Ian M. Whyte

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.

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)

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.

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.

Activated Charcoal Reduces the Need for N-Acetylcysteine Treatment After Acetaminophen (Paracetamol) Overdose

BACKGROUND The evidence for efficacy of gastric lavage and activated charcoal for gastrointestinal decontamination in poisoning has relied entirely on volunteer studies and/or pharmacokinetic studies and evidence for any clinical benefits or resource savings is lacking. AIM OF STUDY To investigate the value of gastrointestinal decontamination using gastric lavage and/or activated charcoal in acetaminophen (paracetamol) poisoning. PATIENTS AND METHODS We analyzed a series of 981 consecutive acetaminophen poisonings. These patients were treated with gastric lavage and activated charcoal, activated charcoal alone, or no gastrointestinal decontamination. The decision as to which treatment was received was determined by patient cooperation, the treating physician, coingested drugs, and time to presentation after the overdose. RESULTS Of 981 patients admitted over 10 years, 10% (100) had serum concentrations of acetaminophen that indicated a probable or high risk of hepatotoxicity. The risk of toxic concentrations for patients ingesting less than 10 g of acetaminophen was very low. In patients presenting within 24 hours, who had ingested 10 g or more, those who had been given activated charcoal were significantly less likely to have probable or high risk concentrations (Odds ratio 0.36, 95% CI 0.23-0.58, p < 0.0001). Gastric lavage, in addition to activated charcoal, did not further decrease the risk (Odds ratio 1.12, 95% CI 0.57-2.20, p = 0.86). CONCLUSIONS Toxic concentrations of serum acetaminophen (paracetamol) are uncommon in patients ingesting less than 10 g. In those ingesting more, activated charcoal appears to reduce the number of patients who achieve toxic acetaminophen concentrations and thus may reduce the need for treatment and hospital stay.

Quetiapine Poisoning: A Case Series

STUDY OBJECTIVE We describe the effects of quetiapine in overdose. METHODS Quetiapine poisonings were identified from a prospective database of poisoning admissions to a regional toxicology service. Data extracted included details of ingestion, clinical features, investigations (including ECG), and other outcomes (length of stay and ICU admission rate). RESULTS There were 45 cases of quetiapine overdose, of which 18 patients with quetiapine assay results were included. Median length of stay was 35 hours (interquartile range [IQR] 14 to 42 hours) for the 18 patients, and 9 were admitted to the ICU. The median ingested dose was 3.5 g (IQR 1.7 to 6.2 g), and reported ingested dose was highly correlated with estimated peak drug concentration (r(2)=0.84; P<.0001), confirming patient-provided history of ingestion. Seizures occurred in 2 patients, delirium occurred in 3 patients, and mechanical ventilation was required in 4 patients. No arrhythmias or deaths occurred. Six of the 18 patients ingested quetiapine alone, with a median length of stay of 35 hours, and 3 were admitted to the ICU. In 1 patient who ingested 24 g, hypotension and seizures occurred. For 10 patients for whom ECGs were available and who had ingested no cardiotoxic drugs, tachycardia occurred in 8 patients. For these 10 patients, the mean corrected QT (QTc) interval was increased at 487 ms, but the mean uncorrected QT interval was 349 ms. Reported dose and peak quetiapine concentrations were significantly associated with ICU admission and length of stay more than 24 hours. A reported dose less than 3 g and a Glasgow Coma Scale score not less than 15 predicted patients not requiring ICU admission or length of stay more than 24 hours. CONCLUSION Quetiapine overdose causes central nervous system depression and sinus tachycardia. In large overdoses, patients may require intubation and ventilation for associated respiratory depression. Although a prolonged QTc occurs, its clinical significance is unclear because it is most likely caused by an overcorrection caused by the tachycardia. In our experience, a reported dose of less than 3 g for patients who are not drowsy (with a Glasgow Coma Scale score of 15) at least 4 hours after ingestion and who did not coingest another toxic agent defined a group not requiring ICU admission or inpatient admission greater than 24 hours.

Aspiration pneumonitis in an overdose population: frequency, predictors, and outcomes.

ObjectiveTo characterize the frequency of aspiration pneumonitis in an unselected population of overdose patients and, further, to identify factors that predispose to aspiration pneumonitis and the outcomes of patients with aspiration pneumonitis compared with those without. DesignRetrospective cohort study. SettingToxicology unit of a tertiary referral hospital. PatientsAll poisoning admissions. Measurements and Main ResultsA total of 71 of 4,562 poisoning admissions to the Hunter Area Toxicology Service between January 1997 and October 2002 had definite aspiration pneumonitis (1.6%; 95% confidence interval, 1.2–2.0). Older age, Glasgow Coma Score of <15, spontaneous emesis, seizures, delayed presentation to hospital, and ingestion of tricyclic antidepressants were associated with an increased risk of aspiration pneumonitis. Paracetamol poisoning and female sex were associated with a decreased risk of aspiration pneumonitis with univariate analysis. Ingestion of alcohol, benzodiazepines, antipsychotics, and administration of activated charcoal were not associated with aspiration pneumonitis. A logistic regression model for predicting aspiration pneumonitis contained seven predictors: age, sex, Glasgow Coma Score of <15 (odds ratio, 3.14; 95% confidence interval, 1.87–5.27), emesis (odds ratio, 4.17; 95% confidence interval, 2.44–7.13), seizure, tricyclic antidepressant ingestion, and time from ingestion to presentation (delay of >24 hrs [odds ratio, 4.42; 95% confidence interval, 2.42–8.10]). The mortality for patients with aspiration pneumonitis was 8.5% compared with 0.4% for those without (odds ratio, 23; 95% confidence interval, 9–60; p < .0001), and they had a significantly higher intensive care unit admission rate. The median length of stay of patients with aspiration pneumonitis was 126 hrs (interquartile range, 62–210 hrs) compared with 14.7 hrs (interquartile range, 7–23 hrs) in patients without (p < .0001). ConclusionsOur study has shown a number of risk factors in overdose patients that are associated with aspiration pneumonitis that may allow the early identification of these patients for appropriate observation and management. Patients with aspiration pneumonitis have a significantly increased mortality and length of stay in the hospital.

Lithium toxicity: an iatrogenic problem in susceptible individuals

Objective: Lithium toxicity, manifesting primarily as neurotoxicity, is a significant health problem and is primarily iatrogenic in nature. Despite 50 years of medical experience with lithium, factors contributing to the development of severe neurotoxicity remain poorly documented. We hypothesized that severe neurotoxicity represents the most clinically significant manifestation of lithium toxicity. We proposed that this occurs primarily in the context of chronic therapeutic administration (‘chronic poisoning’), rather than in the context of an overdose. Furthermore we hypothesized that patients who developed chronic poisoning did so in the presence of identifiable factors which predictably impair lithium clearance. Method: A retrospective analysis of 97 cases of lithium poisoning, treated at a regional centre over a 13-year period was performed. Demographic data and factors considered likely to relate to the risk of developing lithium toxicity were recorded. Patients were classified according to mode of poisoning (acute, acute on chronic, or chronic) and according to severity of neurotoxicity (nil, mild, moderate, severe). The risk of developing severe neurotoxicity as a result of each mode of poisoning was assessed. The association between various risk factors and the development of chronic poisoning was assessed using a logistic regression model. Results: Twenty-eight cases were rated as suffering severe neurotoxicity; in 26 this developed in the context of chronic poisoning and in two in the context of acute on chronic poisoning. All patients who developed severe neurotoxicity had at least one putative risk factor present, regardless of mode of poisoning. Length of stay was significantly longer for cases with severe neurotoxicity compared to those without severe neurotoxicity (12 vs. 2 days, P < 0.001). Peak serum lithium concentrations were significantly higher in cases with severe neurotoxicity compared to those without (2.3 vs. 1.6 mmol/L, P = 0.02). Patients presenting with chronic poisoning had a substantially higher risk of severe neurotoxicity than those presenting after an overdose of lithium (Odds Ratio [OR] 136, 95%% CI 23–1300). A logistic regression model showed three factors contributed independently to the risk of chronic poisoning. These were: nephrogenic diabetes insipidus (adjusted OR 26.96, 95%% CI 2.89–251.94), age over 50 years (adjusted OR 6.20, 95%% CI 1.36–28.32) and thyroid dysfunction (adjusted OR 9.30, 95%% CI 1.36–63.66). A fourth factor, baseline endogenous creatinine clearance below normal limits, was significant at the P = 0.05 level (adjusted OR 6.49, 95%% CI 0.98–43.01). Hyperparathyroidism was noted in three cases of chronic poisoning suffering severe neurotoxicity. Conclusion: Severe lithium neurotoxicity occurs almost exclusively in the context of chronic therapeutic administration of lithium, and rarely results from acute ingestion of lithium, even in patients currently taking lithium. As such it is an iatrogenic illness, occurring in patients who have identifiable clinical risk factors: nephrogenic diabetes insipidus, older age, abnormal thyroid function and impaired renal function. Although administration of drugs which impair lithium clearance appeared to contribute minimally to chronic lithium poisoning in the absence of other factors, these drugs may well ‘uncover’ the predisposing risk factors and certainly should not be considered safe to use as a consequence of this study. The serious morbidity suffered by lithium toxic patients, and the cost to society due to long hospital stays, might be reduced by careful prescribing, vigilant monitoring and awareness of these factors, as they develop in otherwise stable patients. Review of existing therapeutic guidelines may be warranted.

Acetaminophen causes an increased International Normalized Ratio by reducing functional factor VII.

Summary Acetaminophen may increase International Normalized Ratio (INR) in patients taking anticoagulation medication, and in patients with acetaminophen poisoning without hepatic injury. The objective of this study was to describe and investigate the effect of acetaminophen on INR. The authors studied patients admitted to a regional toxicology treatment center with acetaminophen poisoning with INR and without potentially confounding coingestion or hepatic injury. Exposed and nonexposed (control) cohorts were recruited from admissions with acetaminophen poisoning and psychotropic drug poisoning, respectively. From 1,437 acetaminophen poisonings, after exclusions, there were 143 admissions with 205 estimations of INR. INR showed a time-dependent increase. Fifty percent of all patients and 66% of those with an extrapolated 4-hour acetaminophen concentration ≥150 mg/L had an abnormal INR at some time. Dose ingested (p = 0.01) and nomogram-based risk (p for trend = 0.005) were correlated with the effect. N-acetylcysteine had a protective effect. Functional factor VII was lower (p = 0.005) in exposed patients (n = 30) than controls (n = 8), and less than antigenic factor VII in exposed patients (p = 0.03). Factor IX was lower (p = 0.02). Factor VIIIc was not significantly different. The authors concluded that an isolated, small rise in INR is common after acetaminophen poisoning without hepatic injury. It appears to be caused by inhibition of Vitamin K–dependent activation of coagulation factors. This effect suggests a possible mechanism for the observed interaction between acetaminophen and warfarin.