The Hunter Area Toxicology Service is a regional toxicology unit situated at the Newcastle Mater Misericordiae Hospital that services a population of about 350 000 people and is a tertiary referral centre for a further 150 000 [23]. All poisoning presentations to emergency departments in the region are either admitted to the unit or notified to the Hunter Area Toxicology Service and entered prospectively into a clinical database. A validated preformatted admission sheet is used by medical staff to record the history and physical examination at the time of admission [24]. This and additional information from the medical record is entered into the database by two trained personnel, blinded to any study hypotheses, at the time of patient discharge [25]. There was no review or further information retrieved from medical records after formulation of the research question.
Study population
The study population included all benzodiazepine overdose admissions between January 1987 and October 2002 that were a result of a deliberate self poisoning. Cases where patients had ingested two benzodiazepines were excluded so that only single benzodiazepine overdoses were used in the analysis. If a patient had multiple admissions for a benzodiazepine overdose only the first admission was included. Second and subsequent admissions were excluded to remove the bias of an individual susceptibility to a particular drug. Each benzodiazepine overdose admission was then coded by benzodiazepine type: alprazolam, diazepam or other benzodiazepine (bromazepam, clobazam, flunitrazepam, lorazepam, nitrazepam, oxazepam, temazepam and triazolam).
Data analyzed
From the database, the following information was obtained: patient demography (gender, age), details of alprazolam ingestion (time elapsed from ingestion to admission; estimation of amount ingested in defined daily doses [DDD]; co-ingested drugs); clinical features (including Glasgow coma score [GCS]), outcomes (length of stay [LOS] and intensive care unit [ICU] admission rate) and treatment (mechanical ventilation and flumazenil administration). Coma was defined as a GCS < 9. The DDD of alprazolam is 1 mg and of diazepam is 10 mg. For co-ingestant analysis ‘nontricyclic antidepressants’ included fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram, venlafaxine, moclobemide, mirtazapine and nefazodone.ICU admission criteria for patients presenting to the Hunter Area Toxicology Service are: mechanically ventilated or intubated patients, patients with a decreased level of consciousness (GCS < 9); patients requiring haemodynamic monitoring or circulatory support or who have other major organ dysfunction requiring dedicated nursing observation. The Hunter Area Toxicology Service has a standardized discharge policy requiring review by both the medical toxicology team and the psychiatry team.
Prescription data
Prescription data for Australia were obtained from the Health Insurance Commission for the years 1992–2002 (data not available prior to 1992). This contains the total number of prescriptions for each drug supplied under the Pharmaceutical Benefits Scheme. The number of prescriptions of all formulations for each benzodiazepine was obtained. The validity of using nationwide statistics for comparisons between drugs taken in the Hunter region has previously been established [26]. Data on the actual indications for the prescription of benzodiazepines was obtained from the Health Communication Network’s Copernicus Knowledge System. This represents a cross section of indications provided by Australian general practitioners via an electronic prescribing system for the period July 2002 to September 2002. It reflects the actual indication for the prescription rather those recommended in the product information
Statistical analysis
Five outcome variables (LOS, ICU admission rate, GCS < 9, flumazenil administration and requirement for mechanical ventilation) were used for comparison of toxicity of alprazolam with other benzodiazepines. The following potential predictor variables were included in univariate and multivariate analysis: benzodiazepine type (alprazolam, diazepam or other benzodiazepine), patient age (years), gender, benzodiazepine dose (converted to DDD), time from ingestion to hospital presentation and binary predictors for co-ingestion of tricyclic antidepressants (TCA), antipsychotics, non-TCA antidepressants, anticonvulsants, opiates, alcohol and paracetamol. To evaluate the relative toxicity of alprazolam the reference was taken as all other benzodiazepines (excluding diazepam). Diazepam was also compared with other benzodiazepines independently because it is the most commonly ingested, creating a categorical variable for benzodiazepine type with three possible values.Univariate analyses on the binary outcome variables (ICU admission, flumazenil, ventilation, coma) were conducted using simple logistic regression. Multivariate models on these outcome variables were determined using multiple logistic regression, employing both backward and forwards stepwise approaches. The outputs from the final models were reported as odds ratios (OR), with corresponding 95% confidence intervals (CI). Univariate analyses on (the natural log of) LOS was conducted using simple linear regression. Multivariate models of LOS were determined using multiple linear regression, employing both backward and forward stepwise approaches. The output from the final model was reported as coefficients, with corresponding 95% CIs. All statistical analyses were conducted in Stata (version 7, Stata Corporation, Texas USA).