Andrew H. Dawson

Management of acute organophosphorus pesticide poisoning

Summary Organophosphorus pesticide self-poisoning is an important clinical problem in rural regions of the developing world, and kills an estimated 200 000 people every year. Unintentional poisoning kills far fewer people but is a problem in places where highly toxic organophosphorus pesticides are available. Medical management is difficult, with case fatality generally more than 15%. We describe the limited evidence that can guide therapy and the factors that should be considered when designing further clinical studies. 50 years after first use, we still do not know how the core treatments—atropine, oximes, and diazepam—should best be given. Important constraints in the collection of useful data have included the late recognition of great variability in activity and action of the individual pesticides, and the care needed cholinesterase assays for results to be comparable between studies. However, consensus suggests that early resuscitation with atropine, oxygen, respiratory support, and fluids is needed to improve oxygen delivery to tissues. The role of oximes is not completely clear; they might benefit only patients poisoned by specific pesticides or patients with moderate poisoning. Small studies suggest benefit from new treatments such as magnesium sulphate, but much larger trials are needed. Gastric lavage could have a role but should only be undertaken once the patient is stable. Randomised controlled trials are underway in rural Asia to assess the effectiveness of these therapies. However, some organophosphorus pesticides might prove very difficult to treat with current therapies, such that bans on particular pesticides could be the only method to substantially reduce the case fatality after poisoning. Improved medical management of organophosphorus poisoning should result in a reduction in worldwide deaths from suicide.

Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose

Background: Selective serotonin reuptake inhibitors (SSRIs) have increasingly replaced tricyclic antidepressants (TCAs) in the treatment of depression. They appear to be safer in overdose, but there is little information on their spectrum of toxicity in overdose, or relative toxicity of each agent. Objective: To determine the effect of SSRIs in overdose, as a group, and the relative toxicity of five different SSRIs. Methods: A review of consecutive SSRI poisoning admissions to a single toxicology unit. Outcomes examined were length of stay [LOS], intensive care [ICU] admission rate, coma, seizures, electrocardiographic [ECG] abnormalities, and presence of serotonin syndrome [SS]. Logistic regression was used to model the outcome QTc > 440 msec. Results: There were 469 SSRI poisoning admissions analyzed after exclusions. The median LOS for all SSRI overdose admissions was 15.3 h (IQR: 10.5–21.3) and 30 of 469 (6.4%; 95% CI 4.3–9.0%) cases were admitted to ICU. The incidence of seizures was 1.9% and coma was 2.4%. Serotonin syndrome occurred in 14% of overdoses. Comparison of median QTc intervals of the five SSRIs was significantly different (p = 0.0002); citalopram (450 IQR: 436–484) was individually different to fluoxetine (p = 0.045), fluvoxamine (p = 0.022), paroxetine (p = 0.0002), and sertraline (p = 0.001). The proportion of citalopram overdoses with a QTc > 440 msec was 68%, differing significantly from sertraline (adjusted OR: 5.11 95% CI 2.32–11.27). Comparison of median QT intervals of the five SSRIs was statistically different (p = 0.026); citalopram (400 IQR: 380–440) was individually different from sertraline (p = 0.023). Conclusions: This study shows SSRIs are relatively safe in overdose despite serotonin syndrome being common. The exception was citalopram, which was significantly associated with QTc prolongation. We believe that cardiac monitoring should be considered in citalopram overdose, particularly with large ingestions and patients with associated cardiac disease.

Postcards from the EDge project: randomised controlled trial of an intervention using postcards to reduce repetition of hospital treated deliberate self poisoning

Abstract Objective To determine whether an intervention using postcards (postcards from the EDge project) reduces repetitions of hospital treated deliberate self poisoning. Design Randomised controlled trial. Setting Regional referral service for general hospital treated deliberate self poisoning in Newcastle, Australia. Participants 772 patients aged over 16 years with deliberate self poisoning. Intervention Non-obligatory intervention using eight postcards over 12 months along with standard treatment compared with standard treatment alone. Main outcome measures Proportion of patients with one or more repeat episodes of deliberate self poisoning and the number of repeat episodes for deliberate self poisoning per person in 12 months. Results The proportion of repeaters with deliberate self poisoning in the intervention group did not differ significantly from that in the control group (57/378, 15.1%, 95% confidence interval 11.5% to 18.7% v 68/394, 17.3%, 13.5% to 21.0%: difference between groups -2%, -7% to 3%). In unadjusted analysis the number of repetitions were significantly reduced (incidence risk ratio 0.55, 0.35 to 0.87). Conclusion A postcard intervention reduced repetitions of deliberate self poisoning, although it did not significantly reduce the proportion of individual repeaters.

Acute Human Lethal Toxicity of Agricultural Pesticides: A Prospective Cohort Study.

In a prospective cohort study of patients presenting with pesticide self-poisoning, Andrew Dawson and colleagues investigate the relative human toxicity of agricultural pesticides and contrast it with WHO toxicity classifications, which are based on toxicity in rats.

Cardiotoxicity More Common in Thioridazine Overdose than with Other Neuroleptics

On the basis of case reports and small non-comparative series it has been suggested that thioridazine has greater cardiotoxicity in overdose. Limited evidence also suggests an increased association with sudden death in therapeutic doses. The aim of our study is to examine the clinical and electrocardiographic features associated with neuroleptic poisoning and compare thioridazine with other neuroleptics. Consecutive adult patients with neuroleptic poisoning presenting to metropolitan hospitals in Newcastle between 1987 and 1993 were studied. The main outcome measures examined were ECG changes (QRS, QT and QTc intervals), arrhythmias, seizures, degree of sedation, heart rate and blood pressure. Two-hundred ninety-nine patients had ingested thioridazine (104), chlorpromazine (69), trifluoperazine (36), pericyazine (35), haloperidol (33), prochlorperazine (18), fluphenazine (8), or other neuroleptics (7). Sixteen patients had ingested more than one neuroleptic and were excluded from comparative analysis. Thioridazine was more likely to cause tachycardia (odds ratio 1.7, 95% CI 1.1-2.9, p = 0.03), a prolonged QT interval (odds ratio 5.2, 95% CI 1.6-17.1, p = 0.006), prolonged QTc > 450 ms1/2 (odds ratio 4.7, 95% CI 2.7-7.9, p = 0.001), a widened QRS (> 100 ms) (odds ratio 3.1, 95% CI 1.5-6.3, p = 0.001) and arrhythmias (odds ratio infinity, 95% CI 2.4- infinity, p = 0.004). There were no significant differences in the odds of coma (odds ratio 0.5 (0.2-1.5)), hypotension (odds ratio 0.9 (0.4-1.9)) or seizures (odds ratio 3.9 (0.3-43.5)). Adjustment for age, sex, dose ingested and co-ingestion of tricyclic antidepressants or lithium had no major effect on the odds ratios observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Early management after self-poisoning with an organophosphorus or carbamate pesticide - a treatment protocol for junior doctors

Severe organophosphorus or carbamate pesticide poisoning is an important clinical problem in many countries of the world. Unfortunately, little clinical research has been performed and little evidence exists with which to determine best therapy. A cohort study of acute pesticide poisoned patients was established in Sri Lanka during 2002; so far, more than 2000 pesticide poisoned patients have been treated. A protocol for the early management of severely ill, unconscious organophosphorus/carbamate-poisoned patients was developed for use by newly qualified doctors. It concentrates on the early stabilisation of patients and the individualised administration of atropine. We present it here as a guide for junior doctors in rural parts of the developing world who see the majority of such patients and as a working model around which to base research to improve patient outcome. Improved management of pesticide poisoning will result in a reduced number of suicides globally.

Postcards from the EDge: 24-month outcomes of a randomised controlled trial for hospital-treated self-poisoning

BACKGROUND Repetition of hospital-treated self-poisoning and admission to psychiatric hospital are both common in individuals who self-poison. AIMS To evaluate efficacy of postcard intervention after 5 years. METHOD A randomised controlled trial of individuals who have self-poisoned: postcard intervention (eight in 12 months) plus treatment as usual v. treatment as usual. Our primary outcomes were self-poisoning admissions and psychiatric admissions (proportions and event rates). RESULTS There was no difference between groups for any repeat-episode self-poisoning admission (intervention group: 24.9%, 95% CI 20.6-29.5; control group: 27.2%, 95% CI 22.8-31.8) but there was a significant reduction in event rates (incidence risk ratio (IRR) = 0.54, 95% CI 0.37-0.81), saving 306 bed days. There was no difference for any psychiatric admission (intervention group: 38.1%, 95% CI 33.1-43.2; control group: 35.5%, 95% CI 30.8-40.5) but there was a significant reduction in event rates (IRR = 0.66, 95% CI 0.47-0.91), saving 2565 bed days. CONCLUSIONS A postcard intervention halved self-poisoning events and reduced psychiatric admissions by a third after 5 years. Substantial savings occurred in general hospital and psychiatric hospital bed days.

Oral or intravenous N-acetylcysteine: which is the treatment of choice for acetaminophen (paracetamol) poisoning?

BACKGROUND The optimal route and duration of administration for N-acetyl-cysteine in the management of acetaminophen (paracetamol) poisoning are controversial. It has been stated on the basis of a selected post-hoc analysis that oral N-acetylcysteine is superior to intravenous N-acetylcysteine in presentations later than 15 hours. AIM OF STUDY To investigate the efficacy of intravenous or oral N-acetylcysteine. PATIENTS AND METHODS We analyzed a series of acetaminophen poisonings treated with a protocol including activated charcoal and intravenous N-acetylcysteine. The outcomes assessed included use of N-acetylcysteine, adverse effects of intravenous N-acetylcysteine, and the occurrence of hepatotoxicity (transaminase > 1000 U/L). We incorporated these results in a meta-analysis of previously reported series of acetaminophen poisonings to compare the outcomes from intravenous and oral N-acetylcysteine use. RESULTS Of 981 patients admitted over 10 years, 4% (40) presented later than 24 hours and 10% (100) had concentrations of acetaminophen that indicated a probable or high risk of hepatotoxicity. The 30 patients who developed hepatotoxicity presented later, took larger amounts, had higher concentrations, and received N-acetylcysteine later than those who did not. No patients received a liver transplant but 2 patients died (one after referral to a transplant unit and one just before). Adverse reactions to intravenous N-acetylcysteine occurred in 6% (12/205) of patients but none prevented completion of the treatment. In the meta-analysis, those with probable or high risk concentrations had similar outcomes with intravenous (pooled n = 341) and oral N-acetylcysteine (pooled n = 1462) administration. Rates of hepatotoxicity for those treated within 10 hours (3 and 6%), late (10-24 hours: 30 and 26%), and overall (0-24 hours: 16 and 19%) were all similar. The proportion of patients classified as presenting later than 10 hours is much greater in the oral N-acetylcysteine studies (64%) than in many of the intravenous N-acetylcysteine studies (38%, 44%, and 63%). CONCLUSIONS The differences claimed between oral and intravenous N-acetylcysteine regimes are probably artifactual and relate to inappropriate subgroup analysis. A shorter hospital stay, patient and doctor convenience, and the concerns over the reduction in bioavailability of oral N-acetylcysteine by charcoal and vomiting make intravenous N-acetylcysteine preferable for most patients with acetaminophen poisoning.

Pralidoxime in acute organophosphorus insecticide poisoning--a randomised controlled trial.

In a randomized controlled trial of individuals who had taken organophosphorus insecticides, Michael Eddleston and colleagues find that there is no evidence that the addition of the antidote pralidoxime offers benefit over atropine and supportive care.

Relative Toxicity of Beta Blockers in Overdose

OBJECTIVE To compare the toxicity of beta blockers in overdose and to identify clinical features predictive of serious toxicity. DESIGN Comparison of clinical data collected prospectively on a relational database of subjects presenting to hospital with self-poisoning, coroners data and prescription data. SETTING Newcastle and Lake Macquarie, Australia, 1987-1995. MAIN OUTCOME MEASURES Death, seizure, cardiovascular collapse, hypoglycemia, coma and respiratory depression. SUBJECTS Fifty-eight self-poisonings with beta blockers and two deaths investigated by the coroner with evidence of propranolol poisoning. RESULTS All patients who developed toxicity did so within six hours of ingestion. The use of ipecac was temporally associated with cardiorespiratory arrest in one patient. Propranolol was the only beta blocker associated with seizure; of those who ingested more than 2 g of propranolol, two thirds had a seizure. There was a significant association between a QRS duration of > 100 ms and risk of seizures. Propranolol was over represented in beta blocker poisoning when prescription data were also examined. Propranolol was the only beta blocker associated with death. Propranolol was taken by a younger age group. CONCLUSIONS Propranolol should be avoided in patients at risk of self-poisoning. Propranolol poisonings should be observed closely for the first six hours post ingestion. Syrup of ipecac should not be used to decontaminate the gastrointestinal tract after beta blocker overdose.