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1.  Management of acute paracetamol poisoning in a tertiary care hospital 
The Ceylon medical journal  2008;53(3):89-92.
Objectives
To compare the management of acute paracetamol poisoning with the best evidence available, and to determine the effect of plasma paracetamol level estimation on the management.
Design
Descriptive study with an intervention.
Setting
Medical wards of the National Hospital of Sri Lanka, Colombo.
Patients
Patients admitted with a history of acute paracetamol poisoning.
Intervention
Measurement of plasma paracetamol.
Methods
Data were obtained from the patients, medical staff and medical records. Plasma paracetamol was estimated between 4-24 hours of paracetamol ingestion. The current management practices were compared with the best evidence on acute paracetamol poisoning management.
Results
157 patients were included. The mean ingested dose of paracetamol was 333 mg/kg body weight. Majority of the patients (84%) were transfers. Induced emesis and activated charcoal were given to 91% of patients. N-acetylcysteine was given to 66, methionine to 55, and both to 2. A clinically important delay in the administration of antidotes was noted; 68% of patients received antidotes after 8 hours of the acute ingestion. Only 31 (26%) had paracetamol levels above the Rumack-Matthew normogram. 74 patients received an antidote despite having a plasma paracetamol level below the toxic level according to the normogram.
Interpretation
Management of acute paracetamol poisoning could be improved by following best available evidence and adapting cheaper methods for plasma paracetamol estimation.
PMCID: PMC3145136  PMID: 18982801
acute paracetamol poisoning; N-acetylcysteine; methionine
2.  A quick inexpensive laboratory method in acute paracetamol poisoning could improve risk assessment, management and resource utilization 
Indian Journal of Pharmacology  2012;44(4):463-468.
Objectives:
Acute paracetamol poisoning is an emerging problem in Sri Lanka. Management guidelines recommend ingested dose and serum paracetamol concentrations to assess the risk. Our aim was to determine the usefulness of the patient's history of an ingested dose of >150 mg/kg and paracetamol concentration obtained by a simple colorimetric method to assess risk in patients with acute paracetamol poisoning.
Materials and Methods:
Serum paracetamol concentrations were determined in 100 patients with a history of paracetamol overdose using High Performance Liquid Chromatography (HPLC); (reference method). The results were compared to those obtained with a colorimetric method. The utility of risk assessment by reported dose ingested and colorimetric analysis were compared.
Results:
The area under the receiver operating characteristic curve for the history of ingested dose was 0.578 and there was no dose cut-off providing useful risk categorization. Both analytical methods had less than 5% intra- and inter-batch variation and were accurate on spiked samples. The time from blood collection to result was six times faster and ten times cheaper for colorimetry (30 minutes, US$2) than for HPLC (180 minutes, US$20). The correlation coefficient between the paracetamol levels by the two methods was 0.85. The agreement on clinical risk categorization on the standard nomogram was also good (Kappa = 0.62, sensitivity 81%, specificity 89%).
Conclusions:
History of dose ingested alone greatly over-estimated the number of patients who need antidotes and it was a poor predictor of risk. Paracetamol concentrations by colorimetry are rapid and inexpensive. The use of these would greatly improve the assessment of risk and greatly reduce unnecessary expenditure on antidotes.
doi:10.4103/0253-7613.99305
PMCID: PMC3469948  PMID: 23087506
Acute poisoning; paracetamol concentration; risk assessment
3.  Do Targeted Bans of Insecticides to Prevent Deaths from Self-Poisoning Result in Reduced Agricultural Output? 
Environmental Health Perspectives  2008;116(4):492-495.
Background
The pesticides monocrotophos, methamidophos, and endosulfan were a very common cause of severe poisoning in Sri Lanka during the 1980s and early 1990s, before they were banned in 1995 and 1998. Now, the most commonly used insecticides are the less toxic World Health Organization Class II organophosphorus pesticides and carbamates. These bans were followed by a large reduction in both fatal poisonings and suicide in Sri Lanka.
Objective
We aimed to see if these bans adversely affected agricultural production or costs.
Methods
We used data from the World Resources Institute to compare the yields of the main crop groups in Sri Lanka with those from surrounding South Asian countries for 1980–2005. We also examined data from the Sri Lankan Department of Census and Statistics to examine the yields of 13 specific vegetable crops and rice for 1990–2003, along with the costs of rice production.
Results
We found no drop in productivity in the years after the main bans were instituted (1995, 1998). We observed substantial annual fluctuation in estimated yields in all data sources, but these did not coincide with the bans and were no larger than the fluctuations in other countries. Also, there was no sudden change in costs of rice production coinciding with bans.
Conclusions
Countries aiming to apply restrictions to reduce deaths from pesticide poisoning should evaluate agricultural needs and develop a plan that encourages substitution of less toxic pesticides. If farmers have an affordable alternative for pest control for each crop, there is no obvious adverse effect on agricultural output.
doi:10.1289/ehp.11029
PMCID: PMC2291009  PMID: 18414632
food production; pesticide poisoning; pesticide regulation; public health policy; suicide prevention
4.  Paracetamol (acetaminophen) poisoning 
Clinical Evidence  2007;2007:2101.
Introduction
Mortality from paracetamol overdose is now about 0.4%, although severe liver damage occurs without treatment in at least half of people with blood paracetamol levels above the UK standard treatment line. In adults, ingestion of less than 125 mg/kg is unlikely to lead to hepatotoxicity; even higher doses may be tolerated by children without causing liver damage.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for acute paracetamol poisoning? We searched: Medline, Embase, The Cochrane Library and other important databases up to March 2006 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 24 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: activated charcoal (single or multiple dose), gastric lavage, ipecacuanha, liver transplant, methionine, N-acetylcysteine.
Key Points
Paracetamol (acetaminophen) is a common means of self-poisoning in Europe and North America, often taken as an impulsive act of self-harm in young people. Mortality from paracetamol overdose is now about 0.4%, although without treatment, severe liver damage occurs in at least half of people with blood paracetamol levels above the UK standard treatment line.In adults, ingestion of less than 125 mg/kg is unlikely to lead to hepatotoxicity; even higher doses may be tolerated by children without causing liver damage.
Standard treatment of paracetamol overdose is acetylcysteine, which based on animal studies and clinical experience, is widely believed to reduce liver damage and mortality, although few studies have been done. Adverse effects from acetylcysteine include rash, urticaria, vomiting, and anaphylaxis which can, rarely, be fatal.We don't know what the optimal dose, route, and duration of acetylcysteine treatment should be. However, liver damage is less likely to occur if treatment is started within 8 to 10 hours of ingestion.
It is possible that methionine reduces the risk of liver damage and mortality after paracetamol poisoning compared with supportive care, but we don't know for sure.
We don't know whether activated charcoal, gastric lavage, or ipecacuanha reduce the risks of liver damage after paracetamol poisoning. The rapid absorption of paracetamol suggests that a beneficial effect from treatments that reduce gastric absorption is unlikely in many cases.
Liver transplantation may increase survival rates in people with fulminant liver failure after paracetamol poisoning compared with waiting list controls, but long-term outcomes are unknown.
PMCID: PMC2943815  PMID: 19450343
5.  Changing epidemiologic patterns of deliberate self poisoning in a rural district of Sri Lanka 
BMC Public Health  2012;12:593.
Background
Acute poisoning is a major public health issue in many parts of the world. The epidemiology and the mortality rate is higher in low and middle income countries, including Sri Lanka. The aim of this study was to provide details about the epidemiology of acute poisoning in a rural Sri Lankan district and to identify the changing patterns and epidemiology of poisoning.
Methods
A prospective study was conducted from September 2008 to January 2010 in all hospitals with inpatient facilities in Anuradhapura district of North Central Province of Sri Lanka. Acute poisoning data was extracted from patient charts. Selected data were compared to the data collected from a 2005 study in 28 hospitals.
Results
There were 3813 poisoned patients admitted to the hospitals in the Anuradhapura district over 17 months. The annual population incidence was 447 poisoning cases per 100,000 population. The total number of male and female patients was approximately similar, but the age distribution differed by gender. There was a very high incidence of poisoning in females aged 15–19, with an estimated cumulative incidence of 6% over these five years. Although, pesticides are still the most common type of poison, medicinal drug poisonings are now 21% of the total and have increased 1.6 fold since 2005.
Conclusions
Acute poisoning remains a major public health problem in rural Sri Lanka and pesticide poisoning remains the most important poison. However, cases of medicinal drug poisoning have recently dramatically increased. Youth in these rural communities remain very vulnerable to acute poisoning and the problem is so common that school-based primary prevention programs may be worthwhile.
Lalith Senarathna, Shaluka F Jayamanna, Patrick J Kelly, Nick A Buckley,michael J Dibley, Andrew H Dawson. These authors contributed equally to this work.
doi:10.1186/1471-2458-12-593
PMCID: PMC3458971  PMID: 22852867
6.  Fructose-1, 6-diphosphate (FDP) as a novel antidote for yellow oleander-induced cardiac toxicity: A randomized controlled double blind study 
Background
Cardiac toxicity due to ingestion of oleander plant seeds in Sri Lanka and some other South Asian countries is very common. At present symptomatic oleander seed poisoning carries a mortality of 10% in Sri Lanka and treatment of yellow oleander poisoning is limited to gastric decontamination and atropine administration. The only proven effective antidote is digoxin antibodies but these are not available for routine use because of the high cost. The main objective of this study is to investigate the effectiveness of a new and inexpensive antidote for patients with life threatening arrhythmias due oleander poisoning.
Method/design
We set up a randomised double blind clinical trial to assess the effectiveness of Fructose 1, 6 diphosphate (FDP) in acute yellow oleander poisoning patients admitted to the adult medical wards of a tertiary hospital in Sri Lanka. Patients will be initially resuscitated following the national guidelines and eligible patients will be randomised to receive either FDP or an equal amount of normal saline. The primary outcome measure for this study is the sustained reversion to sinus rhythm with a heart rate greater than 50/min within 2 hours of completion of FDP/placebo bolus. Secondary outcomes include death, reversal of hyperkalaemia on the 6, 12, 18 and 24 hour samples and maintenance of sinus rhythm on the holter monitor. Analysis will be on intention-to-treat.
Discussion
This trial will provide information on the effectiveness of FDP in yellow oleander poisoning. If FDP is effective in cardiac glycoside toxicity, it would provide substantial benefit to the patients in rural Asia. The drug is inexpensive and thus could be made available at primary care hospitals if proven to be effective.
Trial Registration
Current Controlled trial ISRCTN71018309
doi:10.1186/1471-227X-10-15
PMCID: PMC2912827  PMID: 20587052
7.  Paracetamol availability and recent changes in paracetamol poisoning: is the 1998 legislation limiting availability of paracetamol being followed? 
Postgraduate Medical Journal  2006;82(970):520-523.
Objective
To determine the degree of adherence to legislation introduced in 1998 restricting the availability of over the counter paracetamol.
Design
A prospective observational study.
Setting
An emergency department in an inner city London teaching hospital. Pharmacy and non‐pharmacy outlets in south London.
Main outcome measures
(1) The source of paracetamol ingested by 107 patients presenting with an acute paracetamol overdose (2001–2003) and (2) the ability to purchase paracetamol from pharmacy and non‐pharmacy outlets in a manner contravening paracetamol pack size legislation (2004).
Results
Potentially toxic amounts of paracetamol in excess of pack size restrictions were purchased in 70% (17 of 24) of outlets. Forty six per cent of patients who had ingested a potentially toxic dose of paracetamol obtained the tablets in a manner contravening the 1998 legislation.
Conclusion
Legislation limiting the availability of over the counter paracetamol is not being adhered to in south London. A significant number of patients ingesting a potentially toxic dose of paracetamol report purchasing the tablets in a manner contravening the legislation. Studies that attempt to assess the impact of the legislation need to be interpreted in the context of these results. Measures to enforce current legislation may help to reduce the severity of paracetamol poisoning in the UK.
doi:10.1136/pgmj.2005.042036
PMCID: PMC2585716  PMID: 16891443
legislation; paracetamol; pack size; overdose
8.  Predicting the requirement for N-acetylcysteine in paracetamol poisoning from reported dose 
Context
There is contention over whether reported dose correlates with toxicity in paracetamol poisoning and risk assessment is currently based on serum paracetamol concentration compared to a nomogram, irrespective of reported dose.
Objective
To determine if reported dose predicts the need for N-acetylcysteine (NAC).
Methods
Data were taken from paracetamol overdoses presenting to a tertiary toxicology service. Age, sex, reported dose, ingestion time, timed paracetamol concentrations between 4 and 16 h, hepatotoxicity (peak alanine transaminase > 1000 U/L) and treatment (single dose-activated charcoal [SDAC] and NAC) were analysed. Data were analysed within a repeated measures logistic regression framework using NONMEM (ver 7.2). The primary outcome was administration of NAC, which was determined based on a serum paracetamol concentration greater than the nomogram line.
Result
There were 1571 admissions in 1303 patients, with a median age of 27 years (12–96 years) and 1140 (73%) were females. The median dose was 10 g (1–100 g). The paracetamol concentration was above the nomogram line in 337 of 1571 (22%) patients. Patients presenting later (first paracetamol concentration between 7 and 16 h post-overdose) compared to those presenting earlier (4–7 h post-overdose) were more likely to have hepatotoxicity (5.5% vs. 0.4%; p < 0.0001), have a toxic paracetamol concentration (34% vs. 18%; p < 0.0001) and receive NAC (48% vs. 23%; p < 0.0001). SDAC reduced the probability of the paracetamol concentration being above the nomogram. Based on SDAC not being administered there was a 5% probability of requiring NAC at a dose of 6–9 g, a 10% chance of requiring NAC at a dose of 13–16 g, a 50% chance of requiring NAC at a dose of 30–34 g and a 90% chance for needing NAC at 48–50 g.
Conclusion
Reported dose was a good predictor of a toxic paracetamol concentration and SDAC reduced the probability of the concentration being above the nomogram. These predictions may assist in determining which patients could be started on NAC immediately.
doi:10.3109/15563650.2013.830733
PMCID: PMC3821377  PMID: 23964853
Paracetamol overdose; Logistric regression; Acetylcysteine; Risk assessment; Reported dose; Hepatotoxicity
9.  Clinical outcomes and kinetics of propanil following acute self-poisoning: a prospective case series 
Background
Propanil is an important cause of death from acute pesticide poisoning, of which methaemoglobinaemia is an important manifestation. However, there is limited information about the clinical toxicity and kinetics. The objective of this study is to describe the clinical outcomes and kinetics of propanil following acute intentional self-poisoning.
Methods
431 patients with a history of propanil poisoning were admitted from 2002 until 2007 in a large, multi-centre prospective cohort study in rural hospitals in Sri Lanka. 40 of these patients ingested propanil with at least one other poison and were not considered further. The remaining 391 patients were classified using a simple grading system on the basis of clinical outcomes; methaemoglobinaemia could not be quantified due to limited resources. Blood samples were obtained on admission and a subset of patients provided multiple samples for kinetic analysis of propanil and the metabolite 3,4-dichloroaniline (DCA).
Results
There were 42 deaths (median time to death 1.5 days) giving a case fatality of 10.7%. Death occurred despite treatment in the context of cyanosis, sedation, hypotension and severe lactic acidosis consistent with methaemoglobinaemia. Treatment consisted primarily of methylene blue (1 mg/kg for one or two doses), exchange transfusion and supportive care when methaemoglobinaemia was diagnosed clinically. Admission plasma concentrations of propanil and DCA reflected the clinical outcome. The elimination half-life of propanil was 3.2 hours (95% confidence interval 2.6 to 4.1 hours) and the concentration of DCA was generally higher, more persistent and more variable than propanil.
Conclusion
Propanil is the most lethal herbicide in Sri Lanka after paraquat. Methylene blue was largely prescribed in low doses and administered as intermittent boluses which are expected to be suboptimal given the kinetics of methylene blue, propanil and the DCA metabolite. But in the absence of controlled studies the efficacy of these and other treatments is poorly defined. More research is required into the optimal management of acute propanil poisoning.
doi:10.1186/1472-6904-9-3
PMCID: PMC2656468  PMID: 19220887
10.  Effect of a Brief Outreach Educational Intervention on the Translation of Acute Poisoning Treatment Guidelines to Practice in Rural Sri Lankan Hospitals: A Cluster Randomized Controlled Trial 
PLoS ONE  2013;8(8):e71787.
Background
In developing countries, including Sri Lanka, a high proportion of acute poisoning and other medical emergencies are initially treated in rural peripheral hospitals. Patients are then usually transferred to referral hospitals for further treatment. Guidelines are often used to promote better patient care in these emergencies. We conducted a cluster randomized controlled trial (ISRCTN73983810) which aimed to assess the effect of a brief educational outreach (‘academic detailing’) intervention to promote the utilization of treatment guidelines for acute poisoning.
Methods and Findings
This cluster RCT was conducted in the North Central Province of Sri Lanka. All peripheral hospitals in the province were randomized to either intervention or control. All hospitals received a copy of the guidelines. The intervention hospitals received a brief out-reach academic detailing workshop which explained poisoning treatment guidelines and guideline promotional items designed to be used in daily care. Data were collected on all patients admitted due to poisoning for 12 months post-intervention in all study hospitals. Information collected included type of poison exposure, initial investigations, treatments and hospital outcome. Patients transferred from peripheral hospitals to referral hospitals had their clinical outcomes recorded. There were 23 intervention and 23 control hospitals. There were no significant differences in the patient characteristics, such as age, gender and the poisons ingested. The intervention hospitals showed a significant improvement in administration of activated charcoal [OR 2.95 (95% CI 1.28–6.80)]. There was no difference between hospitals in use of other decontamination methods.
Conclusion
This study shows that an educational intervention consisting of brief out-reach academic detailing was effective in changing treatment behavior in rural Sri Lankan hospitals. The intervention was only effective for treatments with direct clinician involvement, such as administering activated charcoal. It was not successful for treatments usually administered by non-professional staff such as forced emesis for poisoning.
Trial Registration
Controlled-Trials.com ISRCTN73983810 ISRCTN73983810
doi:10.1371/journal.pone.0071787
PMCID: PMC3747188  PMID: 23990989
11.  Acute yellow oleander (Thevetia peruviana) poisoning: cardiac arrhythmias, electrolyte disturbances, and serum cardiac glycoside concentrations on presentation to hospital 
Heart  2000;83(3):301-306.
OBJECTIVE—To describe the cardiac arrhythmias, electrolyte disturbances, and serum cardiac glycoside levels seen in patients presenting to hospital with acute yellow oleander (Thevetia peruviana) poisoning and to compare these with published reports of digitalis poisoning.
DESIGN—Case series.
SETTING—Medical wards of Anuradhapura District General Hospital, Sri Lanka, and coronary care unit of the Institute of Cardiology, National Hospital of Sri Lanka, Colombo, the national tertiary referral centre for cardiology.
PATIENTS—351 patients with a history of oleander ingestion.
MEASUREMENTS—ECG and blood sample analysis on admission.
RESULTS—Most symptomatic patients had conduction defects affecting the sinus node, the atrioventricular (AV) node, or both. Patients showing cardiac arrhythmias that required transfer for specialised management had significantly higher mean serum cardiac glycoside and potassium but not magnesium concentrations. Although there was considerable overlap between groups, those with conduction defects affecting both sinus and AV nodes had significantly higher mean serum cardiac glycoside levels.
CONCLUSIONS—Most of these young previously healthy patients had conduction defects affecting the sinus or AV nodes. Relatively few had the atrial or ventricular tachyarrhythmias or ventricular ectopic beats that are typical of digoxin poisoning. Serious yellow oleander induced arrhythmias were associated with higher serum cardiac glycoside concentrations and hyperkalaemia but not with disturbances of magnesium.


Keywords: oleander poisoning; arrhythmias; cardiac glycosides
doi:10.1136/heart.83.3.301
PMCID: PMC1729329  PMID: 10677410
12.  Effects of a provincial ban of two toxic organophosphorus insecticides on pesticide poisoning hospital admissions 
Background.
Pesticide self-poisoning causes one third of global suicides. Sri Lanka halved its suicide rate by banning WHO Class I organophosphorus (OP) insecticides and then endosulfan. However, poisoning with Class II toxicity OPs, particularly dimethoate and fenthion, remains a problem. We aimed to determine the effect and feasibility of a ban of the two insecticides in one Sri Lankan district.
Methods.
Sale was banned in June 2003 in most of Polonnaruwa District, but not Anuradhapura District. Admissions with pesticide poisoning to the district general hospitals was prospectively recorded from 2002.
Results.
Hospital admissions for dimethoate and fenthion poisoning fell by 43% after the ban in Polonnaruwa, while increasing by 23% in Anuradhapura. The pesticide case fatality fell from 14.4% to 9.0% in Polonnaruwa (odds ratio [OR] 0.59, 95% confidence interval [CI] 0.41–0.84) and 11.3% to 10.6% in Anuradhapura (OR 0.93, 95%CI 0.70–1.25; p = 0.051). This reduction was not sustained, with case fatality in Polonnaruwa rising to 12.1% in 2006–2007. Further data analysis indicated that the fall in case fatality had actually been due to a coincidental reduction in case fatality for pesticide poisoning overall, in particular for paraquat poisoning.
Conclusions.
We found that the insecticides could be effectively banned from agricultural practice, as shown by the fall in hospital admissions, with few negative consequences. However, the ban had only a minor effect on pesticide poisoning deaths because it was too narrow. A study assessing the agricultural and health effects of a more comprehensive ban of highly toxic pesticides is necessary to determine the balance between increased costs of agriculture and reduced health care costs and fewer deaths.
doi:10.3109/15563650.2012.660573
PMCID: PMC3793265  PMID: 22372788
 Pesticide poisoning; pesticide regulation; interventional study; Sri Lanka; organophosphorus pesticides
13.  Interrupted Time-Series Analysis of Regulations to Reduce Paracetamol (Acetaminophen) Poisoning 
PLoS Medicine  2007;4(4):e105.
Background
Paracetamol (acetaminophen) poisoning is the leading cause of acute liver failure in Great Britain and the United States. Successful interventions to reduced harm from paracetamol poisoning are needed. To achieve this, the government of the United Kingdom introduced legislation in 1998 limiting the pack size of paracetamol sold in shops. Several studies have reported recent decreases in fatal poisonings involving paracetamol. We use interrupted time-series analysis to evaluate whether the recent fall in the number of paracetamol deaths is different to trends in fatal poisoning involving aspirin, paracetamol compounds, antidepressants, or nondrug poisoning suicide.
Methods and Findings
We calculated directly age-standardised mortality rates for paracetamol poisoning in England and Wales from 1993 to 2004. We used an ordinary least-squares regression model divided into pre- and postintervention segments at 1999. The model included a term for autocorrelation within the time series. We tested for changes in the level and slope between the pre- and postintervention segments. To assess whether observed changes in the time series were unique to paracetamol, we compared against poisoning deaths involving compound paracetamol (not covered by the regulations), aspirin, antidepressants, and nonpoisoning suicide deaths. We did this comparison by calculating a ratio of each comparison series with paracetamol and applying a segmented regression model to the ratios. No change in the ratio level or slope indicated no difference compared to the control series. There were about 2,200 deaths involving paracetamol. The age-standardised mortality rate rose from 8.1 per million in 1993 to 8.8 per million in 1997, subsequently falling to about 5.3 per million in 2004. After the regulations were introduced, deaths dropped by 2.69 per million (p = 0.003). Trends in the age-standardised mortality rate for paracetamol compounds, aspirin, and antidepressants were broadly similar to paracetamol, increasing until 1997 and then declining. Nondrug poisoning suicide also declined during the study period, but was highest in 1993. The segmented regression models showed that the age-standardised mortality rate for compound paracetamol dropped less after the regulations (p = 0.012) but declined more rapidly afterward (p = 0.031). However, age-standardised rates for aspirin and antidepressants fell in a similar way to paracetamol after the regulations. Nondrug poisoning suicide declined at a similar rate to paracetamol after the regulations were introduced.
Conclusions
Introduction of regulations to limit availability of paracetamol coincided with a decrease in paracetamol-poisoning mortality. However, fatal poisoning involving aspirin, antidepressants, and to a lesser degree, paracetamol compounds, also showed similar trends. This raises the question whether the decline in paracetamol deaths was due to the regulations or was part of a wider trend in decreasing drug-poisoning mortality. We found little evidence to support the hypothesis that the 1998 regulations limiting pack size resulted in a greater reduction in poisoning deaths involving paracetamol than occurred for other drugs or nondrug poisoning suicide.
Analysis of mortality rates for paracetamol poisoning in England and Wales does not support the view that regulations limiting pack size have been responsible for a reduction in deaths.
Editors' Summary
Background.
Paracetamol—known as acetaminophen in the United States—is a cheap and effective painkiller. It is widely used to relieve minor aches and pains as well as fevers and headaches. Recommended doses of paracetamol are considered safe in humans, but overdoses are toxic and can cause liver failure and death. Because this drug is very easy to get hold of, there are many overdoses each year, either accidental or deliberate. In the UK, paracetamol poisoning is the most common cause of acute liver failure. Toward the end of 1998, new laws were introduced in the UK to try to reduce the number of paracetamol overdoses. These laws said that pharmacies could not sell packs of paracetamol containing more than 32 tablets and other shops could not sell packs with more than 16 tablets. One of the reasons behind the introduction of this law was that many suicides are not preplanned and, therefore, if it was harder for people to get hold of or keep large quantities of tablets, they might be less likely to attempt suicide or accidentally overdose.
Why Was This Study Done?
Following the introduction of these new laws, the number of deaths caused by paracetamol overdose in the UK dropped. However, it is possible that the drop in deaths came about for a variety of different reasons and not just as a result of the new laws on paracetamol pack size. For example, the suicide rate might have been falling anyway due to other changes in society and the fall in death rate from paracetamol might just have been part of that trend. It is important to find out whether the legal changes that were introduced to address a public health problem did in fact bring about a change for the better. This knowledge would also be relevant to other countries that are considering similar changes.
What Did the Researchers Do and Find?
The researchers used data from the Office of National Statistics, which holds information on drug poisoning deaths in England and Wales. These data were then broken down by the type of drug that was mentioned on the death certificate. The researchers compared death rates involving the following drugs: paracetamol; paracetamol-containing compounds (which were not subject to the new pack size laws); aspirin; antidepressant drugs; and then finally non-drug poisoning suicides. The reason for comparing death rates involving paracetamol against death rates involving other drugs, or non-drug suicide, was that this method would allow the researchers to see if the drop in paracetamol deaths followed overall trends in the poisoning or suicide rates or not. If the paracetamol death rate dropped following introduction of the new laws but the rates of other types of poisoning or suicide did not, then there would be a link between the new laws and a fall in paracetamol suicides. The researchers compared these death data within specific time periods before the end of 1998 (when the new laws on paracetamol pack size were introduced) and after.
Overall, there were nearly 2,200 deaths involving paracetamol between 1993 and 2004. The number of deaths per year involving paracetamol dropped substantially when comparing the periods of time before the end of 1998 and after it. However, the number of deaths per year involving any drug, and the non-drug suicides, also fell during this period of time. When comparing the trends for paracetamol deaths with other poisoning or suicide deaths, the researchers did not find any statistical evidence that the fall in paracetamol deaths was any different to the overall trend in poisoning or suicide death rates.
What Do These Findings Mean?
Although the paracetamol death rate fell immediately following the new laws on pack size, this study suggests the link might just be coincidence. The researchers could not find any data supporting the idea that the new laws caused a drop in paracetamol deaths. However, this was an observational study, not a true experimental one: the researchers here were clearly not able to set up equivalent “experimental” and “control” groups for comparison. It is very difficult to prove or disprove conclusively that new laws such as this are, or are not, effective.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040105
Information is available from Medline Plus about suicide
Wikipedia has an entry on paracetamol (note that Wikipedia is an internet encyclopedia anyone can edit)
Information about regulation of drugs in the UK is available from the Medicines and Healthcare Regulatory Agency
The Office for National Statistics provides key economic and social data about the UK, and is involved in many other important projects
doi:10.1371/journal.pmed.0040105
PMCID: PMC1845154  PMID: 17407385
14.  Choice of poison for intentional self-poisoning in rural Sri Lanka 
Background
Although intentional self-poisoning is a major public health problem in rural parts of the Asia-Pacific region, relatively little is known of its epidemiology. We aimed to determine why Sri Lankan self-poisoning patients choose particular poisons, and whether acts of self-harm with highly dangerous poisons were associated with more premeditation and effort.
Methods
We interviewed 268 self-poisoning patients presenting to two district general hospitals in rural Sri Lanka.
Results
85% of patients cited easy availability as the basis for their choice of poison. There was little premeditation: more than 50% ingested the poison less than 30 minutes after deciding to self-harm. Patients had little knowledge about treatment options or lethality of the poison chosen. We found no difference in reasons for choice of poison between people ingesting different poisons, despite marked differences in toxicity, and between people who died and those who survived.
Conclusions
Poisons were chosen on the basis of availability, often at short notice. There was no evidence that people using highly toxic poisons made a more serious or premeditated attempt. Restrictions on availability of highly toxic poisons in rural communities must be considered in strategies to reduce the number of intentional self-poisoning deaths in the Asia Pacific region.
PMCID: PMC1940039  PMID: 16749546
15.  Use of paracetamol for suicide and non-fatal poisoning in the UK and France: are restrictions on availability justified? 
OBJECTIVE: To investigate the relationship between the availability of paracetamol and its use for overdose and suicide. DESIGN: Analysis of routinely collected information on time trends for paracetamol suicides, non-fatal overdoses, and sales. SETTING: England and Wales and France. RESULTS: There were strong correlations between trends in paracetamol sales in the UK and trends in non-fatal paracetamol overdose in Oxford between 1976 and 1993 (Spearman's r = 0.86; 95% confidence interval (CI) 0.54, 0.96) and between paracetamol sales and non-fatal overdoses in France between 1974 and 1990 (r = 0.99; 95% CI 0.97, 1.00). Sales figures were also correlated with paracetamol related suicides in both England and Wales, 1983-91 (r = 0.72; 95% CI 0.11, 0.94) and France, 1974-90 (r = 0.79; 95% CI 0.50, 0.92). Similarly strong relationships were observed between trends in non-fatal overdoses and suicide by paracetamol poisoning in England and Wales (r = 0.85; 95% CI 0.61, 0.95) and France (r = 0.79; 95% CI 0.50, 0.92). It is estimated that approximately 32,000 overdoses involving paracetamol occur annually in England and Wales. Fatality rates from paracetamol overdose were four times as high in England and Wales (0.4%, 95% CI 0.38, 0.46) as in France (0.1%, 95% CI 0.06, 0.17). CONCLUSION: Trends towards greater availability of paracetamol are paralleled by increases in its use for both non-fatal overdose and suicide. Paracetamol related morbidity and mortality seem to be less frequent in France where the quantity of paracetamol in a single purchase is limited. Although not conclusive, these data add to a body of evidence which suggests that restrictions in the quantity of paracetamol available as a single purchase in the UK may reduce suicide and liver failure related to paracetamol.
PMCID: PMC1060441  PMID: 9196648
16.  Effects of legislation restricting pack sizes of paracetamol and salicylate on self poisoning in the United Kingdom: before and after study 
BMJ : British Medical Journal  2001;322(7296):1203.
Objective
To evaluate the effects on suicidal behaviour of legislation limiting the size of packs of paracetamol and salicylates sold over the counter.
Design
Before and after study.
Setting
UK population, with detailed monitoring of data from five liver units and seven general hospitals, between September 1996 and September 1999.
Subjects
People who died by suicidal or accidental overdose with paracetamol or salicylates or who died of undetermined causes; patients admitted to liver units with hepatic paracetamol poisoning; patients presenting to general hospitals with self poisoning after taking paracetamol or salicylates.
Main outcome measures
Mortality from paracetamol or salicylate overdose; numbers of patients referred to liver units or listed for liver transplant; numbers of transplantations; numbers of overdoses and tablets taken; blood concentrations of the drugs; prothrombin times; sales to pharmacies and other outlets of paracetamol and salicylates.
Results
Numbers of tablets per pack of paracetamol and salicylates decreased markedly in the year after the change in legislation on 16 September 1998. The annual number of deaths from paracetamol poisoning decreased by 21% (95% confidence interval 5% to 34%) and the number from salicylates decreased by 48% (11% to 70%). Liver transplant rates after paracetamol poisoning decreased by 66% (55% to 74%). The rate of non-fatal self poisoning with paracetamol in any form decreased by 11% (5% to 16%), mainly because of a 15% (8% to 21%) reduction in overdoses of paracetamol in non-compound form. The average number of tablets taken in paracetamol overdoses decreased by 7% (0% to 12%), and the proportion involving >32 tablets decreased by 17% (4% to 28%). The average number of tablets taken in salicylate overdoses did not decrease, but 34% fewer (2% to 56%) salicylate overdoses involved >32 tablets. After the legislation mean blood concentrations of salicylates after overdose decreased, as did prothrombin times; mean blood concentrations of paracetamol did not change.
Conclusion
Legislation restricting pack sizes of paracetamol and salicylates in the United Kingdom has had substantial beneficial effects on mortality and morbidity associated with self poisoning using these drugs.
What is already known on this topicParacetamol and salicylate overdoses are very common in the United Kingdom and are associated with high levels of mortality and morbidityInternational comparison shows that national mortality from paracetamol overdose may be related to the maximum number of tablets in individual preparationsLegislation to limit the size of packs of paracetamol and salicylates was introduced in the United Kingdom in September 1998What this study addsThe number of tablets in packets of paracetamol and salicylate preparations decreased markedly in the 12 months after the legislationThe number of deaths from self poisoning with paracetamol alone and with salicylates alone decreased after the legislationThere was also a decrease in the number of liver transplants and admissions to liver units with hepatic paracetamol poisoning and in the number of overdoses of paracetamol and salicylates in which large numbers of tablets were taken
PMCID: PMC31616  PMID: 11358770
17.  The Spectrum of Intermediate Syndrome Following Acute Organophosphate Poisoning: A Prospective Cohort Study from Sri Lanka 
PLoS Medicine  2008;5(7):e147.
Background
Intermediate syndrome (IMS) is a major cause of death from respiratory failure following acute organophosphate poisoning. The objective of this study was to determine repetitive nerve stimulation (RNS) predictors of IMS that would assist in patient management and clinical research.
Methods and Findings
Seventy-eight consenting symptomatic patients with organophosphate poisoning were assessed prospectively with daily physical examination and RNS. RNS was done on the right and left median and ulnar nerves at 1, 3, 10, 15, 20, and 30 Hz. The study was conducted as a prospective observational cohort study in the Central Province, Sri Lanka. IMS was diagnosed in ten out of 78 patients using a priori clinical diagnostic criteria, and five of them developed respiratory failure. All ten patients showed progressive RNS changes correlating with the severity of IMS. A decrement-increment was observed at intermediate and high frequencies preceding the onset of clinical signs of IMS. As the patient developed clinical signs of IMS, decrement-increment was progressively noted at low and intermediate frequencies and a combination of decrement-increment and repetitive fade or severe decrement was noted at high frequencies. Severe decrement preceded respiratory failure in four patients. Thirty patients developed forme fruste IMS with less severe weakness not progressing to respiratory failure whose RNS was characterized by decrement-increment or a combination of decrement-increment and repetitive fade but never severe decrements.
Conclusions
Characteristic changes in RNS, preceding the development of IMS, help to identify a subgroup of patients at high risk of developing respiratory failure. The forme fruste IMS with the characteristic early changes on RNS indicates that IMS is a spectrum disorder. RNS changes are objective and precede the diagnosis and complications of IMS. Thus they may be useful in clinical management and research.
Jayawardane and colleagues evaluate a cohort of 78 patients with organophosphate poisoning from Sri Lanka, and identify changes in repetitive nerve stimulation that precede, and may help predict, the onset of intermediate syndrome.
Editors' Summary
Background.
Each year, many thousands of deaths around the world are caused by pesticide poisoning. Often, the pesticide involved is an organophosphate. These highly toxic compounds, which are widely used in agriculture, particularly in developing countries, disrupt the transmission of messages from the brain to the body in insect pests and in people. The brain controls body movements by sending electrical impulses along nerve cells (neurons). At the end of the neurons, these impulses are converted into chemical messengers (neurotransmitters), which cross the gap between neurons and muscle cells (the neuromuscular junction) and bind to proteins on the surface of the muscle cells to pass on the brain's message. One important neurotransmitter is acetylcholine. This is used in the part of the nervous system that controls breathing and other automatic vital functions, at neuromuscular junctions, and in parts of the central nervous system. Normally, acetylcholine is quickly broken down after it has delivered its message, but organophosphates disrupt this process and, consequently, affect nerve transmission to muscles. Organophosphate poisoning causes three syndromes. The cholinergic syndrome, which can be fatal, happens soon after organophosphates are swallowed, inhaled, or absorbed through the skin. The intermediate syndrome (IMS), which results in muscle weakness in the limbs, neck, and throat, develops in some patients 24–96 hours after poisoning. Finally, long-term nerve damage sometimes develops 2–3 weeks after poisoning.
Why Was This Study Done?
Although IMS is a major contributor to the illness caused by organophosphate poisoning and can result in respiratory (breathing) failure and death, the functional changes that are associated with IMS (its pathophysiology) are poorly understood. With a better understanding of these changes, it might be possible to find ways to prevent or treat IMS or to predict which patients with IMS are likely to develop respiratory failure. In this study, the researchers make a set of measurements of nerve transmission in a large group of organophosphate-poisoned patients in Sri Lanka to discover more about the pathophysiology of IMS.
What Did the Researchers Do and Find?
Seventy-eight patients with organophosphate poisoning were assessed several times a day for clinical signs of IMS. In addition, nerve transmission was measured daily in the patients using an electrophysiological technique called repetitive nerve stimulation (RNS). For this, a series of small electrical shocks was applied to the certain nerves in the arm and the responses in the muscles that these nerves control were recorded. In the ten study participants who developed IMS, the researchers observed several characteristic changes in their muscle responses to RNS, some of which were seen before the clinical signs of IMS. Other changes in muscle responses to RNS correlated with the development of clear IMS. Most importantly, in the four patients with IMS who developed respiratory failure, an RNS response pattern called severe decrement (a reduced response to the first electrical shock and then no response to the subsequent shocks) was seen before respiratory failure. Finally, there were other characteristic changes in muscle responses to RNS in 30 patients with muscle weakness not severe enough for a diagnosis of IMS (incomplete or “forme fruste” IMS).
What Do These Findings Mean?
These findings indicate that changes in nerve transmission that can be objectively monitored using RNS evolve during the development of IMS. In other words, IMS is a “spectrum” disorder in which the weakness and neuromuscular junction problems caused by organophosphate poisoning gradually progress over time through a series of electrophysiological changes that will sometimes resolve quickly and only in the most severe cases will result in respiratory failure. These findings need to be validated in further studies, particularly since most of the patients in this study had been exposed to a single organophosphate (chlorpyrifos). However, they suggest that the RNS tests might be useful in the clinical management of patients with organophosphate poisoning, particularly since such tests could provide an early warning of impending respiratory failure.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050147.
This study is further discussed in a PLoS Medicine Perspective by Cynthia Aaron
The US Environmental Protection Agency provides information about all aspects of pesticides (in English and Spanish)
Toxtown, an interactive site from the US National Library of Science, provides information on environmental health concerns including exposure to pesticides (in English and Spanish)
The US National Pesticide Information Center provides objective, science-based information about pesticides
MedlinePlus also provides links to information on pesticides (in English and Spanish)
The International Programme on Chemical Safety has information on poisoning prevention and management; its INTOX databank has a description of the cholinergic syndrome
WikiTox is a clinical toxicology resource
doi:10.1371/journal.pmed.0050147
PMCID: PMC2459203  PMID: 18630983
18.  Acute poisoning: an update. 
Treatment of the patient who has taken an overdose of a harmful substance includes support of vital functions and toxicologic analysis. Early recognition of signs and symptoms indicating poisoning by a specific agent or group of related chemicals is essential since specific antidotes may be lifesaving. Activated charcoal is an effective gastrointestinal decontaminant that adsorbs many common drugs. Administration of weak acids as an antidote to alkali ingestion is to be condemned; the only treatment should be dilution with water. The use of physostigmine as a specific antidote for the anticholinergic syndrome has been very successful; the incidence of this syndrome as a result of poisoning by tricyclic antidepressants is increasing. Effective therapy for acetaminophen overdose is still being investigated, but activated charcoal and methionine, if given early enough, seem to be effective.
PMCID: PMC1879766  PMID: 890634
19.  Comparison of two commonly practiced atropinisation regimens in acute organophosphorus and carbamate poisoning, doubling doses vs ‘ad hoc’ - a prospective observational study 
Human & experimental toxicology  2008;27(6):513-518.
Objective
There is wide variation and lack of evidence in current recommendations for atropine dosing schedules leading to subsequent variation in clinical practice. Therefore we sought to examine the safety and effectiveness of a titrated versus ‘ad hoc’ atropine treatment regimen in a cohort of patients with acute cholinesterase inhibitor pesticide poisoning.
Design
A prospective cohort study was conducted in 3 district secondary referral hospitals in Sri Lanka using a structured data collection form that collected details of clinical symptoms and outcomes of cholinesterase inhibitor pesticide poisoning, atropine doses and signs of atropinisation. We compared two hospitals that used a titrated dosing protocol based on a structured monitoring sheet for atropine infusion with another hospital using an ‘ad hoc’ regime.
Findings
During the study 272 symptomatic patients with anticholinesterase poisoning requiring atropine were admitted to the three hospitals. Outcomes of death and ventilation were analyzed for all patients, 226 patients were prospectively assessed for atropine toxicity. At baseline patients in the titrated dose cohort had clinical signs consistent with greater toxicity. This in part may be due to ingestion of more toxic OPs. They received less pralidoxime and atropine and were less likely to develop features of atropine toxicity such as delirium (1% vs 17%), hallucinations (1% vs 35%) or either (1% vs 35%) and need for patient restraint (3% vs 48%) compared with the ‘ad hoc’ dose regime. After adjusting for the pesticides ingested, there was no difference in mortality and ventilatory rates between protocols.
Conclusions
‘Ad hoc’ high dose atropine regimens are associated with more frequent atropine toxicity without any obvious improvement in patient outcome compared with doses titrated to clinical effect. Atropine doses should be titrated against response and toxicity. Further education and the use of a structured monitoring sheet may assist in more appropriate atropine use in anticholinesterase pesticide poisoning.
doi:10.1177/0960327108091861
PMCID: PMC3145133  PMID: 18784205
Atropine toxicity; Organophosphorous poisoning; atropinisation protocols
20.  A community-based cluster randomised trial of safe storage to reduce pesticide self-poisoning in rural Sri Lanka: study protocol 
BMC Public Health  2011;11:879.
Background
The WHO recognises pesticide poisoning to be the single most important means of suicide globally. Pesticide self-poisoning is a major public health and clinical problem in rural Asia, where it has led to case fatality ratios 20-30 times higher than self-poisoning in the developed world. One approach to reducing access to pesticides is for households to store pesticides in lockable "safe-storage" containers. However, before this approach can be promoted, evidence is required on its effectiveness and safety.
Methods/Design
A community-based cluster randomised controlled trial has been set up in 44,000 households in the North Central Province, Sri Lanka. A census is being performed, collecting baseline demographic data, socio-economic status, pesticide usage, self-harm and alcohol. Participating villages are then randomised and eligible households in the intervention arm given a lockable safe storage container for agrochemicals.
The primary outcome will be incidence of pesticide self-poisoning over three years amongst individuals aged 14 years and over. 217,944 person years of follow-up are required in each arm to detect a 33% reduction in pesticide self-poisoning with 80% power at the 5% significance level. Secondary outcomes will include the incidence of all pesticide poisoning and total self-harm.
Discussion
This paper describes a large effectiveness study of a community intervention to reduce the burden of intentional poisoning in rural Sri Lanka. The study builds on a strong partnership between provincial health services, local and international researchers, and local communities. We discuss issues in relation to randomisation and contamination, engaging control villages, the intervention, and strategies to improve adherence.
Trial Registritation
The trial is registered on ClinicalTrials.gov ref: NCT1146496 (http://clinicaltrialsfeeds.org/clinical-trials/show/NCT01146496).
doi:10.1186/1471-2458-11-879
PMCID: PMC3227631  PMID: 22104027
21.  Identification of strategies to prevent death after pesticide self‐poisoning using a Haddon matrix 
Injury Prevention  2006;12(5):333-337.
Despite pesticide self‐poisoning causing around 300 000 deaths each year in the rural Asia Pacific region, no comprehensive public health response has yet been formulated. The authors have developed a Haddon matrix to identify factors that increase the risk of fatal rather than non‐fatal pesticide self‐poisoning in Sri Lanka. Many important host factors such as age, gender, and genetics are not alterable; factors that could be changed—alcohol use and mental health—have previously proved difficult to change. Interventions affecting agent or environmental factors may be easier to implement and more effective, in particular those limiting the human toxicity and accessibility of the pesticides, and the quality, affordability, and accessibility of health care in the community. Controlled studies are required to identify effective strategies for prevention and harm minimization and to garner political support for making the changes necessary to reduce this waste of life. Lessons learnt from Sri Lanka are likely to be highly relevant for much of rural Asia.
doi:10.1136/ip.2006.012641
PMCID: PMC1950775  PMID: 17018677
Haddon matrix; pesticide; prevention; self‐poisoning; suicide
22.  Identification of Strategies to Prevent Death after Pesticide Self-Poisoning using a Haddon Matrix 
Despite pesticide self-poisoning causing around 300,000 deaths each year in the rural Asia-Pacific region, no comprehensive public health response has yet been formulated. We have developed a Haddon matrix to identify factors that increase the risk of fatal rather than non-fatal pesticide self-poisoning in Sri Lanka. Many important host factors such as age, gender, and genetics are not alterable; factors that could be changed - alcohol use and mental health - have previously proved difficult to change. Interventions affecting agent or environmental factors may be easier to implement and more effective, in particular those limiting the human toxicity and accessibility of the pesticides, and the quality, affordability, and accessibility of health care in the community. Controlled studies are required to identify effective strategies for prevention and harm minimization and to garner political support for making the changes necessary to reduce this waste of life. Lessons learnt from Sri Lanka are likely to be highly relevant for much of rural Asia.
doi:10.1136/ip.2006.012641
PMCID: PMC1950775  PMID: 17018677
23.  Long-term Event-related Potential Changes following Organophosphorus Insecticide Poisoning 
Objective
To determine prolonged effects of organophosphorus (OP) insecticide poisoning on cognitive event-related potentials (ERPs).
Method
ERPs of a group of 32 patients recovered from cholinergic phase of OP insecticide poisoning were compared with those of two matched control groups: 32 healthy volunteers and nine patients hospitalised with paracetamol overdose. A follow-up assessment was done in 21 patients (66% of the initial sample) six months after OP intoxication and the findings were compared with their initial ERP data.
Results
Patients showed highly significant prolongation of P300 latency, compared to healthy controls (p=0.003) and the controls with paracetamol overdose (p=0.016). Follow-up ERP findings of the patients revealed that this impairment remained unchanged even six months after OP poisoning (p=0.790). There was no significant difference in N100, P200 and N200 latencies or P300 amplitude either among the groups or between the two assessments of the patients with OP poisoning.
Conclusion
Our results suggest that acute OP poisoning causes a delay in cognitive processes involved in stimulus classification, lasting at least for six months.
Significance
These findings highlight the possibility of development of long-lasting cognitive deficits following OP insecticide poisoning, and warrant longer-term prospective studies to determine whether this impairment is permanent.
doi:10.1016/j.clinph.2007.09.134
PMCID: PMC3145126  PMID: 18042425
organophosphorus insecticide poisoning; cognitive effects; P300; event-related potentials
24.  UK legislation on analgesic packs: before and after study of long term effect on poisonings 
BMJ : British Medical Journal  2004;329(7474):1076.
Objective To evaluate the long term effect of legislation limiting the size of packs of analgesics sold over the counter.
Design Before and after study.
Setting Suicides in England and Wales, data from six liver units in England and Scotland and five general hospitals in England, and UK data on sales of analgesics, between September 1993 and September 2002.
Data sources Office for National Statistics; six liver units in England and Scotland; monitoring systems in general hospitals in Oxford, Manchester, and Derby; and Intercontinental Medical Statistics Health UK.
Main outcome measures Deaths by suicidal overdose with paracetamol, salicylates, or ibuprofen; numbers of patients admitted to liver units, listed for liver transplant, and undergoing transplantations for paracetamol induced hepatotoxicity; non-fatal self poisonings with analgesics and numbers of tablets taken; and sales figures for analgesics.
Results Suicidal deaths from paracetamol and salicylates were reduced by 22% (95% confidence interval 11% to 32%) in the year after the change in legislation on 16 September 1998, and this reduction persisted in the next two years. Liver unit admissions and liver transplants for paracetamol induced hepatotoxicity were reduced by around 30% in the four years after the legislation. Numbers of paracetamol and salicylate tablets in non-fatal overdoses were reduced in the three years after the legislation. Large overdoses were reduced by 20% (9% to 29%) for paracetamol and by 39% (14% to 57%) for salicylates in the second and third years after the legislation. Ibuprofen overdoses increased after the legislation, but with little or no effect on deaths.
Conclusion Legislation restricting pack sizes of analgesics in the United Kingdom has been beneficial. A further reduction in pack sizes could prevent more deaths.
doi:10.1136/bmj.38253.572581.7C
PMCID: PMC526120  PMID: 15516343
25.  Scottish and Newcastle Antiemetic Pre-treatment for paracetamol poisoning study (SNAP) 
Background
Paracetamol (acetaminophen) poisoning remains the commonest cause of acute liver injury in Europe and North America. The intravenous (IV) N-acetylcysteine (NAC) regimen introduced in the 1970s has continued effectively unchanged. This involves 3 different infusion regimens (dose and time) lasting over 20 hours. The same weight-related dose of NAC is used irrespective of paracetamol dose. Complications include frequent nausea and vomiting, anaphylactoid reactions and dosing errors. We designed a randomised controlled study investigating the efficacy of antiemetic pre-treatment (ondansetron) using standard NAC and a modified, shorter, regimen.
Methods/Design
We designed a double-blind trial using a 2 × 2 factorial design involving four parallel groups. Pre-treatment with ondansetron 4 mg IV was compared against placebo on nausea and vomiting following the standard (20.25 h) regimen, or a novel 12 h NAC regimen in paracetamol poisoning. Each delivered 300 mg/kg bodyweight NAC. Randomisation was stratified on: paracetamol dose, perceived risk factors, and time to presentation. The primary outcome was the incidence of nausea and vomiting following NAC. In addition the frequency of anaphylactoid reactions and end of treatment liver function documented. Where clinically necessary further doses of NAC were administered as per standard UK protocols at the end of the first antidote course.
Discussion
This study is primarily designed to test the efficacy of prophylactic anti-emetic therapy with ondansetron, but is the first attempt to formally examine new methods of administering IV NAC in paracetamol overdose. We anticipate, from volunteer studies, that nausea and vomiting will be less frequent with the new NAC regimen. In addition as anaphylactoid response appears related to plasma concentrations of both NAC and paracetamol anaphylactoid reactions should be less likely. This study is not powered to assess the relative efficacy of the two NAC regimens, however it will give useful information to power future studies. As the first formal randomised clinical trial in this patient group in over 30 years this study will also provide information to support further studies in patients in paracetamol overdose, particularly, when linked with modern novel biomarkers of liver damage, patients at different toxicity risk.
Trial registration
EudraCT number 2009-017800-10, ClinicalTrials.gov IdentifierNCT01050270
doi:10.1186/2050-6511-14-20
PMCID: PMC3626543  PMID: 23556549
Paracetamol; Acetylcysteine; Overdose; Antidotes; Hepatotoxicity

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