post-ingestion) and Prothrombinex-VF 2000 units (at 13 h post-ingestion) were also administered without any observed effect on coagulation studies. Apixaban elimination appeared to display first-order kinetics with an elimination half-life of 7.4 h. His plasma apixaban concentration was within the therapeutic dose range 10 h post-ingestion and he recovered uneventfully. Conclusion: A case of apixaban overdose with associated apixaban concentrations is presented. There was rapid resolution of anticoagulation with no demonstrable benefit of currently available clotting factor replacement.

Analytically confirmed recreational use of Phenibut (β-phenyl-γ-aminobutyric acid) bought over the internet

The internet can be used for the sale of many drugs substances including anxiolytics and sedatives not regulated by government authorities. We describe a case of analytically confirmed severe phenibut toxicity necessitating intensive care unit (ICU) admission and management. The phenibut was purchased readily over the internet.

Accuracy of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity in modified-release paracetamol overdose

Abstract Context: The paracetamol-aminotransferase multiplication product (APAP × ALT) is a risk predictor of hepatotoxicity that is somewhat independent of time and type of ingestion. However, its accuracy following ingestion of modified-release formulations is not known, as the product has been derived and validated after immediate-release paracetamol overdoses. Objective: The aim of this retrospective cohort study was to evaluate the accuracy of the multiplication product to predict hepatotoxicity in a cohort of patients with modified-release paracetamol overdose. Methods: We assessed all patients with modified-release paracetamol overdose presenting to our hospital network from October 2009 to July 2016. Ingestion of a modified-release formulation was identified by patient self-report or retrieval of the original container. Hepatotoxicity was defined as peak alanine aminotransferase ≥1000 IU/L, and acute liver injury (ALI) as a doubling of baseline ALT to more than 50 IU/L. Results: Of 1989 paracetamol overdose presentations, we identified 73 modified-release paracetamol exposures treated with acetylcysteine. Five patients developed hepatotoxicity, including one who received acetylcysteine within eight hours of an acute ingestion. No patient with an initial multiplication product <10,000 mg/L × IU/L developed hepatotoxicity (sensitivity 100% [95%CI 48%, 100%], specificity 97% [90%, 100%]). Specificity fell to 54% (95%CI: 34, 59%) at a product cut-off point <1500 mg/L × IU/L. When calculated within eight hours of ingestion, mild elevations of the multiplication product fell quickly on repeat testing in patients without ALI or hepatotoxicity. Conclusions: In modified-release paracetamol overdose treated with acetylcysteine, the paracetamol-aminotransferase multiplication product demonstrated similar accuracy and temporal profile to previous reports involving mostly immediate-release formulations. Above a cut-point of 10,000 mg/L × IU/L, it was very strongly associated with the development of acute liver injury and hepatotoxicity, especially when calculated more than eight hours post-ingestion. When below 1500 mg/L × IU/L the likelihood of developing hepatotoxicity was very low. Persistently high serial multiplication product calculations were associated with the greatest risk of hepatotoxicity.

N‐acetylcysteine regimens for paracetamol overdose: Time for a change?

Paracetamol overdose is one of the commonest pharmaceutical poisonings in the world. For nearly four decades, intravenous acetylcysteine regimens have been used to treat most patients successfully and prevent or mitigate hepatotoxicity. However, the rate of occurrence of adverse reactions to acetylcysteine is quite high, and there is a potential for these to be reduced. Recent studies show that distributing the loading‐dose of acetylcysteine over the first few hours of treatment may decrease the incidence of adverse reactions. In addition, varying the duration of acetylcysteine administration may potentially benefit certain cohorts of poisoned patients, depending on their risk of developing hepatotoxicity.

The impact of online toxicology training on Fijian emergency doctors’ knowledge: the Global Educational Toxicology Uniting Project (GETUP)

More than one million deaths around the world occur annually because of suicide and accidental poisoning.[1] A significant number of these are attributable to deliberate selfpoisoning. Unfortunately, many physicians worldwide, especially in developing nations, do not have access to formal toxicology training programs.[2] The Global Educational Toxicology Uniting Project (GETUP) was established to help overcome these barriers (www.acmt.net/GETUP.html).[3] Our aim was to investigate whether knowledge of poisoning pathophysiology, risk assessment, and management could be improved by an online toxicology course delivered to emergency doctors in a developing country. We piloted a prospective introductory Internet-based toxicology curriculum delivered to Fijian emergency doctors from the two major Fijian hospital services (Colonial War Memorial Hospital, Suva, Fiji and Lautoka Hospital, Lautoka, Fiji). The 15-module introductory toxicology curriculum was delivered from August to October 2015. The curriculum was adapted from a US-based online course (Physician Education and Assessment Center, Johns Hopkins University, Baltimore, USA) and supplemented with regionally relevant topics (organophosphate and paraquat) adapted from Wikitox. The course required no pre-reading and was structured as series of case-based modules supported by supplied relevant reading material. Doctors participated in a set of preand post-module multiple-choice questions (MCQ) immediately before and after each online case-based module. Pre and post MCQs were not identical, but tested the same educational objectives. The primary outcome was to determine the difference in MCQ score pre and post module for each doctor. Approval to analyze and store the de-identified information was given by the Austin Health Research Ethics Committee, Victoria, Australia. A total of 1280 multiple choice questions were completed by eight emergency doctors and consisted a substantial proportion of medical staff in the emergency training program (8 out of 9, 89%) from these two hospitals. Each doctor completed 80 pre-test and 80 post-test MCQs. The median age of doctors was 30 (IQR 29–35) years old: three were male (37.5%) and five were female (62.5%). Of the emergency residents, four (50%) were current masters of emergency medicine and three (50%) were diploma of emergency medicine students undertaking their degrees through the Fiji National University. Prior to the course, all doctors (100%) identified the lack of toxicology education or services available besides conferences offered through GETUP. Overall, median pre-module MCQ scores improved from 52% (IQR 34,74%) compared to post module MCQ scores 83% (IQR 67,100%) (p< .0001). Across all modules, doctors improved in preand post-test module scores (Table 1). Improving knowledge is one pre-requisite to improving clinical practice. A limitation of this study is that we have not examined whether this training has been retained and translated into practice. In summary, an online toxicology curriculum improved knowledge and had high acceptability in emergency doctors in Fiji. Specific, individualized feedback is immediately available to learners and instructors, who can tailor learning according to their goals and needs. Similar models for toxicology education could benefit other similar contexts, and future inquiries should evaluate the benefits of such courses for emergency medicine practice.