The Clinical Toxicology Recommendations Collaborative: purpose, organization, and methodology.

INTRODUCTION: Scientific societies aim to provide a collective voice and unified stance on important issues. The Clinical Toxicology Recommendations Collaborative was formed in 2016 to develop evidence- and consensus-based recommendations for the management of patients exposed to common and/or serious poisonings for which the management is unclear or controversial. ORGANIZATION: The Clinical Toxicology Recommendations Collaborative is led jointly by the American Academy of Clinical Toxicology, the Asia Pacific Association of Medical Toxicology, and the European Association of Poison Centres and Clinical Toxicologists. The Governance Committee is chaired by a Past-President of one of these Societies and comprised of the six Presidents and Immediate Past-Presidents of the three Societies. A Steering Committee oversees the process of each project workgroup. METHODOLOGY: The overall process is guided by standards set forth by the Institute of Medicine for developing trustworthy guidelines and the Appraisal of Guidelines for Research and Evaluation Instrument. Systematic reviews are produced using the framework set in the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) methodology. Workgroup members jointly review the evidence and prepare statements on which they vote anonymously using a 9-point Likert scale. A two-round modified Delphi method is used to reach a consensus on clinical recommendations using the RAND/UCLA Appropriateness Method. Final recommendations are approved by unanimous consent of the workgroup and are expressed as both levels of evidence and strength of recommendations. LIMITATIONS: The major limitations of the Clinical Toxicology Recommendations Collaborative process centre around the amount and quality of evidence, the assessment of that evidence, and the voting of the panel. CONCLUSIONS: By using a transparent evidence- and consensus-based approach to produce systematic reviews and clinical recommendations, the Clinical Toxicology Recommendations Collaborative aims to create an international framework for clinical toxicology education and decision-making and foster positive change for the benefit of poisoned patients.

Vaccine effectiveness of BNT162b2 and CoronaVac against SARS-CoV-2 omicron infection and related hospital admission among people with substance use disorder in Hong Kong: a matched case-control study.

BACKGROUND: People with substance use disorder have a high risk of SARS-CoV-2 infection and subsequent poor outcomes. Few studies have evaluated COVID-19 vaccine effectiveness among people with substance use disorder. We aimed to estimate the vaccine effectiveness of BNT162b2 (Fosun-BioNTech) and CoronaVac (Sinovac) against SARS-CoV-2 omicron (B.1.1.529) infection and related hospital admission in this population. METHODS: We did a matched case-control study using electronic health databases in Hong Kong. Individuals diagnosed with substance use disorder between Jan 1, 2016, and Jan 1, 2022, were identified. People aged 18 years and older with SARS-CoV-2 infection from Jan 1 to May 31, 2022, and people with COVID-19-related hospital admission from Feb 16 to May 31, 2022, were included as cases and were matched by age, sex, and previous clinical history with controls from all individuals diagnosed with substance use disorder who attended the Hospital Authority health services: up to three controls for SARS-CoV-2 infection and up to ten controls for hospital admission. Conditional logistical regression was used to evaluate the association between vaccination status (ie, one, two, or three doses of BNT162b2 or CoronaVac) and the risk of SARS-CoV-2 infection and COVID-19-related hospital admission, adjusted for baseline comorbidities and medication use. FINDINGS: Among 57 674 individuals with substance use disorder, 9523 people with SARS-CoV-2 infections (mean age 61·00 years, SD 14·90; 8075 [84·8%] males and 1448 [15·2%] females) were identified and matched to 28 217 controls (mean age 60·99 years, 14·67; 24 006 [85·1%] males and 4211 [14·9%] females), and 843 people with COVID-19-related hospital admissions (mean age 70·48 years, SD 14·68; 754 [89·4%] males and 89 [10·6%] females) were identified and matched to 7459 controls (mean age 70·24 years, 13·87; 6837 [91·7%] males and 622 [8·3%] females). Data on ethnicity were not available. We observed significant vaccine effectiveness against SARS-CoV-2 infection for two-dose BNT162b2 vaccination (20·7%, 95% CI 14·0-27·0, p<0·0001) and three-dose vaccination (all BNT162b2 41·5%, 34·4-47·8, p<0·0001; all CoronaVac 13·6%, 5·4-21·0, p=0·0015; BNT162b2 booster after two-dose CoronaVac 31·3%, 19·8-41·1, p<0·0001), but not for one dose of either vaccine or two doses of CoronaVac. Significant vaccine effectiveness against COVID-19-related hospital admission was detected after one dose of BNT162b2 vaccination (35·7%, 3·8-57·1, p=0·032), two-dose vaccination (both BNT162b2 73·3%, 64·3 to 80·0, p<0·0001; both CoronaVac 59·9%, 50·2-67·7, p<0·0001), and three-dose vaccination (all BNT162b2 86·3%, 75·6-92·3, p<0·0001; all CoronaVac 73·5% 61·0-81·9, p<0·0001; BNT162b2 booster after two-dose CoronaVac 83·7%, 64·6-92·5, p<0·0001), but not after one dose of CoronaVac. INTERPRETATION: For both BNT162b2 and CoronaVac, two-dose or three-dose vaccination was protective against COVID-19-related hospital admission and the booster dose provided protection against SARS-CoV-2 infection among people with substance use disorder. Our findings confirm the importance of booster doses in this population during the period dominated by the omicron variant. FUNDING: Health Bureau, the Government of the Hong Kong Special Administrative Region.

Derivation and internal validation of a clinical prediction score to predict major effect or death in acute metamfetamine toxicity.

OBJECTIVE: Metamfetamine use can cause serious complications or death. We aimed to derive and internally validate a clinical prediction score to predict major effect or death in acute metamfetamine toxicity. METHODS: We performed secondary analysis of 1,225 consecutive cases reported from all local public emergency departments to the Hong Kong Poison Information Centre between 1 January 2010 and 31 December 2019. We split the entire dataset chronologically into derivation (first 70% of cases) and validation (the remaining 30% of cases) cohorts. Univariate analysis was conducted, followed by multivariable logistic regression in the derivation cohort to identify independent predictors of major effect or death. We developed a clinical prediction score based on the regression coefficients of the independent predictors in the regression model and compared its discriminatory performance with five existing early warning scores in the validation cohort. RESULTS: The MASCOT (Male, Age, Shock, Consciousness, Oxygen, Tachycardia) score was derived based on the six independent predictors: male gender (1 point), age (≥35 years, 1 point), shock (mean arterial pressure <65 mmHg, 3 points), consciousness (Glasgow Coma Scale <13, 2 points), need for supplemental oxygen (1 point), and tachycardia (pulse rate >120 beats/min, 1 point). The score ranges from 0-9, with a higher score indicating higher risk. The area under the receiver operating characteristic curve of the MASCOT score was 0.87 (95% CI 0.81-0.93) in the derivation cohort and 0.91 (95% CI 0.81-1.00) in the validation cohort, with a discriminatory performance comparable with existing scores. CONCLUSIONS: The MASCOT score enables quick risk stratification in acute metamfetamine toxicity. Further external validation is warranted before wider adoption.

Relation of substance use disorders to mortality, accident and emergency department attendances, and hospital admissions: A 13-year population-based cohort study in Hong Kong.

BACKGROUND: The impact of substance use disorders (SUD) in an Asian population has not been fully explored. We aimed to assess the risk of mortality, accident and emergency (A&E) department attendances, and hospital admissions associated with SUD in a population-based cohort study. METHOD: Patients diagnosed with SUD in public A&E departments from 2004 to 2016 (N = 8,423) were identified in the Clinical Database Analysis and Reporting System of the Hong Kong Hospital Authority and 1:1 matched to patients without SUD by propensity score (N = 6,074 in each group). Relative risks of mortality, A&E attendances and hospital admissions were assessed using Cox regression and Hurdle negative binomial regression. RESULTS: Patients with SUD had higher mortality (hazard ratio=1.43; 95% confidence interval [CI]=1.26-1.62) and more often died from poisoning or toxicity and injuries. The odds ratio (OR) for A&E attendances and all-cause hospital admissions associated with SUD were 2.80 (95% CI=2.58-3.04) and 3.54 (95% CI=3.26-3.83), respectively. The impact of SUD on the above outcomes was greatest among school-aged individuals (≤ 21 years) and decreased with age. The relative risk of mental disorder-related hospital admissions was much higher than that for infections, respiratory diseases, and cardiovascular diseases. In patients with SUD, ketamine and amphetamine use were associated with increased A&E attendances than opioid use. CONCLUSIONS: SUD was associated with increased mortality, A&E attendances and hospital admissions, especially in school-aged individuals. Our findings suggest prioritising early treatment and preventive interventions for school-aged individuals and focusing on the management of comorbid mental disorders and the use of ketamine and amphetamine.

Treatment with Methylphenidate for Attention Deficit Hyperactivity Disorder (ADHD) and the Risk of All-Cause Poisoning in Children and Adolescents: A Self-Controlled Case Series Study.

BACKGROUND: Children and adolescents with attention deficit hyperactivity disorder (ADHD) are at higher risk of all-cause poisoning by drugs and chemicals (intentional or accidental). Currently, there is limited data on whether medication treatment for ADHD can reduce the risk of all-cause poisoning. METHODS: Patients aged 5-18 years with a methylphenidate (MPH) prescription and an incident poisoning diagnosis between January 2001 and June 2020 were identified from the Hong Kong Clinical Data Analysis and Reporting System. A self-controlled case series study design was used to compare the incidence rate ratios (IRRs) of all-cause poisoning during different risk windows (30 days before the first MPH prescription, exposure periods within 30 days of the first prescription, and periods of subsequent exposure) compared with the reference window (other non-exposure periods). RESULTS: 42,203 patients were prescribed ADHD medication in Hong Kong during the study period. Of these, 417 patients who had both an MPH prescription and poisoning incident recorded were included in the main analysis. Compared with other non-exposed periods, a higher risk of poisoning was found in the 30 days before the first prescription (IRR 2.64, 95% confidence interval [CI] 1.33-5.22) and exposure periods within 30 days of the first prescription (IRR 2.18, 95% CI 1.06-4.48), but not during prolonged exposure. However, compared with 30 days before the first prescription as well as exposure periods within 30 days of the first prescription, there was a lower risk during the subsequent exposure (IRRs 0.49 and 0.60, respectively). Similar results to the main analysis were also found in the subgroup analysis of intentional poisoning and females, but not in that of accidental poisoning and males. CONCLUSIONS: The risk of all-cause poisoning was higher shortly before and after the first MPH prescription and became lower during the subsequent prescription period. Our results do not support an association between the use of MPH and an increased risk of all-cause poisoning in children and adolescents and, in fact, suggest that longer-term use of MPH may be associated with a lower risk of all-cause poisoning, although this latter finding requires further study.

Safety profile of snake antivenom (use) in Hong Kong - a review of 191 cases from 2008 to 2015.

INTRODUCTION: The mainstay of treatment for significant envenoming from snakebites is antivenom. However, there is insufficient data regarding the safety of antivenom used in Hong Kong. We describe the incidence of hypersensitivity reactions from antivenom use and review the frequency and reasons for intensive care unit (ICU) admission. METHODS: The Hong Kong Poisons Information Centre database was reviewed. All patients given snake antivenom between 2008 and 2015 were included. Patient demographics, species of snake involved, details of antivenom used, treatment location, use of pre-treatment, reasons for ICU admission (where applicable) and details of early and late antivenom reactions were extracted. RESULTS: There were 191 patients who received snake antivenom. Most (93%) were treated with either the green pit viper antivenom from Thailand or the Agkistrodon halys antivenom from China. The incidences of early hypersensitivity reactions to green pit viper antivenom and Agkistrodon Halys antivenom were 4.7% and 1.4%, respectively. Most patients (69%) were managed in the ED observation ward or general ward. There were 59 patients managed in ICU, most (90%) of whom were admitted for close monitoring during antivenom administration. There were no cases of significant morbidity from antivenom administration. Eight patients (5.6%) had features suggestive of mild serum sickness. CONCLUSIONS: The incidence of immediate hypersensitivity reaction to antivenom commonly used in Hong Kong is low. Majority of patients were managed safely in the emergency department observation ward or general ward. Serum sickness appears to be uncommon and possible cases presented with mild features.

A Public Health Approach in Responding to the Spread of Helium Suicide in Hong Kong.

BACKGROUND: The use of the helium suicide method has been increasing in popularity in Hong Kong since 2012. We have learned a valuable lesson in curbing the spread of charcoal burning (CB) suicide in the past 15 years and hope to prevent the helium suicide method from taking off in the community. AIMS: To document what actions have been taken to contain the spread of the helium suicide method and review the preliminary impact of these actions. METHOD: We adopted a public health approach by engaging stakeholders from multiple sectors, including the police force, the fire services department, coroners, pathologists, mass media, and online media outlets. RESULTS: A monitoring system was established by compiling data extracted from news reports, coroners' reports, and police investigations. Risk and protective factors were identified. Intervention strategies were developed to strengthen protective factors and minimize risk factors. This novel suicide method has not spread as rapidly as the CB suicide method. The preliminary outcomes suggest our actions to be effective. LIMITATIONS: The count of helium suicides in 2015 might be low. The impacts of the interventions are only estimated and require additional empirical verifications. CONCLUSION: The public health approach of engaging multiple partners in the early phase of a potential epidemic can be a good guide to meeting the challenges posed by any new suicide methods that emerge in the future.

Aconite poisoning over 5 years: a case series in Hong Kong and lessons towards herbal safety.

BACKGROUND: Aconite poisoning is a severe, life-threatening poisoning related to the use of traditional Chinese medicine (TCM). Despite current legislation, repeated poisoning cases are steadily encountered. OBJECTIVE: The aim of the study was to summarize the clinical features and to elucidate the causative and contributory factors leading to aconite poisoning. METHODS: This study was conducted within the Hospital Authority Toxicology Reference Laboratory, which is the sole tertiary referral clinical toxicology laboratory in Hong Kong. This retrospective study reviewed all confirmed aconite poisoning cases handled by a clinical toxicology laboratory between April 2004 and July 2009. The diagnosis in all cases was confirmed biochemically by detecting aconitum alkaloids in urine specimens. Additionally, herbal specimens were morphologically identified and herbal formulae were studied and transcribed. The cause of poisoning for each case was determined whenever possible. RESULTS: Fifty-two cases were examined in this aconite poisoning case series. Neurological, cardiovascular and gastrointestinal toxicities were encountered in 49 (94.2%), 46 (88.5%) and 31 (59.6%) patients, respectively. The poisoning was severe in 6 (11.5%) patients, moderate in 17 (32.7%) patients and mild in 29 (55.8%) patients. Amongst 44 patients (84.6%) in whom the underlying reasons of poisoning could be determined, four major causes were found. These included overdose - prescription of a higher than recommended dosage of aconite herbs in 17 (32.7%) cases; 'hidden' poisoning (the aconite herb was not prescribed but dispensed inadvertently) in 17 (32.7%) cases; usage of inadequately processed herbs in 7 (13.5%) cases; and dispensary error in 2 (3.9%) cases. No case fatality was recorded. CONCLUSION: In the majority of cases in this series, the causes of poisoning can be traced to poor-quality herbs, poor quality of prescription practice, or dispensary errors. The quality issues of TCM practice should be critically addressed to minimize this poisoning threat.

Prediction of prognosis in acute paraquat poisoning using severity scoring system in emergency department.

OBJECTIVE: The aim of this study was to validate and compare the performance of serum paraquat level, severity index of paraquat poisoning (SIPP), Acute Physiology And Chronic Health Evaluation II (APACHE II), modified Simplified Acute Physiology Score II (MSAPS II), and modified Expanded Simplified Acute Physiology Score II (MSAPS IIe) calculated immediately after arrival on emergency department (ED) for assessing the mortality of acute paraquat poisoning. METHODS: A retrospective study design was employed with the main outcome measure being mortality from year 2001 to 2010. MSAPS II and MSAPS IIe were employed in that assessment of the 24-hour urine output were not included. The performance of APACHE II, MSAPS II, MSAPS IIe, serum paraquat level and SIPP for prediction of mortality in acute paraquat poisoning were compared. RESULTS: A total of 102 patients were enrolled in the study. The area under the ROC curve for APACHE II (0.800) was statistically lower than those for MSAPS II, MSAPS IIe, SIPP and serum paraquat (0.879, 0.893, 0.924,and 0.951, respectively). The Hosmer-Lemeshow goodness-of-fit test C statistic revealed that APACHE II, MSAPS II, MSAPS IIe and serum paraquat level showed good calibrations (chi-square 8.477 and p = 0.388, chi-square 4.614 and p = 0.798, chi-squared 5.301 and p = 0.725, chi-squared 1.009 and p = 0.985 respectively), but poor calibration for SIPP (chi-square 21.293 and p = 0.006). CONCLUSION: Serum paraquat level is still the most reliable prognosis factor in acute paraquat poisoning. But MSAPS II or MSAPS IIe calculated immediately after arrival on ED may be helpful to predict mortality in acute paraquat poisoning especially when hospital has no facility to measure serum paraquat level.

Image in toxicology: Pseudo-subarachnoid hemorrhage in a case of severe valproic acid poisoning.

Pseudo-subarachnoid hemorrhage (PSAH) is a false-positive finding on cranial computed tomography (CT) in patients with cerebral edema. Its appearance on CT resembles subarachnoid hemorrhage despite the absence of subarachnoid blood. We report the finding of PSAH in a case of massive valproic acid overdose.

Causality assessment of herb-induced liver injury using multidisciplinary approach and Roussel Uclaf Causality Assessment Method (RUCAM).

OBJECTIVE: To evaluate an algorithmic approach involving a multidisciplinary team for causality assessment of suspected herb-induced liver injury (HILI) cases and to compare the causality score using this multidisciplinary approach and Roussel Uclaf Causality Assessment Method (RUCAM). METHODS: A team consisting of hepatologist, clinical toxicologist, analytical toxicologist, and Chinese medicine (CM) pharmacist was formed to do causality assessment based on a protocol for suspected HILI cases. The likelihood of the diagnosis of individual case was first assessed systematically by a hepatologist and clinical toxicologist independently after collecting information about four aspects: (1) clinical course, (2) exclusion of alternative causes, (3) quality of the prescription and herbal product by examining the CM prescriptions and analysis of biological and herb samples, (4) scientific support on comprehensive literature review on English and Chinese medical database, and subsequently concluded in a consensus meeting held by the multidisciplinary team. The final causality score of each patient was compared with the likelihood of causality as assessed by RUCAM. RESULTS: Between 2005 and 2007, 48 consecutive patients with suspected HILI were enrolled and 21 patients were excluded due to the establishment of an alternative cause of liver impairment or the lack of any information on the herbs taken. Twenty-seven patients were recruited, among them 15 consumed Chinese herbal medicines, 10 used proprietary Chinese medicinal products, and 2 used both. The concordance between the causality assessment of the hepatologist and clinical toxicologist was moderate (weighted κ = 0.48, 95%CI 0.30-0.66). The causality assessment process concluded that the likelihood of HILI was "highly probable" in 5 cases and "probable" in 12, whereas there were 5 "highly probable" and 16 "probable" cases as assessed by RUCAM. The causality assessment by the multidisciplinary approach and RUCAM also showed moderate agreement (weighted κ= 0.51, 95%CI 0.22-0.81). CONCLUSION: A multidisciplinary approach using defined algorithms is a scientific approach in causality assessment for HILI. Further study is needed to assess its accuracy and applicability.

Liver injury associated with the use of Fructus Psoraleae (Bol-gol-zhee or Bu-gu-zhi) and its related proprietary medicine.

Fructus Psoraleae (FP) is used by herbalists for the treatment of postmenopausal osteoporosis, vitiligo, and psoriasis. It is used alone, or in combination with other herbs, in some countries in the form of proprietary medicine. It is recognized as one of the emerging hepatotoxins and here we report three cases of acute hepatitis after exposed to FP and its related proprietary medicine. It seems possible that psoralen and its related chemicals may be responsible for the hepatotoxicity. Decoction with other herbs may result in higher concentration of toxic constituents and in more severe liver injury. In summary, FP is associated with hepatotoxicity in some individuals. Pharmacovigilance for the potential side effects of herbal products is necessary.

Acute renal failure and hepatitis following ingestion of carp gallbladder.

INTRODUCTION: Fish gallbladder has long been used as folk remedy in China. Poisoning due to carp gallbladder ingestion has been reported in many countries but the majority of cases are in Chinese journals. We report a case of grass carp gallbladder poisoning and review the literature, including the Chinese reports. CASE REPORT: A 67 year old woman ingested a grass carp gallbladder and complained of nausea and epigastric pain in two hours, and had elevated alanine aminotransferase by 8 hours. She developed oliguria on day three and hemodialysis was performed on day five, following which she gradually recovered and was discharged on day 26. DISCUSSION: Carp gallbladder contains 5 alpha-cyprinol sulphate, which is hepatotoxic and nephrotoxic. The exact mechanism of toxicity is unknown. Mild poisoning causes only gastroenteritis, liver and kidneys are affected in moderate poisoning, and multi-organ failure occurs in severe poisoning. The initial symptoms are nausea, vomiting, diarrhea and abdominal pain, which usually occur 5 to 12 hours after ingestion. Raised liver enzymes or jaundice occurs in 75% to 87% of patients. Acute renal impairment occurs in 72% to 87% of patients, usually on day 3 to 6. Treatment is supportive and often included hemodialysis. CONCLUSION: The ingestion of grass carp gallbladder may result in transient hepatitis with subsequent acute renal failure. This case also illustrated the importance of understanding the use and potential serious complications of alternative medicines. Fish gallbladder poisoning should be considered in unexplained acute renal failure in Chinese and Asian patients.