Dispensing patterns of mental health medications before and during the COVID-19 pandemic in Alberta, Canada: An interrupted time series analysis.

BACKGROUND: The COVID-19 pandemic has negatively impacted the general population in all aspects of life. Estimates of mental health medication dispensing in Alberta were investigated to elucidate areas of need within mental health and pharmacy practice during the pandemic. METHODS: We employed an interrupted time series analysis using linear regression models to estimate community and outpatient medication dispensing trends of 46 medications used to treat mental health disorders. Three parameters were examined. The first was the medication dispensing slope before COVID-19. The second was the immediate effect of COVID-19 on dispensing (i.e., the difference in dispensing rate between the month before and after the first case of COVID-19) and the third was the medication dispensing slope during COVID-19. RESULTS: Dispensing rates of 61% (n = 34) of the examined medications remained similar before and during the COVID-19 pandemic. However, eight medications (i.e., amitriptyline, escitalopram, fluoxetine, paroxetine, bupropion, desvenlafaxine, venlafaxine, and oxazepam) showed an immediate and significant increase in dispensing rate following the onset of the pandemic that was sustained over the first 13-months of the pandemic. CONCLUSION: Initial increases in dispensing patterns of antidepressants may be attributed to a "stockpiling phenomenon" but the sustained higher levels of dispensing suggest an unfavorable shift in the population's mental health. Monitoring of medication dispensing patterns during COVID-19 may serve as a useful indicator of the population's mental health during the current pandemic and better prepare community pharmacists in future pandemic planning, medication dispensing strategies, and care of chronic medical conditions.

Population pharmacokinetic analysis of acetaminophen overdose with immediate release, extended release and modified release formulations.

OBJECTIVES: The introduction of delayed release formulations of acetaminophen (APAP) has created concern about the role of formulation in overdose. We examined the APAP overdose pharmacokinetic (PK) profiles to assess the role of dose, coingestants and formulation: immediate release (IR), extended release (ER), and modified release (MR) on APAP pharmacokinetic measures. METHODS: We collected by-subject APAP PK data: subject description, timed blood APAP concentrations, dose, and coingestants. We sought both overdose and randomized controlled trials (RCTs) for supratherapeutic doses involving ER or MR formulations. Data analysis and simulation used the non-linear mixed-effects modeling program NONMEM-version 7.4. RESULTS: The final dataset comprised 3,033 [APAP] from 356 subjects and 15 sources including 3 RCTs (179 subjects receiving IR, 122 ER, 65 MR). The final population PK (PopPK) model was a linear 2-compartment model with first-order (oral) absorption. Covariate relationships included: APAP absorption rate and bioavailability decreased with increased oral dose (p < 0.00005) for all 3 formulations (MR > ER > IR). Post hoc analyses showed opioid coingestant increased exposure (area under the curve, AUC) by factor of 1.6. Simulations of 100 g vs 10 g doses for IR, ER and MR showed overdose of the ER formulation exhibits slower absorption and lower Cmax, overall exposure (AUC) is less than 80% of an equivalent dose of IR acetaminophen. The overall exposure for the MR formulation is less than 70% of an equivalent dose of IR. CONCLUSIONS: Acetaminophen ER and MR formulations have slower absorption and decreased bioavailability leading to a lower Cmax and later Tmax than the IR formulation. These results have potential clinical implications because delayed absorption could confound use of the Rumack-Matthew nomogram by underestimating the severity of ingestion early in the course of treatment.

Comparing development of liver injury using the two versus three bag acetylcysteine regimen despite early treatment in paracetamol overdose.

INTRODUCTION: Some studies have reported that early administration of acetylcysteine using a 3-bag regimen may not fully prevent development of liver injury in some patients. We compared the incidence of acute liver injury (ALI) in patients receiving acetylcysteine within eight hours of ingestion between the two-bag acetylcysteine regimen (200 mg/kg over four hours, 100 mg/kg over 16 h) and the three-bag regimen (150 mg/kg over 1 h, 50 mg/kg over 4 h, 100 mg/kg over 16 h). METHOD: This was a retrospective cohort study of the two-bag and three-bag acetylcysteine regimens from Monash Health, Victoria, Australia (2009-2020), compared to the three-bag acetylcysteine regimen data from the Canadian Acetaminophen Overdose Study (CAOS) database (1980-2005). The inclusion criteria included patients with an acute single ingestion of paracetamol; normal aminotransferases on presentation and acetylcysteine administered within eight hours post-overdose. The primary outcome was development of ALI (defined as: peak aminotransferase >150 IU/L). RESULTS: At Monash Health, 191 patients were treated with the two-bag acetylcysteine regimen, and 180 patients with the three-bag regimen. The CAOS cohort provided 515 patients treated with the three-bag regimen. ALI developed in 1.6% (3/191) of the two-bag Monash Health group, 2.2% (4/180) of the three-bag Monash Health group (difference -0.6%, p 0.7), and 2.9% (15/515) of the three-bag CAOS group (difference compared to two-bag -1.3%, p 0.4). Hepatotoxicity (ALT >1000) developed in 0.5% (1/191) of patients treated with the two-bag regimen, 1.7% (3/180) in the Monash Health three-bag regimen and 1% (5/515) of the three-bag CAOS group. There were no statistically significant differences between groups. CONCLUSIONS: ALI and hepatotoxicity were observed in a small, comparable percentage of patients despite early acetylcysteine administration using the two-bag and three-bag regimens. Repeating blood tests at the end of acetylcysteine treatment will identify these patients and indicate those requiring continuation of acetylcysteine.

Corrigendum to "Massive Acetaminophen Overdose Treated Successfully with N-Acetylcysteine, Fomepizole, and Hemodialysis".

[This corrects the article DOI: 10.1155/2021/6695967.].

Massive Acetaminophen Overdose Treated Successfully with N-Acetylcysteine, Fomepizole, and Hemodialysis.

Acetaminophen overdose is one of the most common causes of acute hepatic failure in the developed world. There is strong evidence for N-acetylcysteine (NAC) as a safe and effective antidote for acetaminophen toxicity. However, there is less clarity in the management of massive overdoses (acute, single ingestions > 500 mg/kg with 4-hour equivalent concentrations ~6000 µmol/L) which are often associated with metabolic acidosis and multiorgan dysfunction. In such ingestions, the role of adjuvant treatments such as fomepizole and extracorporeal removal is unclear. We present a case of a 20-year-old female presenting with an acute ingestion of over 120 grams (1764.7 mg/kg) and an acetaminophen concentration of 5880 µmol/L who developed refractory shock, decreased level of consciousness, and metabolic acidosis requiring mechanical ventilation and vasopressor support. She was treated with gastric decontamination with activated charcoal, IV NAC, fomepizole, and hemodialysis. The patient had complete clearance of acetaminophen by 32 hours after presentation and normalization of her acid base and hemodynamic status without any organ failure. This case highlights the potential benefit of a triple strategy of NAC, fomepizole, and early hemodialysis in massive acetaminophen overdose, potentially sparing complications of prolonged intubation and ICU hospitalization.

Predicting mortality from acetaminophen poisoning shortly after hospital presentation.

AIMS: Early identification of patients likely to die after acetaminophen (APAP) poisoning remains challenging. We sought to compare the sensitivity and time to fulfilment (latency) of established prognostic criteria. METHODS: Three physician toxicologists independently classified every in-hospital death associated with APAP overdose from eight large Canadian cities over three decades using the Relative Contribution to Fatality scale from the American Association of Poison Control Centres. The sensitivity and latency were calculated for each of the following criteria: King's College Hospital (KCH), Model for End Stage Liver Disease (MELD) ≥33, lactate ≥3.5 mmol/L, phosphate ≥1.2 mmol/L 48+ hours post-ingestion, as well as combinations thereof. RESULTS: A total of 162 in-hospital deaths were classified with respect to APAP as follows: 26 Undoubtedly, 40 Probably, 27 Contributory, 14 Probably not, 25 Clearly not, and 30 Unknown. Cases from the first three classes (combined into n = 93 "APAP deaths") typically presented with supratherapeutic APAP concentrations, hepatotoxicity, acidaemia, coagulopathy and/or encephalopathy, and began antidotal treatment a median of 12 hours (IQR 3.4-30 h) from the end of ingestion. Among all patients deemed "APAP deaths", meeting either KCH or lactate criteria demonstrated the highest sensitivity (94%; 95% CI 86-98%), and the shortest latency from hospital arrival to criterion fulfilment (median 4.2 h; IQR 1.0-16 h). In comparison, the MELD criterion demonstrated a substantially lower sensitivity (55%; 43-66%) and longer latency (52 h; 4.4-∞ h, where "∞" denotes death prior to criterion becoming positive). CONCLUSIONS: Meeting either KCH or serum lactate criteria identifies most patients who die from acetaminophen poisoning at or shortly after hospital presentation.

Identification of high-impact gene-drug pairs for pharmacogenetic testing in Alberta, Canada.

OBJECTIVES: To facilitate decision-making and priority-setting related to Alberta's Pharmacogenomics (PGx) testing implementation strategy by identifying gene-drug pairs with the highest potential impact on prescribing practices in Alberta. PATIENTS AND METHODS: Annual drug dispensing data for Alberta from 2012 to 2016 for 57 medications with PGx-based prescribing guidelines were obtained, along with population estimates and demographics (age and ethnicity). Frequencies of actionable PGx genotypes by ethnicity were obtained from the Pharmacogenomics Knowledgebase (PharmGKB). Annual dispensing activity for each of the 57 medications was calculated for the full population (all ages) and children/youth (0-19 years). Alberta ethnicity data were cross-referenced with genetic frequency data for each of the main ethnic groups from PharmGKB to estimate the proportion of individuals with actionable genotypes. Actionable genotype proportions and drug dispensing frequencies were collectively used to identify high impact gene-drug pairs. RESULTS: We found (a) half of the drugs with PGx-based prescribing guidelines, namely, analgesics, proton pump inhibitors, psychotropics, and cardiovascular drugs, were dispensed at high frequencies (>1% of the entire population), (b) the dispensing rate for about one-third of these drugs increased over the 5-year study period, (c) between 1.1 and 45% of recipients of these drugs carried actionable genotypes, and (d) the gene-drug pairs with greatest impact in Alberta predominatly included CYP2C19 or CYP2D6. CONCLUSIONS: We uncovered specific patterns in drug dispensing and identified important gene-drug pairs that will inform the planning and development of an evidenced-based PGx testing service in Alberta, Canada. Adaptation of our approach may facilitate the process of evidence-based PGx testing implementation in other jurisdictions.

Outcomes After Recurrent Intentional Methanol Exposures Not Treated With Alcohol Dehydrogenase Inhibitors Or Hemodialysis.

BACKGROUND: Relying on a treatment threshold for methanol poisoning of 20 mg/dL (6.2 mmol/L) as a stand-alone criterion may lead to unnecessary and invasive treatment because it is likely too conservative, especially for patients with repeated, intentional methanol exposures. OBJECTIVE: We investigated how often patients with recurrent intentional methanol exposures above this threshold developed biochemical or overt clinical toxicity despite not being treated with either an alcohol dehydrogenase inhibitor (ADHi) or hemodialysis. METHODS: We identified patients with ≥3 methanol-related emergency visits from 2002 to 2015 and selected every visit in which neither ADHi nor hemodialysis were administered despite serum methanol >20 mg/dL but neither metabolic acidosis nor end organ toxicity at presentation. The primary outcome was the incidence of visual deterioration or death. RESULTS: Four patients accounted for the 17 visits that met inclusion criteria. All exposures were intentional substance misuse, and 7 of 17 were via inhalation (i.e., huffing). Initial methanol concentrations ranged from 22 mg/dL to 35 mg/dL (7-11 mmol/L). Four of these 17 visits had undetectable initial ethanol concentrations at presentation, including 1 with an initial methanol concentration of 35 mg/dL. No patients developed visual deterioration, and all were known to have survived the exposure. CONCLUSION: Following recurrent, intentional methanol exposure, isolated serum methanol concentrations as high as 35 mg/dL (11 mmol/L) appear to be well-tolerated without treatment in the absence of metabolic acidosis or end-organ toxicity. To better define the methanol treatment threshold, prospective studies are warranted in which patients are followed closely while fomepizole is withheld.

Resident Physician Wellness Curriculum: A Study of Efficacy and Satisfaction.

Background Recent literature highlights the alarming prevalence of burnout, depression, and illness during residency training; a trend that is also linked to suboptimal patient care. Dedicated wellness curricula may be one solution to this concerning issue. Purpose To determine the effect of a multi-faceted wellness curriculum during emergency medicine residency training on wellness scores and to assess resident satisfaction with the program. Methods This study was conducted via a longitudinal survey. In 2009, a faculty-derived resident wellness curriculum (F-RWC) was initiated. This program was then bolstered with a parallel resident-derived curriculum (R-RWC) one year later, in 2010. Emergency medicine residents were surveyed in 2009, 2010, and 2011 to assess wellness at baseline, after one year of the F-RWC, and after one year of combined RWCs, respectively. Surveys included two validated assessment instruments (the Brief Resident Wellness Profile (BRWP) and the SF-8TM Health Survey), a satisfaction Likert scale, and a demographics information sheet. Results The survey response rates were 89% (n=17), 100% (n=17), and 83% (n=24) from 2009, 2010, and 2011, respectively, for a total of 58 participants. From baseline in 2009, there was a significant improvement in resident wellness, with the addition of parallel RWC by 2011, as measured by the BRWP (p=0.024). The faces scale, a subset of the BRWP, showed a trend toward benefit but did not reach statistical significance (p=0.085). There was no evidence of a statistically significant change in SF-8TM scores over time. Participants consistently reported positive satisfaction scores with RWC initiatives. Conclusions Dedicated RWC, with input from both faculty and resident physicians, improved wellness during residency training with a high degree of participant satisfaction. Such programs are needed to support resident physicians during their training.

Changing nomogram risk zone classification with serial testing after acute acetaminophen overdose: a retrospective database analysis.

CONTEXT: The Rumack-Matthew nomogram stratifies patients into discrete risk zones following acetaminophen (APAP) overdose. Treatment decisions have traditionally been based on the initial risk zone. "Line-crossing" between zones occurs and is poorly understood. The study objective was to characterize line-crossing behavior in acute APAP overdose patients, especially moving from below to above the nomogram treatment threshold. METHODS AND MATERIALS: The study was a secondary analysis of the Canadian Acetaminophen Overdose Study (CAOS) database, a large medical record review of patients hospitalized in eight large Canadian cities (1980-2005) following APAP poisoning. Population consisted of acute APAP overdose patients with at least two serum concentrations performed during hospitalization. Using ordinal logistic regression, we studied the effects of patient demographics, ingestion size/timing, APAP concentrations, time to N-acetylcysteine (NAC), and co-ingestants on a three-level dependent variable: patients whose risk increased two or more zones, those remaining in the same or adjacent zone, and those whose risk fell by two or more zones. RESULTS: Of the 3201 eligible hospitalizations with 7705 APAP concentrations, half (1679, 52.5%) crossed at least one zone (up or down) within 24 h of acute ingestion, including 190 (5.9%), who crossed at least two lines into a higher risk zone, and 516 (16.1%) at least two lines into a lower risk zone. Of the 1251 patients initially below the nomogram treatment line of 150 µg/mL, 131 (10.8%) patients crossed above this line. Being older, male, and co-ingesting opioids, antimuscarinics, or NSAIDs were independently associated with line-crossing. CONCLUSIONS: Patients commonly crossed nomogram risk zones, including from below to above the current treatment threshold. These findings support recommendations for serial APAP testing until the individual risk of hepatic injury is clearly established.

Correction to: Anaphylactoid Reactions to Intravenous N-Acetylcysteine during Treatment for Acetaminophen Poisoning.

The original article has been corrected. Table 4 in PDF version of this article has been corrected since the original publication of the article because the first column of numbers (under the heading "Female") in the original PDF version was typeset poorly.

Anaphylactoid Reactions to Intravenous N-Acetylcysteine during Treatment for Acetaminophen Poisoning.

BACKGROUND: Anaphylactoid reactions to intravenous (IV) N-acetylcysteine (NAC) are well-recognized adverse events during treatment for acetaminophen (APAP) poisoning. Uncertainty exists regarding their incidence, severity, risk factors, and management. We sought to determine the incidence, risk factors, and treatment of anaphylactoid reactions to IV NAC in a large, national cohort of patients admitted to hospital for acetaminophen overdose. METHODS: This retrospective medical record review included all patients initiated on the 21-h IV NAC protocol for acetaminophen poisoning in 34 Canadian hospitals between February 1980 and November 2005. The primary outcome was any anaphylactoid reaction, defined as cutaneous (urticaria, pruritus, angioedema) or systemic (hypotension, respiratory symptoms). We examined the incidence, severity and timing of these reactions, and their association with patient and overdose characteristics using multivariable analysis. RESULTS: An anaphylactoid reaction was documented in 528 (8.2%) of 6455 treatment courses, of which 398 (75.4%) were cutaneous. Five hundred four (95.4%) reactions occurred during the first 5 h. Of 403 patients administered any medication for these reactions, 371 (92%) received an antihistamine. Being female (adjusted OR 1.24 [95%CI 1.08, 1.42]) and having taken a single, acute overdose (1.24 [95%CI 1.10, 1.39]) were each associated with more severe reactions, whereas higher serum APAP concentrations were associated with fewer reactions (0.79 [95%CI 0.68, 0.92]). CONCLUSION: Anaphylactoid reactions to the 21-h IV NAC protocol were uncommon and involved primarily cutaneous symptoms. While the protective effects of higher APAP concentrations are of interest in understanding the pathophysiology, none of the associations identified are strong enough to substantially alter the threshold for NAC initiation.

PHArmacists' perspective oN the Take hOme naloxone prograM (The PHANTOM Study).

OBJECTIVE: To evaluate pharmacists' attitudes toward the Take Home Naloxone (THN) program and identify areas that could be improved to support pharmacists' involvement. METHODS: Pharmacists on the Alberta College of Pharmacists' directory were invited to complete an online survey between July 10 and August 8, 2016. The survey consisted of 19 questions. Descriptive statistics were used to analyze the data. RESULTS: Four hundred seventy pharmacists completed the survey (response rate = 11.2%). A total of 76.8% of respondents strongly agreed or agreed that pharmacists should be screening patients to identify those at risk of opioid overdose. Full-time pharmacists were more likely to agree (p = 0.02). A total of 79.8% of respondents strongly agreed or agreed that pharmacists should be recommending THN kits. Pharmacists working in large population centres (p = 0.008) and full-time pharmacists (p = 0.02) were more likely to agree with this statement. Furthermore, 60.6% of pharmacists were extremely willing or very willing to participate in the THN program. Pharmacists in practice for ≤15 years were more willing to participate in the THN program than pharmacists in practice >15 years (p = 0.03). The most common perceived barriers to implementation of the THN program were lack of time in pharmacists' current work environment and education about the program. CONCLUSIONS: Overall, pharmacists had positive attitudes toward screening patients to identify those at risk of opioid overdose, recommending THN kits and willingness to participate in the program. Factors that may facilitate increased participation in the program include addressing time issues and improving education about the THN program.

Alberta's provincial take-home naloxone program: A multi-sectoral and multi-jurisdictional response to overdose.

SETTING: Alberta is a prairie province located in western Canada, with a population of approximately 4.3 million. In 2016, 363 Albertans died from apparent drug overdoses related to fentanyl, an opioid 50-100 times more toxic than morphine. This surpassed the number of deaths from motor vehicle collisions and homicides combined. INTERVENTION: Naloxone is a safe, effective, opioid antagonist that may quickly reverse an opioid overdose. In July 2015, a committee of community-based harm reduction programs in Alberta implemented a geographically restricted take-home naloxone (THN) program. The successes and limitations of this program demonstrated the need for an expanded, multi-sectoral, multi-jurisdictional response. The provincial health authority, Alberta Health Services (AHS), used previously established incident command system processes to coordinate implementation of a provincial THN program. OUTCOMES: Alberta's provincial THN program was implemented on December 23, 2015. This collaborative program resulted in a coordinated response across jurisdictional levels with wide geographical reach. Between December 2015 and December 2016, 953 locations, including many community pharmacies, registered to dispense THN kits, 9572 kits were distributed, and 472 reversals were reported. The provincial supply of THN kits more than tripled from 3000 to 10 000. IMPLICATIONS: Alberta was uniquely poised to deliver a large, province-wide, multi-sectoral and multi-jurisdictional THN program as part of a comprehensive response to increasing opioid-related morbidity and mortality. The speed at which AHS was able to roll out the program was made possible by work done previously and the willingness of multiple jurisdictions to work together to build on and expand the program.

A cohort study of unstable overdose patients treated with intravenous lipid emulsion therapy.

OBJECTIVES: Intravenous lipid emulsion (ILE) has been used increasingly over the last decade for a range of drug overdoses. Although the use of ILE in local anesthetic toxicity (LAST) is well established, the hemodynamic effectiveness of ILE in non-LAST poisonings is still unclear. Thus, the primary objective of this study was to examine a cohort of poisoned patients in whom ILE was administered. METHODS: Consecutive patients were identified by calls to a regional poison center from May 1, 2012 to May 30, 2014. Patients were enrolled if they ingested a drug, developed hemodynamic instability, failed conventional treatment, and received ILE therapy. Data were collected by medical record review. The primary outcome was the change in mean arterial pressure (MAP) in the first hour after ILE administration. Secondary outcomes included survival, length of stay, and the effect of drug class on patient outcome. RESULTS: Thirty-six patients were enrolled. Agents ingested included calcium channel blockers and beta blockers (10/36, 27.8%), tricyclic antidepressants (5/36, 13.9%), bupropion (3/36, 8.3%), and antiepileptic agents (1/36, 2.8%). Seventeen patients (47.2%) ingested multiple agents. Twenty-five patients survived (69.0%). Overall, MAP increased by 13.79 mm Hg (95% CI 1.43-26.15); this did not meet our a priori definition of clinical significance. CONCLUSIONS: Our study did not find a clinically important improvement in MAP after ILE administration. Until future research is done to more definitively study its efficacy, ILE should remain a potential treatment option for hemodynamically unstable overdose patients only after conventional therapy has failed.

Can a serum acetaminophen concentration obtained less than 4 hours post-ingestion determine which patients do not require treatment with acetylcysteine?

CONTEXT: The interpretation of acetaminophen concentrations obtained prior to 4 hours after an acute, single overdose remains unclear. Patient care decisions in the Emergency Department could be accelerated if such concentrations could reliably exclude the need for treatment. OBJECTIVE: To determine the agreement between a serum acetaminophen concentration obtained less than 4 hours after an acute ingestion and the subsequent 4 + hour concentration, and the predictive accuracy of early concentrations for identifying patients with potentially toxic exposures. METHODS: A secondary analysis of patients admitted for acetaminophen poisoning at one of the 34 hospitals in eight Canadian cities from 1980 to 2005. We examined serum acetaminophen concentrations obtained less than 4 hours post-ingestion, and again 4 or more hours post-ingestion. For the diagnostic accuracy analysis, we specified a cutpoint of 100 µg/mL (662 µmol/L) obtained between 2 and 4 hours and a subsequent 4 to 20 hour acetaminophen concentration above the nomogram treatment line of 150 µg/mL (993 µmol/L). RESULTS: Of 2454 patients identified, 879 (36%) had a subsequent acetaminophen concentration above the nomogram treatment line. The 2-4 hour concentration demonstrated a sensitivity of 0.96 [95% CI; 0.94, 0.97] and a negative likelihood ratio of 0.070 [0.048, 0.10]. Coingested opioids reduced this sensitivity to 0.91 [0.83, 0.95], and antimuscarinics to 0.86 [0.72, 0.94]. Only very low to undetectable acetaminophen concentrations prior to 4 hours reliably excluded a subsequent concentration over the treatment line. CONCLUSIONS: Applying an acetaminophen concentration cutpoint of 100 µg/mL (662 µmol/L) at 2-4 hours after an acute ingestion as a threshold for repeat testing and/or treatment would occasionally miss potentially toxic exposures. Absorption of acetaminophen is only slightly delayed by coingested opioids or antimuscarinics. Our analysis validates the practice of not retesting when the first post-ingestion acetaminophen concentration is below the lower limit of quantification.