prn8099 - Number 6, February 1996

 PRN 1995: Defining Moments 
Dzulkifli Abdul Razak

Looking back is often the key to moving ahead. In this anniversary issue of prn8099, we are looking back at the year 1995 as it unfolded in Malaysia and many countries around the globe. The one lesson learned is the need for an even greater awareness and commitment to a SAFER LIFESTYLE, one that is devoid of any unwarranted exposure to poisonous substances. Below are some of the major events that seem to characterise the direction for the coming year in terms of poisoning.

What happened in 1995?

At the home front in particular, major poison-related incidences could be traced almost every month last year. Some of these could have caused dire consequences if they had been poorly handled. Fortunately this was not the case but still the larger population were unnecessarily exposed to the risk of being poisoned. The biggest shock was certainly the dumping of 41 drums of potassium cyanide on the resort island of Pangkor in March last year. The poison alleged to be for industrial use, was estimated to be more than 2,000 kg, enough to kill 7 million people, let alone the devastation on the environment. This incident that caught almost everyone by surprise left us wondering as to how low our awareness about lethal chemicals is. It also raises many other questions that relate to importation, transportation, storage and even our capability to response to such-like emergencies should they were to occur. How such a large quantity got dumped in a resort island is a wonder in the first place. The one lesson learnt from the cyanide incident is that we are all vulnerable unless something concrete is done in a concerted manner. The danger of cyanide disaster was later exemplified in Guyana, South America in the month of August. It was caused by the indiscriminate discharge of more than 325 gallons of deadly cyanide-containing effluent produced in the mining of gold. Consequently more than 80 km of the Essequibo river, Guyana's longest, was poisoned affecting lives surrounding it. It was the country's worst environmental catastrophe.

Malaysia in this regard is still very fortunate but unless we multiply our efforts such disaster would be at our door step now that some states have shown interest to mine gold.

A month prior to the Pangkor cyanide incident was the nationwide alert on the retailing of a few brands of colour pencils containing excessive lead. The potential victims in this incident were school children who unknowingly bought the items. Another incident involving lead was the discovery of high content of the metal in salt of a particular commercial brand in December 1995. The sales of such items were eventually banned and the products withdrawn from the market. The relevant authorities should be commended for having spotted the problems, thus averting any untoward incidences.

A recurring poisoning theme last year relates to food. This is yet another form of poison exposure, albeit more insidious in nature. Apart from the contaminated salt case, in March there were cases of excessive benzoic acid (ranging from 1,400 to 13,000 ppm) in ground chilli paste (cili boh), while earlier in January, some brands of Indonesian-made layer cakes (kek lapis) were found to contain not only excessive benzoic acid but also sorbic acid. The occurrence of food poisoning was rather prevalent. For example, there were more than one incident involving more than a hundred people especially school children last year. In fact, according to the Ministry of Health there has been an increase in food poisoning cases from 1599 in 1993 to 2283 in 1994. Food poisoning even resulted in death as reported in April where a mother was found dead after having dinner in her house. Her two daughters were in coma. Thus the problems related to food poisoning need urgent attention and should be minimised with the new initiatives to be taken by the Health Ministry later in the year.

Related to this is the continued usage of two 'popular' poisons, namely cigarettes and alcohol. Their usage have caused a lot of concern associated with health and safety. Beginning from January 1995, manufacturers were required to state on cigarette boxes the new limits of nicotine and tar contained in a cigarette. There were also other new regulations to restrict smoking at public places. As for alcohol, law against drunk-driving was enforced on July 1 in the Klang Valley in view of the increasing number of motor accidents due to drunkenness. The ruling was later expanded to major cities in the country.

Yet another major incident is the chlorine gas exposure in Ipoh in May 1995, where more than 30 people were affected. The gas was released from 2 cylinders disposed at a metal scrap yard. Five months later, four people were reported dead allegedly caused by poisonous gas inhalation while cleaning a boat at Port Klang. Others were incidences involving a lorry tanker carrying more than 2,000 kg of hydrochloric acid that leaked near Taiping in June, and the dumping of 300-odd drums of lubricating oil in Kemaman in November 1995.

These few cases are already demonstrative of the dimensions and variety of problems that are related to poisoning. While these and other events were highlighted under News Headlines in the back issues of prn8099, there were numerous individual cases of poisoning that were reported directly to PRN. Until the end of the year as many as 46.7% of the cases reported to PRN involved pesticides; 24.6%, pharmaceuticals and 17.4% were household products. These cases, though did not make the headlines were nevertheless equally disconcerting and had caused a lot of sufferings. It is obvious that what captured the public attention is just the tip of the iceberg. The incidence of poisonings nationwide is a cause of grave concern.

How did PRN respond?
The year 1995 thus, provided many defining moments for PRN. Despite being newly established, it is faced with a number of pressing issues as mentioned above. It is indeed a challenging task given the fact PRN is still encountering several teething problems. To meet these challenges PRN immediately set up three main services, namely the Drug and Poison Information Services, Poison Prevention and Education Services and Research and Documentation Services as detailed in the inaugural issue of prn8099. Through these services, PRN is able to offer the much needed assistance and at the same time took a number of proactive measures. These are broadly in areas of prevention and education, as well as research. They include:

• installing a toll-free line (800-8099) - in February that would allow emergency cases to be dealt with more rapidly. This line has since then become the main line of communication in many poisoning cases. Clearly this has helped in the provision of information at the later stages of the services.
• enhancing awareness among the public and professionals about the activities of PRN by launching two bulletins. The first was through 'PenawaRacun' a bulletin in Bahasa Malaysia which began circulation in February, followed by other bimonthly issues. The second was another bimonthly bulletin prn8099, in English for professionals, which started in March. In all, ten issues were produced and circulated followed by an index issue 'PRN Index/Indeks '95'.
• starting weekly/biweekly columns in collaboration with the media namely The Sun, New Straits Times and Utusan Malaysia, as well as a monthly write-up in 'Dewan Kosmik', a science and technology magazine aimed at students. Via these means thousands were reached and in all more than 100 articles were written. This is a very popular initiative judging from the feedback received from the readers.
• pioneering a month long 'Anti-Smoking Telecampaign' in conjunction with the World Health No-Tobacco Day on May 31, 1995, and in support of the effort of the government to eliminate smoking. The campaign was well-received from all walks of life throughout the nation. The campaign has remained as a feature of PRN since.
• initiating a programme of Continuous Education on Clinical Toxicology (CECT) through its English bulletin. In 1995 about 50 professionals participated in the programme. The aim is to motivate professionals to be active in areas of toxicology and also build a critical mass of professionals that could offer assistance in cases of poisoning.
• providing training to staff from other centres in the handling drug and poison information as well as advising in the setting up of such centres. PRN also received attachments for research students from other foreign universities.
• providing consultancy. For example, one was concluded with an Italian company on matters relating to venomous snake. Others involved international agencies like WHO.
• signing a Memorandum of Understanding with Yayasan Sabah to conduct research on lead poisoning in pre-school children. The study will look at the extent of such poisoning in the state, if any. This is a pioneering effort to be undertaken in Malaysia.
• networking with other national and international centres.

And now, looking back, 1995 has given us some useful glimpses as to what lies ahead.

What is the future?

A full length diary of 1995 poisoning events around the globe was published in our weekly poison information column in The Sun Megazine - Healthtrack. It covers a global overview of major poisoning events around the world. Coupled with what were recorded in Malaysia, it is apparent that poisoning is very much an integral part of modern societies, be it accidental or deliberate. In view of this, PRN will intensify its effort in 1996 to continue and upgrade the provision of the various services. For example, PRN will expand into laboratory services as one of its primary goal. This would enable PRN to give more meaningful advise in cases that warrant such services. PRN is scheduled to move into its own premise in the second quarter of 1996. This would further enable PRN to further enhance its capability in line with its stated mission. It cannot be overstated that the work that lies ahead will be more challenging and certainly more exciting. As for now, PRN would like to record our thanks to all those who have cooperated very closely with us in seriously trying to make Malaysia a safer place to live in. We look forward to further heightened this collaborative partnerships.

PRN CONSULT                                                                                

Review of BENZODIAZEPINE Overdose
Abu Bakar Abdul Majeed, PhD

In Malaysia there are at least 11 types of benzodiazepines in the market. They are mostly prescribed either as minor tranquilizer or hypnotics/sedative.

Minor tranquilizer

• Alprazolam
• Bromazepam
• Chlordiazepoxide
• Clobazam
• Clorazepate
• Diazepam
• Lorazepam

Hypnotics/sedative 

• Flurazepam
• Midazolam
• Nitrazepam
• Triazolam

These products basically differ in their pharmacokinetic properties. Thus, they can also be divided into three groups on the basis of elimination half-life.

• Ultra-short acting (<10 hours)
  Midazolam 2-5 hours
  Triazolam 1.7-3 hours
• Short-acting (10-24 hours)
  Alprazolam 11-14 hours
  Bromazepam 8-20 hours
  Lorazepam 10-20 hours
• Long-acting (>24 hours)
  Chlordiazepoxide 5-30 hours
  Clorazepate 367-200 hours
  Clobazam 11-77 hours
  Diazepam 20-50 hours
  Flurazepam 50-100 hours
  Nitrazepam 21-25 hours

Are Benzodiazepine really safe?

Because of its supposedly wide safety margin, in many developed economy, benzodiazepines are considered the most common prescription drugs taken in overdose. Oral ingestion of up to 1,500 mg of diazepam with only minor toxicity has been reported. The body appears to adapt rapidly to high blood levels. This tolerance tends to limit central cardiorespiratory depression. Benzodiazepines also generally do not cause undesirable damages to the brain, heart, liver or kidneys. Respiratory depression may occur in overdose. Deep coma is rare, even following massive overdoses. Nevertheless, newly available data suggest that extra caution should be taken when prescribing the drug, as large differences were noted in the number of fatal poisoning of different benzodiazepine. For example, over 10 years in the United Kingdom, 1512 fatal poisonings have been attributed to benzodiazepine with or without alcohol. Of drugs frequently prescribed, temazepam had the highest number of deaths per million prescriptions (fatal toxicity index) at 11.9, above that of some tricyclic antidepressants. In contrast, oxazepam had an index of 2.3 while the index for all benzodiazepine combined was 5.7.

How do benzodiazepines induce toxic effects in overdose?
Specific benzodiazepine binding sites were discovered in 1977. These benzodiazepine receptors appear to be closely related to GABAA receptors in the cerebral cortex, limbic system, midbrain, brain stem and spinal cord. GABAA receptors produce an increase in chloride conductance. There is a mutual augmentation of binding between GABA and benzodiazepines. The two agents bind to independent sites on the same receptor-ion-channel complex, in a synergistic manner. Increased chloride conductance leads to hyperpolarization which tends to inhibits neuronal activity, thus resulting in the anti-anxiety effect of the drug.

At the same time, generalised depression of spinal reflexes and the reticular activating system may cause coma and respiratory arrest. Respiratory arrest is more likely with newer short-acting triazolobenzodiazepines such as triazolam, alprazolam and midazolam. Cardiopulmonary arrest may occur after rapid injection of diazepam, possibly due to CNS-depressant effects or because of the toxic effects of the diluent propylene glycol.

In general, the toxic-therapeutic ratio for benzodiazepines is very high. Oral overdoses of diazepam have been reported in excess of 15-20 times the therapeutic dose without serious depression of consciousness. In contrast respiratory arrest has been reported after ingestion of 5 mg of triazolam and after rapid intravenous injection of diazepam, midazolam, and many other benzodiazepines.

How do patients present with benzodiazepine poisoning?
Onset of CNS depression may be observed within 30-120 minutes of ingestion, depending on the compound. Lethargy, slurred speech, ataxia, coma, and respiratory arrest may occur. Generally, patients with benzodiazepine-induced coma have hyporeflexia and mid-position or small pupils. Hypothermia may occur. Serious complications are more likely when newer short-acting agents are involved or whenever other depressant drugs have been ingested. In young and middle-aged adults, benzodiazepine toxicity is usually mild unless the drug is taken in conjunction with other sedatives and alcohol.

Elderly and very young children are more susceptible to the central depressant action of benzodiazepines. Among the elderly, the toxicity of benzodiazepines takes on an additional dimension. Subtle but measurable cognitive impairment may be associated with both acute and chronic therapeutic doses of benzodiazepines. Unsteadiness and an increased predisposition to falling are not uncommon, so that extra caution must be exercised when benzodiazepines are prescribed.

The use of benzodiazepines in children has yet to be established. Nevertheless, two cases of psychosis had been reported in children who were given benzodiazepines. This involved visual and tactile hallucinations, sensitivity to bright light, impaired coordination, insomnia and frightened effect.

Although it is generally believed that an overdose of benzodiazepine alone does not cause death, however, temazepam overdose has been associated with at least two fatal poisonings. Two other patients with multiple severe medical problems died following overdoses of 25, 0.5 mg tablets of triazolam.

How does one diagnose and confirm benzodiazepine poisoning?
Diagnosis is usually based on the history of ingestion or recent injection. The differential diagnosis should include other sedative-hypnotic agents, antidepressants, antipsychotics, and narcotics. Coma and small pupils do not respond to naloxone but will reverse with administration of flumazenil, the benzodiazepine antagonist.

Benzodizepines plasma levels are not usually clinically useful. It can only confirm acute ingestion. Tolerance, drug coingestion (which is very common), active metabolites, and distant tissue binding sites reduce the correlation of blood benzodiazepine level to clinical effect. Nevertheless, they may be used as a useful guide. For diazepam, 5 to 20 (g/ml is considered as toxic while over 20(g/ml as lethal level. Massive chronic daily consumption of benzodiazepines results in blood levels of 5 to 6 (g/ml. A benzodiazepine blood levels of 11(g/ml has been detected in an alert patient and 22 (g/ml in a stuporous patient.

Respiratory depression is the main clinical abnormality leading to alveolar hypoventilation, hypoxia, and metabolic acidosis (coma).

What are the recommended emergency and supportive measures in cases of benzodiazepine overdose?

• Summary
  • Aggressive treatment of the respiratory depression with ventilatory support and flumazenil. Good primary care and continuous monitoring for respiratory depression is essential.
  • In case of overdose, if substances ingested may include tricyclic antidepressants, then use flumazenil cautiously. If patient shows signs of tricyclic overdose or has a known seizure disorder, flumazenil is not recommended.
  • Laboratory investigations are usually not helpful, unless otherwise indicated.
• Oral exposure
  • Emesis is generally not recommended because of the potential for CNS depression and coma with benzodiazepine overdose.
  • Gastric lavage should be initiated for ingestion greater than several times the therapeutic dose when the patient presents within 2 hours of ingestion, or in-patients who are comatose. Use 150-200 ml lukewarm water or saline per wash (for patients of 5 years and above) and 50 to 100 ml of normal saline per wash in young children. Continue until lavage return is clear. The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
  • Airway should always be protected either by body positioning or cuffed endotracheal intubation.
• Activated charcoal
  • If patient is presented within 4 hours of ingestion activated charcoal and cathartics should be given.
  • Administer charcoal as slurry (either aqueous or mixed with saline cathartic or sorbitol) 10 times the estimated ingested dose, or 10 to 300 g in adults, 15 to 30 g in children and 1 to 2 g/kg body weight for infants.
• Cathartics
  • CONTRAINDICATIONS: Cathartics should not be used in patients who have an ileus. Saline cathartics should not be used in patients with impaired renal function.
  • Administration of cathartics should be done in a health care facility with constant monitoring of fluid and electrolytes. Hypermagnesemia may occur after repeated administration of magnesium containing cathartics. Repeated cathartic administration, if at all required, should be done with extreme caution. In any case, cathartics should be stopped when charcoal stool appears.
  • A single dose administration of a saline cathartic or sorbitol, either separately or mixed with charcoal.
  • Saline cathartic One Oral Dose: Adult - 20 to 30 g of magnesium sulfate or magnesium citrate 4 ml/kg, up to 300 ml. Paediatric - 250 mg/kg magnesium/sodium sulphate or magnesium citrate, same dose as adult.
  • Sorbitol cathartic Oral Single Dose: Adult - 1 to 2 g/kg to maximum of 150 g. Paediatric (over 1 year) - 1 to 1.5 g/kg as a 35% solution to a maximum of 50 g.
    Note:During cathartic administration extra caution should be applied if adverse reactions are detected.
• Forced elimination
  • Diuresis/haemodialysis are ineffective.
  • Multiple-dose activated charcoal/cathartic may be initiated.
• Supportive care
  Most patients require only medical observation. Patients who are ambulating after 6 to 8 hours of observation may be discharged after appropriate psychiatric counseling.

Benzodiazepine overdose: Is flumazenil useful?
The currently available pure, competitive benzodiazepine antagonist is flumazenil. Flumazenil has been shown to be safe and effective for the reversal of benzodiazepine-induced sedation in volunteer studies and the clinical management of patients undergoing short procedures such as endoscopy or cardioversion. Adverse effects were rare, and include seizures, agitation, and restlessness, all of which were well tolerated. Thus, in cases of benzodiazepine poisoning in elderly, debilitated patients or when benzodiazepine intoxication is combined with other drugs, the use of the antidote is recommended.

Flumazenil was introduced in 1981 for use in the diagnosis of coma or conscious change due to unknown origin, the treatment of severe cardiopulmonary suppression caused by benzodiazepine poisoning and rapid reversal of sedation in anaesthesia of short surgical procedures. The most commonly used dose in clinical practice is 1 mg, although the manufacturer's recommended adult dose of 0.2 mg to 3 mg. However many doctors have found that higher doses (1-10 mg in adults) may be necessary to treat the profound coma in some overdoses. The duration of action of the normally prescribed dose of flumazenil is 1 to 4 hours.

Patients with a pure benzodiazepines poisoning would normally return to full consciousness within minutes while those who respond only partially would be considered as having ingested a mixed-drug overdose. Respiratory depression is also reversed. The reversal of cardiovascular depression is secondary to benzodiazepine use. There has also been a report of the successful use of flumazenil to reverse foetal benzodiazepine intoxication. A 22-year-old primipara at 36 weeks gestation who consumed fifty to sixty 5-mg tablets of diazepam was given 0.3 mg flumazenil at two different times. The treatment restored the normal beat-to-beat variation and periodic oscillations of amplitude of foetal heart rate. A healthy baby was safely delivered two weeks later.

In a report on the use of flumazenil in the diagnosis and treatment of acute self-poisoning in 13 patients admitted to an emergency room or intensive care unit, intravenous administration of 1.5 to 10 mg reversed the central nervous system depression induced by different benzodiazepine compounds within one to two minutes (see table below).

Why do some doctors prefer not to use flumazenil?
Although considered by many as being highly specific, some doctors, however, have questioned the role of flumazenil in uncomplicated benzodiazepine poisoning. This is due to the fact that st udies have indicated that patients suspected of benzodiazepine overdose frequently demonstrate only a partial response to flumazenil. Recently, a group of doctors from Taipei Veterans General Hospital reported that certain underlying problems may have contributed to the differences in patient's response to flumazenil. These include the level of coma (as measured by the Glasgow Come Score) associated with intoxication, the presence of concomitant disease (such as lung cancer with metastasis or old c erebrovascular attack; CVA) or complications of benzodiazepine overdose (such as aspiration pneumonia), and mixed drug intoxication. Alcohol has been mostly blamed as a cause of partial response to flumazenil and mixed-drug intoxication in benzodiazepine overdose

What are problems associated with chronic benzodiazepine use?
Although generally believed to be a safe drug for the treatment of anxiety, therapeutic dose of benzodiazepines may still induce potential hazards to the patient. True physical dependence can emerge from chronic therapeutic use. Following abrupt withdrawa l, three categories of symptoms may appear.

Rebound

• worse anxiety
• insomnia
• restlessness

Recurrence

• anxiety
• insomnia
• muscle spasm

Withdrawal

• depression
• tinnitus
• a sensation of sea-sickness
• seizures
• psychosis

For patients who have acute withdrawal symptoms, initial diazepam loading (10 to 20 mg) can be administered until symptoms are suppressed, thereafter dosage can be reduced by 5 to 10% daily. The introduction of nonpharmacologic treatments for anxiety, such as relaxation training and cognitive restructuring and problem solving techniques may be helpful.

Conclusion
Although benzodiazepine is safe if used under proper supervision, the drug however, may produce serious undesirable manifestations and develop potential complications. It is also commonly used in self-poisoning. The newer potent short-acting agents have been considered the sole cause of death in recent forensic cases. However, toxic manifestation may be alleviated with the introduction of the specific benzodiazepine antagonist flumazenil which has been reported to rapidly reverse coma caused by benzodiazepine overdose.

Dr Abu Bakar is an Associate Researcher at PRN