Medical management of paraquat ingestion Gawarammana, Indika B.; Buckley, Nicholas A.
British journal of clinical pharmacology,
November 2011, Letnik:
72, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Poisoning by paraquat herbicide is a major medical problem in parts of Asia while sporadic cases occur elsewhere. The very high case fatality of paraquat is due to inherent toxicity and lack of ...effective treatments. We conducted a systematic search for human studies that report toxicokinetics, mechanisms, clinical features, prognosis and treatment. Paraquat is rapidly but incompletely absorbed and then largely eliminated unchanged in urine within 12–24 h. Clinical features are largely due to intracellular effects. Paraquat generates reactive oxygen species which cause cellular damage via lipid peroxidation, activation of NF‐κB, mitochondrial damage and apoptosis in many organs. Kinetics of distribution into these target tissues can be described by a two‐compartment model. Paraquat is actively taken up against a concentration gradient into lung tissue leading to pneumonitis and lung fibrosis. Paraquat also causes renal and liver injury. Plasma paraquat concentrations, urine and plasma dithionite tests and clinical features provide a good guide to prognosis. Activated charcoal and Fuller's earth are routinely given to minimize further absorption. Gastric lavage should not be performed. Elimination methods such as haemodialysis and haemoperfusion are unlikely to change the clinical course. Immunosuppression with dexamethasone, cyclophosphamide and methylprednisolone is widely practised, but evidence for efficacy is very weak. Antioxidants such as acetylcysteine and salicylate might be beneficial through free radical scavenging, anti‐inflammatory and NF‐κB inhibitory actions. However, there are no published human trials. The case fatality is very high in all centres despite large variations in treatment.
Hump-nosed pit viper (HNV; Hypnale spp.) bites account for most venomous snakebites in Sri Lanka. Acute kidney injury (AKI) is the most serious systemic manifestation (1-10%) following HNV ...envenoming. We aimed to identify the value of functional and injury biomarkers in predicting the development of AKI early following HNV bites.
We conducted a prospective cohort study of patients with confirmed HNV envenoming presenting to two large tertiary care hospitals in Sri Lanka. Demographics, bite details, clinical effects, complications and treatment data were collected prospectively. Blood and urine samples were collected from patients for coagulation and renal biomarker assays on admission, at 0-4h, 4-8h, 8-16h and 16-24h post-bite and daily until discharge. Follow-up samples were obtained 1 and 3 months post-discharge. Creatinine (sCr) and Cystatin C (sCysC) were measured in serum and kidney injury molecule-1 (uKIM-1), clusterin (uClu), albumin (uAlb), β2-microglobulin (uβ2M), cystatin C (uCysC), neutrophil gelatinase associated lipocalin (uNGAL), osteopontin (uOPN) and trefoil factor-3 (uTFF-3) were measured in urine. Definite HNV bites were based on serum venom specific enzyme immunoassay. Kidney Disease: Improving Global Outcomes (KDIGO) criteria were used to stage AKI. Two patients had chronic kidney disease at 3 month follow-up, both with pre-existing abnormal sCr, and one developed AKI following HNV envenoming.
There were 52 patients with confirmed HNV envenoming; median age 48y (Interquartile range IQR:40-59y) and 29 (56%) were male. Median time to admission was 1.87h (IQR:1-2.75h). Twelve patients (23%) developed AKI (AKI stage 1 = 7, AKI stage 2 = 1, AKI stage 3 = 4). Levels of five novel biomarkers, the functional marker serum Cystatin C and the damage markers urinary NGAL, cystatin C, β2-microglobulin and clusterin, were elevated in patients who developed moderate/severe acute kidney injury. sCysC performed the best at 0-4 h post-bite in predicting moderate to severe AKI (AUC-ROC 0.95;95%CI:0.85-1.0) and no biomarker performed better than sCr at later time points.
sCysC appears to be a better marker than sCr for early prediction of moderate to severe AKI following HNV envenoming.
Many countries have recently legalized medicinal and recreational cannabis. With increasing use and access come the potential for harms. We aimed to examine the effect of cannabis ...legalization/decriminalization on acute poisoning.
A systematic review and meta-analysis registered with PROSPERO (CRD42022323437). We searched Embase, Medline, Scopus and Cochrane Central Register of Controlled Trials from inception to March 2022. No restrictions on language, age or geography were applied. Abstracts from three main clinical toxicology conferences were hand-searched. Included studies had to report on poisonings before and after changes in cannabis legislation, including legalization and decriminalization of medicinal and recreational cannabis. Where possible, relative risk (RR) of poisoning after legalization (versus before) was calculated and pooled. Risk of bias was assessed with ROBINS-I.
Of the 1065 articles retrieved, 30 met inclusion criteria (including 10 conference abstracts). Studies used data from the United States, Canada and Thailand. Studies examined legalization of medicinal cannabis (n = 14) and decriminalization or legalization of recreational cannabis (n = 21). Common data sources included poisons centre records (n = 18) and hospital presentations/admissions (n = 15, individual studies could report multiple intervention types and multiple data sources). Most studies (n = 19) investigated paediatric poisoning. Most (n = 24) reported an increase in poisonings; however, the magnitude varied greatly. Twenty studies were included in quantitative analysis, with RRs ranging from 0.81 to 29.00. Our pooled estimate indicated an increase in poisoning after legalization RR = 3.56, 95% confidence interval (CI) = 2.43-5.20, which was greater in studies that focused on paediatric patients (RR = 4.31, 95% CI = 2.30-8.07).
Most studies on the effect of medicinal or recreational cannabis legalization/decriminalization on acute poisoning reported a rise in cannabis poisoning after legalization/decriminalization. Most evidence is from US legalization, despite legalization and decriminalization in many countries.
The spectrum of anticholinergic delirium is a common complication following drug overdose. Patients with severe toxicity can have significant distress and behavioural problems that often require ...pharmacological management. Cholinesterase inhibitors, such as physostigmine, are effective but widespread use has been limited by concerns about safety, optimal dosing and variable supply. Case series support efficacy in reversal of anticholinergic delirium. However doses vary widely and higher doses commonly lead to cholinergic toxicity. Seizures are reported in up to 2.5% of patients and occasional cardiotoxic effects are also recorded.
This article reviews the serendipitous path whereby physostigmine evolved into the preferred anticholinesterase antidote largely without any research to indicate the optimal dosing strategy. Adverse events observed in case series should be considered in the context of pharmacokinetic/pharmacodynamic studies of physostigmine which suggest a much longer latency before the maximal increase in brain acetylcholine than had been previously assumed. This would favour protocols that use lower doses and longer re‐dosing intervals. We propose based on the evidence reviewed that the use of cholinesterase inhibitors should be considered in anticholinergic delirium that has not responded to non‐pharmacological delirium management. The optimal risk/benefit would be with a titrated dose of 0.5 to 1 mg physostigmine (0.01–0.02 mg kg−1 in children) with a minimum delay of 10–15 min before re‐dosing. Slower onset and longer acting agents such as rivastigmine would also be logical but more research is needed to guide the appropriate dose in this setting.
Naloxone is the usual drug used in opioid-induced respiratory depression but it has a short half-life, precipitates withdrawal in dependent patients, and thus for persistent reversal of long-acting ...opioids has to be given by titrated doses and infusions. The partial agonist buprenorphine has a much longer duration of action and causes less severe withdrawal, but still should largely reverse respiratory depression induced by full agonist opioids. We aimed to compare the efficacy/safety of buprenorphine and naloxone in reversing respiratory depression in methadone-poisoned opioid-dependent patients.
Patients with methadone-induced respiratory depression were randomized to receive naloxone (titrated doses), or lower or higher doses of buprenorphine (10 μg/kg or 15 μg/kg). The primary outcome was immediate reversal of respiratory depression. We also recorded acute opioid withdrawal, need for intubation/recurrent apnea, repeated doses of opioid antagonists, length of hospital stay, other morbidity, and mortality. The study was registered with the Iranian Registry of Clinical Trials (Trial ID: 18265; Approval code: IRCT2015011020624N1).
Eighty-five patients were randomized; 55/56 patients who received buprenorphine had rapid reversal of respiratory depression, which persisted for at least 12 h. Naloxone was effective in 28/29 patients, but often required very high titrated doses (thus delaying time to respond) and prolonged infusions. Intubation (8/29 vs 5/56) and opioid withdrawal (15/29 vs 7/56) were less common with buprenorphine. There were no serious complications or deaths in those receiving buprenorphine. The 15-μg/kg buprenorphine dose appeared to provide a longer duration of action, but precipitated withdrawal more frequently than the 10-μg/kg dose.
Buprenorphine appears to be a safe and effective substitute for naloxone in overdosed opioid-dependent patients. Further studies are warranted to explore the optimal dosing strategy for buprenorphine to consistently maintain reversal of respiratory depression but not precipitate withdrawal.
IRCT2015011020624N1. Registered 30 September 2015.
Background and aims
Pregabalin is a gamma‐aminobutyric acid (GABA) analogue, used to treat neuropathic pain and epilepsy. Pregabalin was registered in Australia in 2005, and subsidized publically in ...2013. We aimed to describe Australian patterns of pregabalin use and intentional poisoning, and identify people potentially at high risk of misuse.
Design and setting
Population‐based retrospective cohort study of dispensings in the 10% sample of Australian Pharmaceutical Benefits Scheme (July 2012–February 2017); intentional poisoning calls to New South Wales Poisons Information Centre (NSWPIC) (2004–2016); intentional poisonings in two Australian toxicology service databases; and poisoning fatalities in NSW coronial records (2005–2016).
Participants
A total of 122 572 people dispensed pregabalin, people with intentional pregabalin overdoses managed by NSWPIC and the toxicology services and pregabalin‐associated deaths referred to the NSW coroner.
Measurements
Trends in dispensing, poisoning, death; demographics and patient characteristics, proportion of users at high risk of misuse (latent class analysis, LCA) and characteristics of high‐risk users.
Findings
Pregabalin dispensing increased by 73 424 per year 95% confidence interval (CI) = 61726–85 121 P < 0.001 between 2013 and 2016. NSWPIC received 1158 reports of intentional pregabalin poisonings, with a 53.8% increase per year, 2005–2016 (95% CI = 44.0–64.2%, P < 0.001). We identified 88 pregabalin‐associated deaths, 57.8% yearly increase (95% CI = 30.0–91.6%, P < 0.001). Patients overdosing on pregabalin commonly co‐ingested opioids, benzodiazepines and illicit drugs, and had high rates of psychiatric and substance use comorbidities; 14.7% of pregabalin users were classed by the LCA as at high risk of misuse, and were more likely to be younger, male, co‐prescribed benzodiazepines or opioids, have more individual prescribers and higher pregabalin strengths dispensed.
Conclusions
There has been a dramatic increase in pregabalin use, poisonings and deaths in Australia since it became subsidized publicly in 2013. One in seven Australians dispensed pregabalin appears to be at high risk of misuse.
•In Australia, codeine was rescheduled from over-the-counter to prescription only in 2018.•Codeine rescheduling appears to have reduced paracetamol poisoning-related hospital admissions.•This ...reduction was due to decrease in poisonings with likely paracetamol-codeine combinations.
Codeine was restricted to prescription only in Australia in 2018. This intervention aimed to reduce harms from codeine dependance and use, including toxicity from co-formulated paracetamol. We aimed to quantify the impact of this intervention on paracetamol poisoning hospital admissions in a national hospital admissions database.
We analyzed the number of paracetamol overdoses resulting in hospital admissions from the Australian Institute of Health and Welfare National Hospital Morbidity Database, January 2011 to June 2020. We used interrupted time series analysis to quantify the effect of codeine re-scheduling on the monthly number of paracetamol poisoning-related hospital admissions in Australia. We compared paracetamol poisonings with no opioid combinations, and poisonings with probable paracetamol-codeine combinations.
There was an immediate and sustained decrease (level shift) in the number of paracetamol poisoning-related hospital admissions following codeine re-scheduling (RR=0.85; 95% CI 0.80–0.89). This reduction was due to the decrease in poisonings with likely paracetamol-codeine combinations (RR=0.62; 95% CI 0.57–0.67) while there was no change in other paracetamol poisonings (RR=0.91; 95% CI 0.96–1.01).
Codeine re-scheduling in Australia appears to have reduced paracetamol poisoning-related hospital admissions.
Serotonin syndrome (toxicity) describes adverse drug effects from toxic amounts of intra-synaptic central nervous system serotonin. A wide range of drugs have been implicated to cause serotonin ...toxicity, not all justifiably. The plausible agents all have a final common pathway resulting in a substantial increase in central nervous system serotonergic neurotransmission. Serotonin toxicity is characterized by neuromuscular excitation, mental status changes, and autonomic dysregulation. Signs and symptoms represent a spectrum of toxicity (mild to life-threatening) related to increasing serotonin concentrations. As there is no consensus on the threshold for "toxicity" or diagnostic criteria, the true incidence of serotonin toxicity is unknown. The incidence in overdose is easier to quantify and is reasonably common in serotonergic antidepressant overdoses. In a large case series of overdoses, moderate serotonin toxicity occurred in 14% of poisonings with a selective serotonin reuptake inhibitor. While half those ingesting a monoamine oxidase inhibitor in combination with a serotonergic agent in overdose exhibit at least moderately severe serotonin toxicity. In contrast, the incidence of serotonin toxicity in those on therapeutic serotonergic agents appears to be very low.
To provide a narrative review of the current diagnostic criteria, utilizing case reports of fatalities to evaluate how many meet the various diagnostic criteria and propose practical solutions to resolve controversies in diagnosis.
A review of serotonin toxicity diagnostic criteria in the English literature was completed by searching Embase and PubMed from January 1990 to July 2021 for the keywords "serotonin syndrome/toxicity" paired with "diagnostic criteria" or "diagnosis." Also, fatal cases of serotonin toxicity identified from a recent systematic review were independently examined to determine what diagnostic criteria were met and whether serotonin toxicity or another cause was most likely.
Serotonin toxicity is a clinical diagnosis, four diagnostic criteria (Sternbach, Serotonin Syndrome Scale, Radomski, and Hunter) have been proposed. However, the Serotonin Syndrome Scale has not been validated in patients with serotonin toxicity and only utilized in those on a serotonergic agent. The remaining three criteria are utilized more widely but have undergone little refinement or validation.
Shortfalls with diagnostic criteria can be illustrated by examining case fatalities. Of 55 fatal cases reviewed, 12 (22%) were unlikely to be serotonin toxicity. Sternbach and Radomski criteria were met by 25 (45%), 20 (36%) had insufficient data reported and 10 (18%) met an exclusion criterion. Few had sufficient information reported to determine whether Hunter Criteria were met, with only 13 (24%) documented as meeting the criteria, the remaining 42 (76%) had insufficient data.
As serotonin toxicity is a clinical diagnosis, issues arise when basing the diagnosis on symptom criteria alone, without considering whether the drug/s ingested increase central nervous system serotonin or whether there is an alternative diagnosis. This has resulted in case reports and government warnings for drugs that cannot plausibly cause significant serotonin toxicity (e.g., ondansetron and antipsychotics). We propose when assessing for a serotonin toxidrome, both the causative agent(s) and clinical scenario is considered to determine the likelihood of serotonin toxicity. Then the clinical features assessed, those with a moderate to high prior probability (e.g., serotonergic drug-drug interaction, overdose, recent initiation or increase in dose of serotonergic agent/s) could be diagnosed based on the Hunter criteria. However, those with a low probability (e.g., stable therapeutic doses of a serotonergic agent) require more specific and stringent criteria. Finally, we propose a minimum dataset for case reports/series of serotonin toxicity.
More complete and accurate reporting of serotonin toxicity cases is required in the future, to avoid further misleading associations that are physiologically implausible.
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