Extracorporeal treatments in poisonings from four non‐traditionally dialysed toxins (acetaminophen,digoxin, opioids and tricyclic antidepressants): A combined single‐centre and national study

The use of extracorporeal treatments (ECTRs) for poisonings with four non‐traditionally dialysed toxins (NTDTs) is increasing in the United States. This study evaluated whether ECTRs are prescribed for toxin removal or the treatment of other medical illnesses or complications. We performed a 2‐Phase retrospective analysis evaluating the main indication for ECTRs in patients with poisoning from a NTDT (defined for this study as acetaminophen, opioids, tricyclic antidepressants (TCAs) or digoxin) and ECTR. The first phase assessed all cases from a single site (New York City Poison Control Center) between the years 2000 and 2016, and the second phase surveyed all United States Poison Control Centers (PCCs). In Phase 1, demographics, toxin ingested and main indication for ECTR were extracted. In Phase 2, a query to the National Poison Data System using the a pragmatic subset of inclusion criteria from Phase 1 restricted to single toxin ingestions over a narrower time frame (2014‐2016) provided the cases for study. A structured online questionnaire was sent to all United States PCCs to request their database review regarding the indication for ECTR for their cases. In Phase 1, 92 cases met inclusion criteria. In Phase 2, 519 cases were screened and 425 met inclusion criteria. In Phase 1 91/92 (98.9%) and Phase 2 411/425 (96.7%), of extracorporeal treatments were used to treat underlying medical conditions or poisoning‐related complications rather than accelerate toxin removal. The increasing number of ECTRs reported in patients who ingested one of the four NTDTs thus appears to be for medical indications rather than attempts at toxin removal, a distinction that is important.     

Developments in extracorporeal therapy for the poisoned patient

The modern use of extracorporeal therapies to treat poisoning and drug overdoses dates back to the early 20th century and has evolved along with their use as treatment for acute kidney injury or as maintenance therapy in advanced kidney disease. As our understanding of drug pharmacokinetics and membrane materials has increased, the technologies of extracorporeal therapy and their applications have become more sophisticated. Despite that, there is little robust evidence to guide clinicians on the optimal use of extracorporeal therapy in treating poisoning beyond case reports and series. New efforts are underway to remedy that: the Extracorporeal Treatments in Poisoning Workgroup (EXTRIP) is an international effort on the part of nephrologists, pharmacists and toxicologists to review the available data and formulate evidence-based guidelines on how to use extracorporeal techniques to treat poisoning and improve patient outcomes. Meanwhile, new techniques and membranes are under development. This review will summarize those key scientific and technologic developments, the efforts to optimize their use and new directions in research.     

Isoniazid overdose : a case series, literature review and survey of antidote availability

Tuberculosis has re-emerged as a significant public health threat over the last decade both globally and within Australia. This is thought to be largely due to the HIV epidemic, a growing itinerant population, and immigration. The antibiotic isoniazid remains an integral part of drug therapy. With the numbers of patients receiving isoniazid remaining high, the number of cases of acute poisoning is expected to be significant. This paper presents a series of two cases of isoniazid poisoning presenting to a tertiary referral centre in North Queensland. Isoniazid toxicity produces a triad of coma, metabolic acidosis and seizures. The seizures are often refractory to traditional antiepileptics. A specific antidote is available (pyridoxine [vitamin B6]) and both patients were administered this as part of their treatment. We also surveyed all hospitals in Australia with an accredited adult Emergency Department to assess the availability of pyridoxine.     

Treatment of acute isoniazid toxicity.

The clinical symptoms and treatment of acute isoniazid toxicity are presented. The use of supportive measures and chemotherapy are discussed in detail. The pharmacology and biochemistry underlying the symptons of isoniazid poisoning are aslo presented. It is concluded that diazepam in combination with pyridoxine is the treatment of choice for the management of convulsions associated with isoniazid toxicity. Pyridoxine should be administered intravenously in amounts equal to the estimated quantity of isoniazid ingested, even if seizures have not occurred.     

Seizures induced by theophylline and isoniazid in mice.

Isoniazid-induced seizures respond poorly to anticonvulsants but well to pyridoxine (Vitamin B6); theophylline produces difficult-to-treat seizures with substantial morbidity and mortality. Theophylline therapy depresses plasma pyridoxal-5'-phosphate (PLP), the active metabolite of pyridoxine, suggesting that theophylline-induced seizures might be amenable to treatment with pyridoxine. Our study established the dose-response relationship for convulsions due to isoniazid and theophylline in mice and determined if pyridoxine antagonized such seizures. Female CD-1 outbred mice weighing 25 to 30 g were used. Clonic seizures had clonic activity lasting 5 sec; tonic seizures had loss of the righting reflex with tonic hindlimb extension. Groups of 10 mice received single doses of 50, 100, 150, 200, 250 or 300 mg aminophylline/kg i.p. or 100, 150, 200, 250, 300 or 350 mg isoniazid/kg i.p. and were observed for seizures or death. Pyridoxine or saline with aminophylline or isoniazid were administered simultaneously. The LD50 for aminophylline was 266 mg/kg; for isoniazid it was 160 mg/kg. Doses of 150 mg aminophylline/kg or 100 mg isoniazid/kg did not induce seizures. Pyridoxine with aminophylline or isoniazid did not alter the frequency or time of onset of seizures or death. This was unexpected because pyridoxine antagonizes theophylline-induced seizures in mice and reverses isoniazid-induced seizures in humans. We found no evidence that PLP depletion in mice is a mechanism for seizures induced by isoniazid or aminophylline in a fashion similar to isoniazid in humans.     

Acute isoniazid toxicity and the need for adequate pyridoxine supplies

A 25-year-old, 54-kg Hispanic man who had recently started multidrug therapy for pulmonary tuberculosis presented in status epilepticus after ingesting 9 g of isoniazid in a suicide attempt. Successful management of this patient required collaboration between several institutions to provide the large amount of necessary intravenous pyridoxine. Ultimately, this single overdose depleted the supply of intravenous pyridoxine for a significant region of the state of Nebraska. Isoniazid is commonly used to treat tuberculosis, but it is encountered relatively infrequently as the cause of an acute overdose. Severe isoniazid overdoses may present as seizure activity that is refractory to conventional antiepileptic therapy. Although intravenous pyridoxine is an effective antidote for isoniazid overdoses in patients presenting with status epilepticus, this agent has few indications and is typically stocked in limited quantities. In regions with large populations of patients who receive antituberculosis therapy, collaborative networks must be created to ensure that adequate supplies of intravenous pyridoxine (> or = 20 g) are available for effective treatment of isoniazid poisonings.     

Severity of Deliberate Acute Baclofen Poisoning: A Nonconcurrent Cohort Study

Interest in high‐dose baclofen treatment for alcohol dependence has increased over the past few years. In the meantime, the rate of acute baclofen poisoning has increased and life‐threatening cases have been reported. Thus, severity of acute poisoning could lessen the benefit of baclofen treatment. Our aim was to evaluate the severity of acute baclofen poisoning independently of confounders and to assess whether severity is correlated with the reported ingested dose. We prospectively included consecutive patients with acute and deliberate baclofen overdose and compared them with gender and age‐matched patients from a retrospective cohort of common acute medicine self‐poisoning. The primary end‐point was the adjusted risk ratio of mechanical ventilation. We also analysed the lengths of mechanical ventilation and risks of aspiration pneumonitis and convulsions. We finally examined the correlation between the supposed reported ingested dose and the severity of poisoning. Fourteen baclofen‐poisoned patients were included and matched to 56 poisoned patients. Median age was 45y/o (40–58), and men comprised 43% of patients. In logistic regression, the adjusted risk ratio of mechanical ventilation was 7.9 (1.4–43.5; p = 0.02) for baclofen‐treated patients. Aspiration pneumonitis was more frequent in baclofen‐treated patients (29% versus 2%; p = 0.005), and the length of mechanical ventilation was significantly correlated with the reported ingested dose of baclofen (Spearman coefficients: 0.48; p < 0.001). Our results show that acute baclofen poisoning is more severe than other acute medicine overdoses, and severity seems to be correlated with the ingested dose of baclofen. These results raise some questions about the safety of high‐dose baclofen treatment for alcohol dependence.     

急性重度异烟肼中毒9例救治分析

目的探讨重度异烟肼中毒救治的有效方法。方法对9例重度异烟肼中毒病例进行回顾性分析。对于吞服异烟肼剂量明确患者,均给予大剂量维生素B6（与中毒异烟肼比1：1）静脉注射,同时联合地西泮静脉注射,控制抽搐。结果 9例患者中,8例痊愈出院,死亡1例。结论对于重度异烟肼中毒,大剂量维生素B6静脉注射,可有效拮抗异烟肼。     

Scoping review of rational polytherapy in patients with drug-resistant epilepsy

There is a paucity of literature regarding the optimal selection of combination antiseizure medications (ASMs) for drug-resistant epilepsy (DRE). The aim of this scoping review is to evaluate current evidence related to “rational polytherapy” among adults with DRE. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-SCr) guidelines, PubMed, ProQuest, CINAHL, and Cochrane databases were searched using DRE- and polytherapy-related keywords. The exclusion criteria applied included: non-English; non-human studies; non-research studies; participants less than 18 years; status epilepticus; ASM monotherapy; and certain ASMs. In Covidence, two researchers independently reviewed articles for inclusion at each phase, with a third resolving conflicts. Data were extracted, with quality appraisal using the Mixed Methods Appraisal Tool (MMAT). Of the 6477 studies imported for screening, 33 studies were included. Clinical, humanistic, and economic outcomes were reported by 26, 12, and one study, respectively. Common efficacy-related clinical outcomes included ≥50% reduction in seizure frequency (n = 14), seizure freedom (n = 14), and percent reduction in seizure frequency (n = 8). Common humanistic outcomes included quality of life (n = 4), medication adherence (n = 2), sleep-related outcomes (n = 2), and physician and patient global assessments (n = 2). The economic study reported quality-adjusted life years. The median MMAT score was 80 (range: 60–100). Two studies referenced the standard definition of DRE, whereas five studies did not specifically define DRE. Gaps in the literature include limited generalizability, minimal reports in pregnancy, and lack of optimal ASM combinations, among others. Strengths of the evidence include addressing a variety of outcomes. Inconsistent definitions of DRE, small sample sizes, and heterogeneity among studies limit the ability to draw meaningful conclusions. Optimal combinations of ASMs for rational polytherapy for DRE is unclear.     

Potentiation of pyridoxine by depressants and anticonvulsants in the treatment of acute isoniazid intoxication in dogs

Treatments for acute isoniazid (INH) intoxication have included, singly and in various combinations, a great variety of drugs. As a consequence it is difficult to evaluate the efficacy of these antidotes, except for pyridoxine, the most commonly recommended one. In some cases of INH poisoning evaluation is further complicated because of concurrent alcohol ingestion. The objectives of this investigation were to determine whether ethanol enhances the toxic effects of acute INH overdose, as suggested by some clinical reports, and to evaluate the antidotal efficacy of phenobarbital, pentobarbital, phenytoin, ethanol, or diazepam when each is administered in combination with pyridoxine. Male dogs were either pretreated with iv ethanol and challenged 1 hr later with po INH, 50 or 75 mg/kg, or they were given INH, 75 mg/kg, and injected iv 30 min later with the test drugs, alone or in combination with pyridoxine. Ethanol pretreatment not only did not enhance the toxicity of INH but, in fact, it reduced the severity of convulsions, although it did not change the mortality rate. In the antidotal study, none of the five CNS depressants or anticonvulsants protected against clonic-tonic seizures or death. Pyridoxine, however, reduced the severity of the seizures and prevented death, although it did not completely block convulsions. The combination antidotal treatments (pyridoxine plus each of the CNS drugs) were the most effective; they prevented both convulsions and lethality. It is suggested that pyridoxine is the basic antidote for treatment of acute INH poisoning, and that the addition of an anticonvulsant or a CNS depressant to the therapy enhances effectiveness.     

Rare Alleles within the CYP2E1 (MEOS System) Could be Associated with Better Short‐Term Health Outcome after Acute Methanol Poisoning

Genetic polymorphisms influence the metabolism of ethanol and methanol, but the potential effects of genetic predisposition on the clinical course, outcome and short‐term health sequelae of acute methanol poisoning are unknown. To evaluate the role of the MEOS system in methanol poisoning, we analysed the effect of three polymorphisms (RsaI – rs2031920; PstI – rs3813867; insertion/deletion I/D) within the CYP2E1 enzyme (MEOS system) in 50 adult survivors of methanol poisoning and compared their genotype frequencies with 460 controls. The minor allele frequencies of all three polymorphisms were below 5% in both groups. We did not detect significant differences in the genotype frequencies between survivors of methanol poisoning and controls (p = 0.34 for the RsaI variant; p = 0.59 for the PstI variant and p = 0.21 for the I/D polymorphism). The carriers of at least one minor allele in the CYP2E1 gene had less severe clinical symptoms and better short‐term outcome after acute poisoning. Variants within the CYP2E1 gene are likely not significant genetic determinants of acute methanol poisoning (if survivors are analysed), but they may influence the severity of methanol poisoning and its visual/central nervous system (CNS) outcome.     

Methodological quality and risk of bias of meta-analyses of pharmacy services: A systematic review

BackgroundA suboptimal meta-analysis with misleading conclusions, frequently published in the healthcare journals, can compromise decision making in clinical practice.ObjectiveTo evaluate the reporting quality, methodological quality, and risk of bias of meta-analyses of pharmacy services.MethodsSystematic searches to identify all the meta-analyses reporting the effect of pharmacy services were performed in PubMed, Scopus, and Web of Science. The reporting quality, the methodological quality, and the risk of bias of the included meta-analyses were evaluated using PRISMA checklist, R-AMSTAR, and ROBIS, respectively.ResultsA total of 109 meta-analyses were eligible for the study. The heterogeneity, the quality of evidence, and the quality analyses were poorly reported on authors’ conclusions (14.3%, 14.7%, and 17.4%, respectively). The median scores of PRISMA and R-AMSTAR tolls were 24 (IQR 21.75–25), and 30 (IQR 27–32.5), respectively. Additionally, most of the studies were considered as high risk of bias (n = 83, 76.1%). No association between the date of publication and guideline compliance exists. PRISMA score was higher in studies published in high impact factor journals (rho = 0.313; p = 0.002), in articles that reported the quality of evidence obtained (p = 0.018), and in those that stated the need for future studies in their conclusions (p = 0.011). R-AMSTAR score was higher in studies published in high impact factor journals (rho = 0.338; p = 0.001), in those which reported the quality of evidence (p = 0.002), and in articles that described the quality analyses in their conclusions (p = 0.046). An association between the risk of bias and the recognition of the need for further studies in their conclusions (p = 0.041) was also found.ConclusionThe rapid increase of the meta-analyses of pharmacy services was not associated with higher quality. Mechanistic meta-analyses with poor conclusions are commonly published. Quality of the analyses, strength of evidence, heterogeneity, and absence of confrontation with current guidelines are rarely considered when synthetizing evidence and making recommendations.     

Deliberate Drug Poisoning with Slight Symptoms on Admission: Are there Predictive Factors for Intensive Care Unit Referral? A three‐year Retrospective Study

Deliberate drug poisoning leads to 1% of emergency department (ED) admissions. Even if most patients do not exhibit any significant complication, 5% need to be referred to an intensive care unit (ICU). Emergency physicians should distinguish between low‐ and high‐acuity poisoned patients at an early stage to avoid excess morbidity. Our aim was to identify ICU transfer factors in deliberately self‐poisoned patients without life‐threatening symptoms on admission. We performed a 3‐year retrospective observational study in a university hospital. Patients over 18 years of age with a diagnosis of deliberate drug poisoning were included. Clinical and toxicological data were analysed with univariate tests between groups (ED stay versus ICU transfer). Factors associated with ICU admission were then included in a logistic regression analysis. Two thousand five hundred and sixty‐five patients were included. 63.2% were women, and median age was 40 (28–49). 142 patients (5.5%) were transferred to ICU. Cardiac drugs [adjusted OR (aOR) = 19.81; 95% confidence interval (95% CI): 7.93–49.50], neuroleptics (aOR = 2.78; 95% CI: 1.55–4.97) and meprobamate (aOR = 2.71; 95% CI: 1.27–5.81) ingestions were significantly linked to ICU admission. A presumed toxic dose ingestion (aOR = 2.27; 95% CI: 1.28–4.02), number of ingested tablets (aOR = 1.01; 95% CI: 1.01–1.02 for each tablet) and delay between ingestion and ED arrival <2 hr (aOR = 2.85; 95%CI: 1.62–5.03) were also factors for ICU referral. The Glasgow Coma Scale was the only clinical feature associated with ICU admission (aOR = 1.57; 95% CI: 1.44–1.70 for each point loss). These results suggest that emergency physicians should pay particular attention to toxicological data on ED admission to distinguish between low‐ and high‐acuity self‐poisoned patients.     

Acute CO Poisoning is Associated with Impaired Fibrinolysis and Increased Thrombin Generation

Carbon monoxide (CO) poisoning is a leading cause of unintentional poisoning deaths in many countries. In ex vivo studies, CO released from carbon monoxide‐releasing molecules has been shown to attenuate fibrinolysis via increased alpha‐2‐antiplasmin activity. Hypofibrinolysis is associated with coronary ischaemia, which is also commonly observed in CO poisoning. We examined fibrin clot properties in acutely poisoned CO patients. Ex vivo plasma fibrin clot permeability, turbidimetry and efficiency of fibrinolysis were investigated in 48 patients and controls matched for age and sex. CO‐poisoned patients had 11.6% longer clot lysis time than the controls (p < 0.0001). No intergroup differences in clot permeability or turbidimetric variables were observed. Plasma tissue‐type plasminogen antigen (tPA), plasminogen activator inhibitor‐1 (PAI‐1) antigen and activity and F1.2 prothrombin fragments were higher in the patients than in the controls (all p < 0.0001). Plasma tPA activity was lower in the CO‐poisoned group. Multiple linear regression showed that a thrombin generation marker, F1.2, is the strongest predictor of clot lysis time, followed by PAI‐1 activity and carboxyhaemoglobin levels. In conclusion, this report is the first to demonstrate that acute CO poisoning in human beings is linked to increased thrombin generation and impaired fibrinolysis, which might contribute to ischaemic complications.     

Comparative Drug Dose and Drug Combinations in Patients that Present to Hospital Due to Self‐Poisoning

Self‐poisoning is a common reason for acute presentation to hospital. Commonly involved drugs have been reported, but few data exist concerning the different combinations of agents or comparative doses ingested. The present study sought to better characterise the typical patterns of drug overdose that may present via the emergency department. Consecutive adults ≥16 years of age that presented to York Hospital owing to self‐poisoning were studied for 2010–2011 inclusive. The primary outcome measure was reported dose, expressed as a multiple of the defined daily dose (DDD) to allow comparison between different agents. There were 1024 patients, including 622 women (60.7%), and median age was 32 years (range, 16 to 92 years). Overdose in men was associated with a higher overall quantity of drugs: arithmetic mean of 20 DDD multiples (95% CI, 15–26) versus 13 (11–15), p = 0.001. Overdose involved a single agent only in 538 patients (52.5%). The mean paracetamol dose was 4.0 (95% CI, 3.7–4.3) DDD multiples; the doses of antidepressants (19.4, 17.0–21.7, p < 0.0001) and benzodiazepines (18.0, 12.8–23.2, p < 0.0001) were comparatively higher. The types of agents involved in self‐poisoning and common combinations of agents are characterised. Psychotropic medications were ingested in comparatively larger quantities than analgesic agents and had worse clinical outcome. Further work is required to understand the factors that determine the quantity of drug ingested in patients at risk of drug overdose so as to minimise the risk of significant toxicity.     

Association of genetic polymorphisms in GADD45A, MDM2, and p14 with the risk of chronic benzene poisoning in a Chinese occupational population

Benzene reactive metabolites can lead to DNA damage and trigger the p53-dependent defense responses to maintain genomic stability. We hypothesized that the p53-dependent genes may play a role in the development of chronic benzene poisoning (CBP). In a case-control study of 303 patients with benzene poisoning and 295 workers occupationally exposed to benzene in south China, we investigated associations between the risk of CBP and polymorphisms in three p53-dependent genes. Potential interactions of these polymorphisms with lifestyle factors were also explored. We found p14^ARF rs3731245 polymorphism was associated with risk of CBP (P = 0.014). Compared with those carrying the GG genotype, individuals carrying p14^ARF rs3731245 GA+AA genotypes had a reduced risk of CBP ([adjusted odds ratio (OR_adj) = 0.57, 95%CI = 0.36–0.89]. Further analysis showed p14^ARF TGA/TAG diplotype was associated with an increased risk of CBP (P = 0.0006), whereas p14^ARF TGG/TAA diplotype was associated with a decreased risk of CBP (P = 0.0000001). In addition, we found individuals carrying both MDM2 Del1518 WW genotype and p14^ARF rs3731245 GA+AA genotypes had a lower risk of CBP (OR_adj = 0.25; 95%CI = 0.10–0.62; P = 0.003). Although these results require confirmation and extension, our findings suggest that genetic polymorphisms in p14^ARF may have an impact on the risk of CBP in the study population.     

Impact of pharmacist and physician collaborations in primary care on reducing readmission to hospital: A systematic review and meta-analysis

BackgroundReadmissions to hospital due to medication-related problems are common and may be preventable. Pharmacists act to optimise use of medicines during care transitions from hospital to community.ObjectiveTo assess the impact of pharmacist-led interventions, which include communication with a primary care physician (PCP) on reducing hospital readmissions.MethodsPubMed, EMBASE, Cochrane Central Register of Controlled Trials, CINAHL and Web of Science were searched for articles published from inception to March 2021 that described interventions involving a pharmacist interacting with a PCP in regards to medication management of patients recently discharged from hospital. The primary outcome was effect on all-cause readmission expressed as Mantel-Haenszel risk ratio (RR) derived from applying a random effects model to pooled data. Sensitivity analysis was also conducted to investigate differences between randomised controlled trials (RCTs) and non-RCTs. The GRADE system was applied in rating the quality of evidence and certainty in the estimates of effect.ResultsIn total, 37 studies were included (16 RCTs and 29 non-RCTs). Compared to control patients, the proportion of intervention patients readmitted at least once was significantly reduced by 13% (RR = 0.87, CI:0.79–0.97, p = 0.01; low to very low certainty of evidence) over follow-up periods of variable duration in all studies combined, and by 22% (RR = 0.78, CI:0.67–0.92; low certainty of evidence) at 30 day follow-up across studies reporting this time point. Analysis of data from RCTs only showed no significant reduction in readmissions (RR = 0.92, CI:0.80–1.06; low certainty of evidence).ConclusionsThe totality of evidence suggests pharmacist-led interventions with PCP communication are effective in reducing readmissions, especially at 30 days follow-up. Future studies need to adopt more rigorous study designs and apply well-defined patient eligibility criteria.     

Treatment of severe pediatric ethylene glycol intoxication without hemodialysis

BACKGROUND: There is limited experience treating severe ethylene glycol poisoning in children without hemodialysis. The objective of this study was to describe the clinical course and outcome of severe pediatric ethylene glycol poisoning treated without hemodialysis. METHODS: Patient records were identified retrospectively by hospital discharge diagnosis (ICD-9 code) of ethylene glycol poisoning from 1999 through 2002 at a pediatric medial center. Patients with initial serum ethylene glycol concentrations less than 50 mg/dL or those who received hemodialysis were excluded. RESULTS: Six patients with an age range of 22 months to 14 years were admitted for treatment of ethylene glycol poisoning over a four-year period. Initial serum ethylene glycol concentrations ranged from 62 to 304 mg/dL (mean 174.0 mg/dL). The lowest-measured individual serum bicarbonates ranged from 4 to 17 mEq/L. All patients were initially admitted to intensive care. One patient received ethanol only, two patients received fomepizole only, and three patients received a loading dose of ethanol and then were converted to fomepizole therapy. None of the patients received hemodialysis. Treatment was continued until the serum ethylene glycol was less than 10 mg/dL. Metabolic acidosis resolved with intravenous fluid and supplemental bicarbonate within 24h. All patients had a normal creatinine upon presentation and at discharge. The mean length of stay in intensive care was 21h and on the ward was 33.7h. One episode of hypoglycemia occurred in a 22-month-old. All patients recovered without evidence of renal insufficiency or other major complications at discharge. CONCLUSION: Six pediatric patients with severe ethylene glycol intoxication and normal renal function were successfully treated without hemodialysis.