The miscellaneous anxiolytics, sedatives and hypnotics are a diverse group of drugs mostly with unknown mechanisms of action that produce central nervous system depression in overdose. Most are older drugs (chloral hydrate was synthesised in 1832) that have been superseded in clinical practice by the benzodiazepines. In relatively small doses, the older agents can cause a profound, prolonged and occasionally cyclical coma, respiratory depression and death (especially when cardiac arrhythmias accompany the toxic profile as in chloral hydrate). Toxicity is even more severe with sedative coingestants, especially alcohol and opiates, and advanced age is an additional risk factor for severe toxicity. These features have led to a questioning of their therapeutic role (1).

Acute overdose toxicity and risk of death has been observed disproportionately with chloral hydrate but death has been reported after overdose with all the older agents.

In any discussion of toxic doses of sedative-hypnotic drugs, there will always be considerable variation due to interindividual differences in tolerance and the contribution or otherwise of active metabolites.

Chloral hydrate was by far the most commonly implicated single compound in fatal overdoses in Brisbane, Australia between 1979 and 1987 (17) and had one of the highest odds ratios for death from deliberate self-poisoning when adjusted for prescription numbers (58.1; 95% CI, 18.1-187) (18).

Doses of 80 to 100 mg/kg have been given to children (< 5 years old) with sedation as the only effect (19). Paradoxical excitement occurred in 18% of children receiving a mean dose 87 mg/kg as pre-medication (20). A preterm infant developed severe chloral hydrate toxicity after its therapeutic administration as an adjunct to the treatment of hyaline membrane disease (21). Therapeutic doses of chloral hydrate may produce arrhythmias when used to sedate children with stimulant ingestions (22). A 2-year old had a respiratory arrest after aspiration of 250 mg of chloral hydrate but survived (23). More than 1.5 to 2.0 g of chloral hydrate has produced excessive sedation in children and adults (19). Toxic effects of lethargy and ataxia are seen in adults at doses of 2 – 3 g (13) although tolerant individuals have been known to consume up to 25 g per day without mishap (24).

Two cases of intravenous administration of a therapeutic dose of oral chloral hydrate resulted in central nervous system depression and minimal local effects at the injection site (25). Ingestion of 219 mg/kg of chloral hydrate resulted in transient bigeminy, ingestion of up to 960 mg/kg caused torsades des pointes and ventricular fibrillation (25).

The intentional ingestion of 5 g of chloral hydrate by a 67-yr-old man resulted in cardiac arrhythmia including tachyarrhythmia and polymorphic ventricular extrasystoles (26). A 42-year-old woman had an accidental overdose of chloral hydrate due to repeated dosing of a therapeutic dose of chloral syrup for insomnia. The total ingestion was estimated at 8 g. There was mild CNS depression with ventricular bigeminy (27). An adult who ingested 10 g of chloral hydrate became unconscious with respiratory depression and hypotension (28). Doses of 10 to 37.5 g (29) and 38 g (19) were associated with severe toxicity (coma and arrhythmia) but ultimate survival.

Gastric perforation and gastrointestinal hemorrhage with later gastroesophageal stricture formation have been reported after doses of 30 g (30) and 18 g (31). Coma and signs of cardiac toxicity appeared 2 hours after ingestion of approximately 38 g of chloral hydrate (32). A 29-year-old male was admitted after ingestion of 70 g of chloral hydrate. He was hypotensive, hypothermic and profoundly unconscious but survived (33).

The minimum lethal dose of chloral hydrate for an adult is unclear and has been variously quoted as 3 g (24), 4 g (34) or 5 – 10 g (13;35). A young healthy female died after taking a therapeutic dose of chloral hydrate syrup before surgery to extract third molars (36). Forty grams of chloral hydrate resulted in the death of a 33-year-old woman (34) and 35 grams resulted in the death of a 35-year-old woman (37).

In most cases, it is the development of tolerance to sedative-hypnotics that determines the recovery of consciousness after overdose rather than the clearance of the drug. In general, because of tolerance and the active metabolites of these drugs, there is a poor correlation between concentration and effect.

After a single oral chloral hydrate dose of 1000 mg, mean peak trichloroethanol concentration in blood was 8.0 mg/L (range 2 – 12) at 1 h (80) with an elimination half-life of 8 –12 h (13). In chloral hydrate intoxication, there may be delayed absorption and some slowing of metabolism (81). Two hours after ingestion of 38g in a 38-year old female, the plasma concentration of trichloroethanol was 330 mg/L and the half-life was 35 hours (32).

The sedative effects of chloral hydrate are attributed to its metabolite trichloroethanol but the mechanism of action is unknown (35). The parent compound is quite irritant and caustic to mucosal surfaces (30). Trichloroethanol mediated enhanced automaticity of supraventricular and ventricular pacemaker cells (117) with increased myocardial irritability to circulating catecholamines (118) is believed to be the mechanism of the cardiac arrhythmias. Tolerance to the sedative effects appears rapidly and prominently with a high potential for abuse/dependence and a major withdrawal syndrome (13).

The acrid pear-like odor of chloral hydrate on the breath is distinctive and disagreeable (13;156). Typical presentation of a significant chloral hydrate ingestions is with CNS depression, which rapidly progresses to profound unconsciousness with hypotension (33;118) and hypothermia (33). Patients are often found already in coma (157) with respiratory failure (33;157) or frank cardiorespiratory arrest (118;157). Death, if it occurs in this context, is usually due to the effects of cerebral hypoxia (157).

Mortality is increased if cardiac arrhythmias are present. These manifest as supraventricular and ventricular tachyarrhythmias (29;117;158;159). The ventricular arrhythmias vary from extrasystoles which may be polymorphic (26), to polymorphic ventricular tachycardia (160), torsades des pointes (25;161) and ventricular fibrillation (25). These arrhythmias also occur in children (162-164).

The arrhythmias may be precipitated by catecholamines used to treat the hypotension (33;118) and can also occur when chloral hydrate is used to treat agitation due to stimulants (22) or when flumazenil is used to reverse the sedation (165). In one case report, reversible symptomatic myocardial ischaemia of 4 h duration was attributed to chloral hydrate overdose (166).

The caustic effect of chloral hydrate can result in gastro-esophageal necrosis (30), with or without perforation (167) and subsequent stricture formation (31).

Withdrawal from central nervous system depressants is dealt with in more detail in the drug withdrawal monograph. Suddenly stopping treatment in dependent people may produce withdrawal symptoms and signs including anxiety, dysphoria, irritability, insomnia, nightmares, sweating, memory impairment, hallucinations, hypertension, tachycardia, psychosis, tremors and seizures (227). The withdrawal syndromes associated with the older agents are similar to those associated with barbiturates (228); they are severe and likely to be associated with life-threatening events such as seizures. Acute withdrawal from sedative-hypnotics may present solely as a confusional state due to non-convulsive status epilepticus (toxic ictal delirium) which can easily be missed (229).

Chloral hydrate has an unpleasant taste and is corrosive to skin and mucous membranes unless well diluted. The most frequent adverse effect is gastric irritation; abdominal distension and flatulence may also occur. CNS effects such as drowsiness, light-headedness, ataxia, headache, and paradoxical excitement, hallucinations, nightmares, delirium, and confusion (sometimes with paranoia) occur occasionally (122). Paradoxical excitement can occur after therapeutic use of chloral hydrate in up to 18% of children (20).

Routine quantitative drug estimation is not readily available for any of these agents and not indicated for routine management. Chloral hydrate is radio-opaque and large amounts may be seen plainly on X-ray film of the abdomen (239).

Mortality is closely related to the development of cardiac arrhythmias so an electrocardiograph and cardiac monitoring are mandatory in chloral hydrate poisoning. Hepatic and renal function tests are indicated. Measurement of creatine kinase in cases of coma will help in the assessment of rhabdomyolysis. Core body temperature should be assessed as hypothermia is common. Chest X-ray is helpful to assess for non-cardiogenic pulmonary oedema in a patient with oxygen desaturation. Measurement of partial pressure of carbon dioxide via expired air or arterial blood gases is the best way to assess respiratory compromise from sedation.

Oesophago-gastroscopy may be indicated after large chloral hydrate ingestions to assess mucosal damage and potential for stricture formation.

For many drugs, there is a postmortem diffusion of drugs along a concentration gradient, from sites of high concentration in solid organs, into the blood with resultant artifactual elevation of drug concentrations in blood (postmortem redistribution). Highest drug concentrations are found in central vessels such as pulmonary artery and vein, and lowest concentrations are found in peripheral vessels such as subclavian and femoral veins. This creates major difficulties in interpretation and undermines the reference value of data bases where the site of origin of postmortem blood samples is unknown (240). It is widely agreed, however, that the femoral vein site represents the optimum sampling site and this site is now standardised amongst forensic pathologists.

Oral activated charcoal within 1 hour of ingestion may be of some value in poisoning with the other drugs in this monograph. Given the caustic nature of chloral hydrate, gastric lavage is not indicated.

More aggressive respiratory and cardiovascular support will be required for the older agents. Non-cardiogenic pulmonary oedema should be managed along conventional lines. In the face of continuing hypotension not responding to fluid resuscitation, inotropic agents may be required. Adrenergic inotropes should be not be used in chloral hydrate poisoning because of the risk of precipitating an arrhythmia.

Chloral hydrate induced arrhythmias are frequently life-threatening and often resistant to conventional antiarrhythmics (29;158-160). There is good case evidence for the routine use of an intravenous beta-blocker (propranolol or esmolol) in these patients (25;29;158–160).

Patients with a significant sedative drug overdose should be advised not to drive until potential interference with psychomotor performance has resolved (260). For overdose of most of these agents this will be at least 48 hours after discharge.

The use of flumazenil is dealt with in more detail in benzodiazepines. There is one report of reversal of CNS sedation after chloral hydrate with flumazenil (28) but ventricular arrhythmias have been precipitated by flumazenil in this context (165) and its use cannot be recommended.

Principles of elimination enhancement are discussed in the Treatment monograph.

For chloral hydrate, which has relatively low plasma protein binding and volume of distribution of less than or near 1 L/kg, there is likely to be a relatively high elimination rate with extracorporeal techniques. There is good evidence that elimination half-lives can be significantly reduced for trichloroethanol by haemodialysis (32;81;297), resin haemoperfusion (298) and combined haemoperfusion and haemodialysis (33). In all these cases there was clinical improvement coincident with the procedure but it is unknown whether the same outcome would have been achieved with conservative therapy.

Routine observation of vital signs, especially GCS airway patency and blood pressure, is indicated. For chloral hydrate, continuous cardiac monitoring until the patient is clearly awake is mandatory. Measurement of partial pressure of carbon dioxide via expired air or arterial blood gases is the best way to assess respiratory compromise from sedation.

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