Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

A)

1) 2,2,2-Trichloro-1,1-ethanediol
2) Chloral
3) Chloral hydrate
4) Kloralhydrat
5) Knockout drops
6) Trichloroacetaldehyde, monohydrate
7) Trichloroethylidine glycol

1) CAS 480-30-8

1) Phosphoric ester of trichloroethyl alcohol

1) Chlorbutol

Available Forms Sources

A)

1) CHLORAL HYDRATE -

a) Capsules 250 and 500 mg
b) Syrup 250 mg/5 mL and 500 mg/5 mL
c) Suppositories 325 mg, 500 mg, and 650 mg
d) Noctec(R) (Squibb) is one of the more common trade names available.
e) Chloraldurat(R) is one of the common trade names in Germany. Available German dosage forms include 250 and 500 mg capsules, and 600 mg enemas.

2) Chlorobutanol is available in concentrations of 0.5% as a preservative in pharmaceutical ophthalmic, parenteral, and otic preparations.
3) Dichloralphenazone is a complex consisting of 2:1 molar ratio of chloral hydrate and antipyrine.

a) Dichloralphenazone is dissociated in aqueous solution to form chloral hydrate and antipyrine. Each 100 mg of dichloralphenazone (contained in one capsule of Midrin(R)) contains 64 mg of chloral hydrate and 36 mg of antipyrine (Prod Info).

B)

1) CHLOROBUTANOL - Is structurally related to trichloroethanol, the active metabolite of chloral hydrate, and is used as a sedative/hypnotic in doses of 300 to 1200 mg/day.

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Chloral hydrate is a sedative-hypnotic agent used for procedural sedation, particularly in the pediatric population, and to treat anxiety, insomnia, and alcohol withdrawal syndrome. Related agents include chlorobutanol (a preservative in ophthalmic, parenteral, and otic preparations), dichloralphenazone (a 2:1 combination of chloral hydrate and antipyrine, used in the medication Midrin(R) to treat migraine headaches), and chlorobutanol (a sedative-hypnotic structurally similar to chloral hydrate’s active metabolite, trichloroethanol). This summary focuses on chloral hydrate.
B) PHARMACOLOGY: CNS depression occurs via active metabolite trichloroethanol. The exact mechanism is not known but acts similarly to barbiturates.
C) TOXICOLOGY: Cardiac dysrhythmias thought to be caused by myocardial sensitization to catecholamines by trichloroethanol. Choral hydrate and its metabolites also reduce myocardial contractility and shorten the refractory period.
D) EPIDEMIOLOGY: Poisoning is uncommon in controlled settings but may be severe when poisoning is intentional or combined with other sedatives. Chloral hydrate is available in oral and rectal formulations. It is less commonly used due to the wide variety of other sedative-hypnotic medications now available.
E) WITH THERAPEUTIC USE

1) At therapeutic doses, effects such as CNS depression, ataxia, GI irritation including gastritis and vomiting, may occur. Because chloral hydrate crosses the placenta and enters breast milk, adverse effects including withdrawal, may be seen in neonates.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Somnolence, confusion, ataxia, vomiting, gastritis, mild hypotension, tachycardia, and PVCs. Transient elevation in serum transaminases may occur.
2) SEVERE TOXICITY: Severe effects may include coma, severe respiratory depression, hypotension, ventricular tachycardia and fibrillation, torsades de pointes, and death. Gastric hemorrhage, perforation and strictures are rare complications of large ingestions (10 to 20 g).

0.2.20)

A) Chloral hydrate crosses the placenta; chronic use during pregnancy may result in withdrawal effects in the neonate. Chloral hydrate and its metabolites are excreted into breast milk.

0.2.21)

A) Chloral hydrate has been classified as probably carcinogenic to humans (Group 2A) by IARC following a systematic review and evaluation

Laboratory Monitoring

A)

B)

C)

D)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Most chloral hydrate overdoses may be safely managed with supportive care that includes monitoring airway, breathing, and circulation. Intravenous fluids may be needed for mild hypotension. Activated charcoal may be given if the patient presents soon after ingestion and shows no evidence of altered mentation.

B) MANAGEMENT OF SEVERE TOXICITY

1) Orotracheal intubation for airway protection should be performed if increasing somnolence or coma causing loss of airway protective reflexes. Gastric lavage rarely indicated as liquid preparations are rapidly absorbed, may be considered in a potentially life-threatening ingestion if the patient presents early and their airway is adequately protected. Beta-adrenergic blockers (propranolol (1 to 2mg IV), esmolol (500 mcg/kg bolus followed by infusion of 50 mcg/kg/min, if needed every 4 minutes repeat bolus and step up infusion sequentially to 100, 150, 200, 250, and 300 mcg/kg/min until dysrhythmia is controlled), metoprolol (5 mg IV, repeat every 5 minutes up to 15 mg if needed) have been successfully used to treat chloral hydrate-induced ventricular ectopy (PVCs, ventricular tachycardia). Consider lidocaine in refractory cases. Should torsades de pointes occur, treat stable patients with magnesium (ADULTS: 2 g IV over 1 to 2 min, repeat 2 g bolus and begin infusion of 0.5 to 1 g/hr if dysrhythmias recur. CHILDREN: 25 to 50 mg/kg diluted to 10 mg/mL; infuse IV over 5 to 15 min), and/or atrial overdrive pacing; correct electrolyte abnormalities. Unstable patients require immediate electrical cardioversion. Avoid drugs that prolong the QTc such as the antidysrhythmics in class Ia (quinidine, disopyramide, procainamide), class Ic (flecainide, encainide, propafenone) and most class III (N-acetylprocainamide, sotalol). Hypotension should be treated with intravenous fluids and treatment of any associated dysrhythmias. Vasopressors should be avoided if possible as catecholamines may precipitate ventricular dysrhythmias in patients with chloral hydrate overdose.

C) DECONTAMINATION

1) PREHOSPITAL: Not recommended because of potential for somnolence and vomiting due to gastric irritation.
2) HOSPITAL: Activated charcoal if recent, large ingestion, and patient able to safely drink. Gastric lavage rarely indicated as liquid preparations are rapidly absorbed; consider if recent, life-threatening ingestion, and airway is protected.

D) AIRWAY MANAGEMENT

1) Intubate if unable to protect airway due to worsening somnolence, coma, or if unstable dysrhythmias develop.

E) ANTIDOTE

1) None.

F) ENHANCED ELIMINATION

1) Hemodialysis and exchange transfusion may be indicated in life-threatening ingestions refractory to usual therapeutic measures.

G) PATIENT DISPOSITION

1) HOME CRITERIA: Accidental ingestions in asymptomatic patients (children less than 50 mg/kg, adults less than 1 g) who have no synergistic coingestions may be monitored at home.
2) OBSERVATION CRITERIA: Patients with deliberate ingestions, children with ingestions of greater than 50 mg/kg, adults with ingestions greater than 1 g, synergistic coingestions, unclear history, symptomatic patients, or those in unstable social situations should be sent to a health care facility for observation.
3) ADMISSION CRITERIA: Patients with persistent or worsening gastrointestinal irritation, CNS depression, respiratory depression, ventricular ectopy, dysrhythmias should be admitted. Intensive care unit is indicated for aggressive airway and cardiac monitoring. Patient should be monitored for at least 24 hours for cardiac dysrhythmias.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (respiratory depression, coma, or dysrhythmias), concerns about decontamination, or in whom the diagnosis is not clear.

H) PITFALLS

1) Decontamination with charcoal or gastric lavage should be carefully decided as these patients often present with vomiting and are at risk for progressive somnolence and aspiration. Hypotensive patients may need beta blocking agents to treat chloral hydrate-induced dysrhythmias. Use of catecholamines to treat hypotension may precipitate dysrhythmias.

I) PHARMACOKINETICS

1) Onset of action within 30 min, duration 4 to 6 hours, protein binding 40% for trichloroethanol , elimination half life for trichloroethanol 7 to 12 hours; metabolized by liver, via alcohol dehydrogenase, to trichloroethanol, the active metabolite, which is further metabolize to inactive trichloroacetic acid. Less than 30% excreted in urine; volume of distribution 0.6 to 1.6 L/kg.

J) TOXICOKINETICS

1) Significant toxicity generally develops within 2 to 3 hours of ingestion. The half life of trichloroethanol (toxic metabolite of chloral hydrate) is prolonged (35 hours) after overdose and in infants.

K) DIFFERENTIAL DIAGNOSIS

1) Sedation and respiratory depression from opiates, benzodiazepines, muscle relaxants, ethanol; CNS infections; intracranial catastrophes (massive hemorrhage or stroke).

Range Of Toxicity

A)

B)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

E)

1) At therapeutic doses, effects such as CNS depression, ataxia, GI irritation including gastritis and vomiting, may occur. Because chloral hydrate crosses the placenta and enters breast milk, adverse effects including withdrawal, may be seen in neonates.

F)

1) MILD TO MODERATE TOXICITY: Somnolence, confusion, ataxia, vomiting, gastritis, mild hypotension, tachycardia, and PVCs. Transient elevation in serum transaminases may occur.
2) SEVERE TOXICITY: Severe effects may include coma, severe respiratory depression, hypotension, ventricular tachycardia and fibrillation, torsades de pointes, and death. Gastric hemorrhage, perforation and strictures are rare complications of large ingestions (10 to 20 g).

Vital Signs

3.3.3)

A) HYPOTHERMIA has been described in patients with CNS depression(Zahedi et al, 1999; Lin & Ma, 2006; Ludwigs et al, 1996; Vellar et al, 1972; Shahar et al, 1979; Vaziri et al, 1977; Orwin & Schroeder, 1968).

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) MIOSIS: Pupils are usually miotic initially (Zahedi et al, 1999; Lin & Ma, 2006; Gaulier et al, 2001), but later may be dilated (Pershad et al, 1999). Pinpoint pupils were reported following ingestion of 15 g of chloral hydrate along with up to 100 mg of diazepam (Graham et al, 1988).

3.4.6)

A) WITH POISONING/EXPOSURE

1) CASE REPORT (INFANT): An 8-month-old infant, with a swollen right eyelid, presented to the emergency department unresponsive with hypothermia and hypotension (57/11 mmHg), a respiratory rate of 20 breaths/min, and oxygen saturation of 80% approximately 10 minutes after inadvertently receiving 8 grams of chloral hydrate orally for sedation prior to an ophthalmologic exam instead of the prescribed 0.4 gram. The chloral hydrate was also insufficiently diluted with only 15 mL of water prior to administration (diluted concentration of 53%, pH 3.45; normal diluted concentration is 10%). On admission, the patient's oropharyngeal mucous membranes and perioral skin was hyperemic and edematous. On hospital day 2, the patient regained consciousness, however physical examination showed generalized exanthema on his body and white plaques and sloughing of the oropharyngeal mucosa. An esophagogastroscopy revealed diffuse white plaques, and mucosal sloughing and ulceration of the esophagus, indicating esophageal burns, along with concomitant hemorrhagic gastritis. With supportive care, the patient recovered without sequelae (Lin & Ma, 2006).

Cardiovascular

3.5.2)

A) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypotension is frequently reported after overdose (Nordt et al, 2014; Zahedi et al, 1999; Laurent et al, 2006; Bowyer & Glasser, 1980; Graham et al, 1988; Ludwigs et al, 1996; Lin & Ma, 2006; Lee & Vassalluzzo, 1998).

B) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

a) VENTRICULAR DYSRHYTHMIAS

1) Cardiac dysrhythmias (ranging from sinus tachycardia to multifocal PVC's, ventricular tachycardia, ventricular fibrillation, AV block and asystole) are frequently reported following overdose (Zahedi et al, 1999; Graham et al, 1988; Ludwigs et al, 1996; Bowyer & Glasser, 1980; Wiseman & Hampel, 1978; Marshall, 1977; Gustafson et al, 1977; Brown & Cade, 1980; DiGiovanni, 1969).
2) INCIDENCE: Graham et al (1988) report that 11 out of 12 cases admitted to the intensive care unit because of overdose from chloral hydrate resulted in ventricular ectopic activity (Graham et al, 1988).
3) PVC'S: Multiple multifocal premature ventricular contractions were reported in a 2-year-old 12.7 kg male within 75 minutes of ingesting 1500 mg chloral hydrate (Nordenberg et al, 1971).
4) CASE REPORT: A 3-year-old boy became unresponsive after receiving 6,000 mg (400 mg/kg) of chloral hydrate prior to a dental procedure, instead of the prescribed 500 mg (50 mg/kg). Vital signs of the patient revealed persistent sinus tachycardia (120 to 130 bpm) and hypotension (91/55 mmHg). His Glasgow Coma Scale score was 3, and cardiac monitoring indicated dysrhythmias (ventricular bigeminy and trigeminy, and episodes of non-sustained ventricular tachycardia). With supportive treatment, including an esmolol infusion, the patient gradually recovered and was discharged home without sequelae (Nordt et al, 2014).

C) TORSADES DE POINTES

1) WITH POISONING/EXPOSURE

a) Ventricular tachycardia with torsades de pointes characteristics was described in a 30-year-old woman following ingestion of 15 g of chloral hydrate. Rapid ventricular pacing was required to control the dysrhythmia (Young et al, 1986).
b) Sing et al (1996) reported the case of a 30-year-old woman who ingested an unknown amount of chloral hydrate from a bottle initially containing 48 grams (Sing et al, 1996). The patient developed runs of ventricular tachycardia and torsades de pointes. The dysrhythmias were refractory to lidocaine but were later controlled by metoprolol infusion.

D) VENTRICULAR TACHYCARDIA

1) WITH POISONING/EXPOSURE

a) A 25-year-old woman developed coma, hypotension, hypoventilation, and recurrent ventricular tachycardia and torsades de pointes after ingesting 12.5 g chloral hydrate (250 mg/kg). She had recurrent ventricular tachycardia despite treatment with lidocaine, amiodarone, fluid, procainamide, and magnesium sulfate. Dysrhythmias resolved after use of a pacemaker and propranolol. On the third hospital day she developed T wave inversion in precordial (V1-4) and inferior (II, III, AVF) leads with apical akinesia on echocardiography. Cardiac enzymes remained normal and angiography revealed normal coronary arteries. Echocardiogram normalized by day 10 and ECG by day 12 (Laurent et al, 2006).
b) A 27-year-old man developed multifocal PVCs and both sustained and unsustained runs of ventricular tachycardia after ingesting 20 grams of chloral hydrate along with loxapine 1 gram and fluoxetine 180 mg. Ventricular dysrhythmias terminated 15 minutes after a propranolol infusion was initiated (Zahedi et al, 1999).

Respiratory

3.6.2)

A) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) NON-CARDIOGENIC PULMONARY EDEMA and aspiration pneumonitis have been reported after massive overdose (Bowyer & Glasser, 1980; Vellar et al, 1972; Gleich et al, 1967; Graham et al, 1988).

B) HYPOVENTILATION

1) WITH POISONING/EXPOSURE

a) RESPIRATORY DEPRESSION is common; abrupt respiratory failure may occur (Vaziri et al, 1977; Graham et al, 1988).

C) EDEMA OF LARYNX

1) WITH POISONING/EXPOSURE

a) CASE REPORT (CHILD): Acute dyspnea, stridor, and barking cough occurred 15 minutes after ingestion of 100 mg/kg in a 1.5-year-old boy with achondroplasia. Laryngeal edema and erythema were found at laryngoscopy (Farber & Abramow, 1985).

D) HYPOXEMIA

1) WITH THERAPEUTIC USE

a) In a prospective study of 405 children receiving chloral hydrate sedation prior to echocardiography, 24 patients (6%) had decreases in oxygen saturation greater than 5%. Decrease in oxygen saturation was more common in children with trisomy 21 or other genetic syndromes (Napoli et al, 1996).
b) In a prospective study of 410 children aged 4 years or younger undergoing CT and MR imaging, mild hypoxia (O2 saturation 90% to 95%) occurred in 9% of children receiving chloral hydrate alone, with 1 child developing severe hypoxia (O2 saturation <85%) requiring oxygen supplementation and airway support. In children receiving a combination of hydroxyzine and chloral hydrate, hypoxia incidence was 5%, with one child developing moderate hypoxia (O2 saturation 88% to 89%) requiring treatment (Vade et al, 1995).

2) WITH POISONING/EXPOSURE

a) CASE REPORT (INFANT): An 8-month-old infant became unresponsive, necessitating mechanical ventilation, after inadvertently receiving 8 grams of chloral hydrate orally for sedation prior to an ophthalmic exam instead of the prescribe 0.4 gram. His respiratory rate was 20 breaths/min and his O2 saturation was 80%. With supportive care, the patient gradually recovered without sequelae (Lin & Ma, 2006).
b) CASE REPORT (INFANT): A 28-day-old infant developed agitation, hypersalivation, and respiratory depression with hypoxia after inadvertently receiving a single oral chloral hydrate dose of 250 mg/kg (a total of 1000 mg) instead of the prescribed dose of 50 mg/kg. A chest x-ray was normal and all serum electrolyte concentrations, and renal and liver function tests were within normal limits. The patient spontaneously recovered approximately 7 hours post-ingestion (Kirimi et al, 2002).
c) CASE REPORT (CHILD): A 15-month-old girl, with severe neurodevelopmental deficits, experienced stridorous respirations (respiratory rate 18 breaths/min), followed by cyanosis and apnea with O2 saturation of 64% approximately 25 minutes after administration of 1,200 mg chloral hydrate (100 mg/kg) for sedation prior to an ophthalmic evaluation. Assisted bag-valve-mask ventilation with 100% oxygen was performed, resulting in improvement in respiratory status. She was then maintained on oxygen 6 L/min by facemask, gradually weaning to room air over a 45-minute period. Following observation for 12 hours, the patient was discharged home without sequelae (Nordt et al, 2014).

E) RESPIRATORY OBSTRUCTION

1) WITH THERAPEUTIC USE

a) CASE SERIES: Use of chloral hydrate in 2 children with obstructive sleep apnea resulted in respiratory failure. The two 24-month old children developed airway obstruction and respiratory failure requiring bag ventilation after sedation with chloral hydrate 80 mg/kg for lung function studies (Biban et al, 1993).

F) ACUTE RESPIRATORY FAILURE

1) WITH POISONING/EXPOSURE

a) INADVERTENT INTRAVENOUS ADMINISTRATION

1) CASE SERIES: Sing et al (1996) reported 2 cases in which patients were mistakenly given chloral hydrate elixir intravenously. Patient 1, a 3-year-old girl, was given 39 mg/kg intravenously. The patient became lethargic and developed mild skin sloughing at the infusion site. Patient 2, a 15-month-old boy, was given 800 mg chloral hydrate (88 mg/kg) intravenously and became cyanotic with respiratory depression. Ventilation was required and the patient recovered without incident (Sing et al, 1996).

Neurologic

3.7.2)

A) COMA

1) WITH THERAPEUTIC USE

a) The drug is a marked depressant and deep coma may ensue within 30 minutes (DiGiovanni, 1969) to 2 hours of ingestion (Vaziri et al, 1977).

2) WITH POISONING/EXPOSURE

a) Deep coma was reported in 18% of intoxicated patients in one series with 15% requiring intubation (Matthew et al, 1972).
b) CASE REPORT (INFANT): An 8-month-old infant became unresponsive with flaccid extremities and decreased tendon reflexes after inadvertently receiving 8 grams of chloral hydrate orally for sedation prior to an ophthalmic examination instead of the prescribed 0.4 gram. With supportive care, the patient recovered without neurologic sequelae (Lin & Ma, 2006).
c) CASE REPORT (CHILD): A 4-year-old child became unresponsive approximately 6 hours after receiving chloral hydrate 900 mg (70 mg/kg) prior to dental extraction. Emergency personnel administered cardiopulmonary resuscitation (CPR) prior to emergency department (ED) presentation. At the ED, the patient was asystolic and had a Glasgow Coma Scale score of 3. Arterial blood gases revealed severe acidosis. CPR continued with immediate intubation and vasopressor administration. Despite continued aggressive cardiac resuscitative efforts, the patient remained unresponsive with pupils fixed and dilated. Approximately 12 hours post-arrival, the patient died after experiencing another cardiopulmonary arrest episode and could not be resuscitated (Nordt et al, 2014).
d) CASE REPORT: A 3-year-old boy became unresponsive after receiving 6,000 mg (400 mg/kg) of chloral hydrate prior to a dental procedure, instead of the prescribed 500 mg (50 mg/kg). Vital signs of the patient revealed persistent sinus tachycardia (120 to 130 bpm) and hypotension (91/55 mmHg). His Glasgow Coma Scale score was 3, and cardiac monitoring indicated dysrhythmias (ventricular bigeminy and trigeminy, and episodes of non-sustained ventricular tachycardia). With supportive treatment, the patient gradually recovered and was discharged home without neurologic sequelae (Nordt et al, 2014).
e) CASE REPORT (ADULT): A 25-year-old woman became comatose within 1 hour after intentionally ingesting 250 mL of a syrup containing chloral hydrate (equivalent to 12.5 g of chloral hydrate). Her Glasgow Coma Scale score was 3 and she had dilated and non-reactive pupils. She was also hypotensive and she developed severe cardiac dysrhythmias (multifocal PVCs, ventricular tachycardia, torsades de pointes). With supportive care, the patient gradually recovered without sequelae (Laurent et al, 2006).

B) SEIZURE

1) WITH THERAPEUTIC USE

a) CASE REPORT (CHILD): A 2-year-old boy had two seizures, approximately 60 and 90 minutes after receiving chloral hydrate 70 mg/kg for sedation prior to echocardiography. Laboratory values were within normal limits and EEG and CT brain scan revealed no abnormalities (Munoz et al, 1997).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: A 30-year-old man developed seizures after being found in respiratory arrest secondary to chloral hydrate overdose. He had likely sustained anoxic brain injury and died 9 days after presentation (Gaulier et al, 2001).

C) CENTRAL STIMULANT ADVERSE REACTION

1) WITH THERAPEUTIC USE

a) In a study of 140 children undergoing sedation with chloral hydrate for prior to echocardiography, paradoxical excitement occurred in 25 children (18%). Children with this type of reaction had received significantly higher doses of chloral hydrate and were significantly older than children who did not experience excitement (Lipshitz et al, 1993).

2) WITH POISONING/EXPOSURE

a) CASE REPORT (INFANT): A 28-day-old infant developed agitation, hypersalivation, and respiratory depression with hypoxia after inadvertently receiving a single oral chloral hydrate dose of 250 mg/kg (a total of 1000 mg) instead of the prescribed dose of 50 mg/kg. A chest x-ray was normal and all serum electrolyte concentrations, and renal and liver function tests were within normal limits. The patient spontaneously recovered approximately 7 hours post-ingestion (Kirimi et al, 2002).

D) DISTURBANCE IN SPEECH

1) WITH POISONING/EXPOSURE

a) CHLOROBUTANOL: In a review of chlorobutanol toxicity, slurred speech and dysarthria were reported in a 40-year-old man abusing chlorobutanol (900 mg to 1500 mg daily). The slowness of speech resolved after 4 weeks (Nordt, 1996).

E) SEDATED

1) WITH THERAPEUTIC USE

a) Prolonged sedation is fairly common when chloral hydrate is used therapeutically, especially in children (Malviya et al, 2000).

Gastrointestinal

3.8.2)

A) VOMITING

1) WITH THERAPEUTIC USE

a) Emesis is common in these patients although it is not clear whether this is due primarily to the drug or associated alcoholic gastritis or perforation.

1) ADVERSE EFFECT: Vomiting after therapeutic doses occurred in 48% of children in one study (Houpt et al, 1985).
2) However, in a prospective study of 405 children receiving chloral hydrate sedation prior to echocardiography, 23 patients (6%) had vomiting, with 19 of 23 patients vomiting within 10 minutes of chloral hydrate administration (Napoli et al, 1996).

b) Patients who are not deeply comatose may complain of marked gastric irritation with pyrosis.
c) Gastric necrosis and enteritis may be observed (Pershad et al, 1999).

B) GASTROINTESTINAL HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) PERFORATION: Gastric hemorrhage, gastric perforation, and strictures have occurred following 18 and 20 gram ingestions (Vellar et al, 1972; Gleich et al, 1967).
b) CASE REPORT: A 68-year-old woman developed an acute perforated gastric ulcer after the ingestion of 10 grams chloral hydrate in a suicide attempt. Initial examination revealed increased abdominal girth and peritoneal irritation with radiologic findings showing a pneumoperitoneum. The ulcer was repaired with emergency surgery (Lee & Vassalluzzo, 1998).
c) CASE REPORT (INFANT): Hemorrhagic gastritis was reported in an 8-month-old infant who inadvertently received 8 grams of chloral hydrate orally for sedation prior to an ophthalmic exam instead of the prescribed 0.4 gram. The chloral hydrate was also insufficiently diluted with only 15 mL of water prior to administration (diluted concentration of 53%, pH 3.45; normal diluted concentration is 10%)(Lin & Ma, 2006).

C) EXCESSIVE SALIVATION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 28-day-old infant developed agitation, hypersalivation, and respiratory depression with hypoxia after inadvertently receiving a single oral chloral hydrate dose of 250 mg/kg (a total of 1000 mg) instead of the prescribed dose of 50 mg/kg. A chest x-ray was normal and all serum electrolyte concentrations, and renal and liver function tests were within normal limits. The patient spontaneously recovered approximately 7 hours post-ingestion (Kirimi et al, 2002).

Hepatic

3.9.2)

A) LIVER ENZYMES ABNORMAL

1) WITH POISONING/EXPOSURE

a) Transient aminotransferase elevations may occur (Bloom, 1966; Mindham, 1968).

Genitourinary

3.10.2)

A) ALBUMINURIA

1) WITH POISONING/EXPOSURE

a) Albuminuria and casts may appear between 2 and 5 days following ingestion which indicates renal tubular toxicity. Rarely is this serious or prolonged.

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Severe acidosis (pH 6.54, pCO2 70, pO2 271, BE -32.9) was reported in a 4-year-old child who received chloral hydrate 900 mg (70 mg/kg) prior to a dental extraction (Nordt et al, 2014).

Hematologic

3.13.2)

A) AGRANULOCYTOSIS

1) WITH POISONING/EXPOSURE

a) DICHLORALPHENAZONE: Since the dichloralphenazone component of Midrin(R) dissociates in aqueous solution to yield chloral hydrate and antipyrine, the unwanted effects of antipyrine should be considered (Meyler & Herxheimer, 1972).

1) Note that while other pyrazolone derivatives (ie, amidopyrine) may cause fatal agranulocytosis, this seems to be very rare with antipyrine (Meyler & Herxheimer, 1972).
2) There is evidence that the phenazone nucleus is important in the pathogenesis of agranulocytosis caused by pyrazolones and it cannot be assumed that antipyrine and its derivatives are entirely free of risk (Meyler & Herxheimer, 1972).

Dermatologic

3.14.2)

A) FIXED DRUG ERUPTION

1) WITH POISONING/EXPOSURE

a) FIXED DRUG ERUPTION has been described following ingestion of dichloralphenazone (Verbov, 1972).

Musculoskeletal

3.15.2)

A) MYOCLONUS

1) WITH POISONING/EXPOSURE

a) CHLOROBUTANOL: In a review of chlorobutanol toxicity, clonic jerks lasting 10 to 15 seconds were reported in a 40-year-old man hospitalized for abusing chlorobutanol (900 mg to 1500 mg daily) (Nordt, 1996) .

Immunologic

3.19.2)

A) ANAPHYLACTOID REACTION

1) WITH POISONING/EXPOSURE

a) ANAPHYLAXIS has been reported after ingestion of dichloralphenazone, presumably due to the phenazone component (Perl, 1977; Limb, 1977).

Reproductive

3.20.1)

A) Chloral hydrate crosses the placenta; chronic use during pregnancy may result in withdrawal effects in the neonate. Chloral hydrate and its metabolites are excreted into breast milk.

3.20.2)

A) LACK OF INFORMATION

1) At the time of this review, no data were available to assess the teratogenic potential of this agent.

3.20.3)

A) WITHDRAWAL SYNDROME

1) Chloral hydrate crosses the placenta; chronic use during pregnancy may result in withdrawal effects in the neonate (USPDI, 1990).

B) PREGNANCY CATEGORY

CHLORAL HYDRATE	C
Reference: Briggs et al, 1998

3.20.4)

A) SOMNOLENCE

1) Chloral hydrate and its metabolites are excreted into breast milk; use by the mother may cause sedation in the nursing infant (USPDI, 1990) Briggs et al, 1990).

Carcinogenicity

3.21.2)

A) Chloral hydrate has been classified as probably carcinogenic to humans (Group 2A) by IARC following a systematic review and evaluation

3.21.3)

A) SUMMARY

1) The International Agency for Research on Cancer (IARC) has determined that chloral hydrate is probably carcinogenic to humans (Group 2A) after a systematic review and evaluation of the scientific evidence by leading independent experts (International Agency for Research on Cancer, 2015).
2) In a review of the potential carcinogenicity of chloral hydrate, the authors suggested that clinicians weigh the risks versus benefits of conscious sedation with this agent, due to chloral hydrate's similarity to known carcinogens and several studies showing evidence of genotoxicity and carcinogenicity (Salmon et al, 1995).

3.21.4)

A) LACK OF EFFECT

1) Chloral hydrate, given to rats in drinking water over the entire lifetime (124 to 128 weeks) at dosages of 15 mg/kg, 45 mg/kg, and 135 mg/kg, was not carcinogenic (Leuschner & Buescher, 1998).

Genotoxicity

A)

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs and mental status.
B) Chloral hydrate and metabolite plasma levels are not clinically useful or readily available. No specific lab work is needed in most patients.
C) If diagnosis is unclear, significant vomiting or cardiac ectopy, check general labs including electrolytes, chest X-ray or CT to exclude esophageal perforation if indicated.
D) In those with worsening symptoms or known large ingestions, closely monitor airway, breathing, circulation and cardiac ectopy via continuous cardiac monitoring, (including pulse oximetry, capnography, and ECG).

Radiographic Studies

A)

1) Chloral hydrate tablets and capsules may be visualized by x-ray.

Methods

A)

1) Chloral hydrate and trichloroethanol in plasma can be analyzed by gas chromatography.
2) Trichloroethanol may be quantified by the Fujwara reaction with UV spectrophotometry and by chromatography with either flame ionization detection or electron capture detection (Flanagan et al, 1978; Jain et al, 1967; Berry, 1975; Van Der Hoeven et al, 1979; Meyer et al, 1995).
3) Chloral hydrate and its metabolites monochloroacetate, dichloroacetate, trichloroacetate, and trichloroethanol concentrations can be measured in biological fluids by gas chromatography-mass spectrometry (Yan et al, 1999).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with persistent or worsening gastrointestinal irritation, CNS depression, respiratory depression, ventricular ectopy, dysrhythmias should be admitted. Intensive care unit is indicated for aggressive airway and cardiac monitoring. Patient should be monitored for at least 24 hours for cardiac dysrhythmias.

6.3.1.2) HOME CRITERIA/ORAL

A) Accidental ingestions in asymptomatic patients (children less than 50 mg/kg, adults less than 1 g) who have no synergistic coingestions may be monitored at home with frequent telephone follow up (Pershad et al, 1999).

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (respiratory depression, coma, or dysrhythmias), concerns about decontamination, or in whom the diagnosis is not clear.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with deliberate ingestions, children with ingestions of greater than 50 mg/kg, adults with ingestions greater than 1 g, synergistic coingestions, unclear history, symptomatic patients, or those in unstable social situations should be sent to a health care facility for observation (Pershad et al, 1999).

Monitoring

A)

B)

C)

D)

Oral Exposure

6.5.1)

A) EMESIS/NOT RECOMMENDED

1) Rapid absorption may result in deep stupor or coma within 30 to 60 minutes (DiGiovanni, 1969).

B) ACTIVATED CHARCOAL

1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.2)

A) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

B) GASTRIC LAVAGE

1) Chloral hydrate is rapidly absorbed, particularly after ingestion of liquid formulations. Gastric lavage is unlikely to be of benefit in most cases. If performed, lavage should be done carefully because of the risk of perforation. In the case of liquid ingestions a small flexible tube may be indicated to prevent esophageal damage.
2) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

3) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

4) LAVAGE FLUID:

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

5) COMPLICATIONS:

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

6) CONTRAINDICATIONS:

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

6.5.3)

A) MONITORING OF PATIENT

1) Monitor ECG and vital signs carefully. Cardiac dysrhythmias are frequently reported following overdose. Baseline liver and renal function studies should be obtained.

B) VENTRICULAR ARRHYTHMIA

1) BETA ADRENERGIC BLOCKERS

a) Chloral hydrate-induced ventricular dysrhythmias seem to respond to beta blocking drugs (Zahedi et al, 1999; DiGiovanni, 1969; Brown & Cade, 1980).
b) PROPRANOLOL: Propranolol has been the most commonly used beta adrenergic blocker for chloral hydrate-induced dysrhythmias (Zahedi et al, 1999; Bowyer & Glasser, 1980; Graham et al, 1988).

1) A 25-year-old woman developed coma, hypotension, hypoventilation, and recurrent ventricular tachycardia and torsades de pointes after ingesting 12.5 g chloral hydrate (250 mg/kg) (Laurent et al, 2006). She had recurrent ventricular tachycardia despite treatment with lidocaine, amiodarone, fluid, procainamide, and magnesium sulfate. Dysrhythmias resolved after use of a pacemaker and propranolol infused at 2 mg/hr.
2) PROPRANOLOL/ADULT DOSE

a) INTRAVENOUS: 0.5 mg to 1 mg per dose IV over 1 minute. May repeat dose up to a total of 0.1 mg/kg, if needed (Neumar et al, 2010a). A second dose may be repeated in 2 minutes, if necessary; however, any additional drug administration should be given at least 4 hours later (Prod Info propranolol HCl IV injection, 2008).
b) The maximum dose is 3 mg; the rate should not exceed 1 mg/min (Prod Info propranolol HCl IV injection, 2008).

3) PROPRANOLOL/PEDIATRIC DOSE

a) INTRAVENOUS: 0.01 to 0.15 mg/kg IV every 6 to 8 hours (Luedtke et al, 1997).

4) MONITORING

a) The drug should be administered with cardiac monitoring or central venous pressure monitoring. Monitor for bradycardia, hypotension and congestive heart failure (Prod Info propranolol HCl IV injection, 2008).

5) CASE REPORT: Graham et al (1988) successfully treated ventricular dysrhythmias with a 2 mg bolus of propranolol followed by an infusion of propranolol (1 to 2 mg/hr titrated to a heart rate of 80 to 100 beats/min) (Graham et al, 1988).
6) CASE REPORT: A 27-year-old man developed multifocal PVCs and both sustained and unsustained runs of ventricular tachycardia after ingesting 20 grams of chloral hydrate along with loxapine 1 gram and fluoxetine 180 mg. Ventricular dysrhythmias terminated 15 minutes after a propranolol bolus of 1 mg and an infusion of 3 mg/hr were initiated (Zahedi et al, 1999).

c) ESMOLOL: A short-acting beta-blocker, offers advantages over other beta-blockers due to its rapid onset and short duration of action, enabling rapid attenuation of adverse effects if the patient's status deteriorates (Pershad et al, 1999).

1) ESMOLOL/PREPARATION

a) Add 2.5 grams of esmolol to 250 mL of dextrose 5% in water or 0.9% sodium chloride (final concentration 10 mg/mL).
b) ESMOLOL/ADULT LOADING DOSE

1) Infuse 500 mcg/kg for one minute.

c) ESMOLOL/ADULT MAINTENANCE DOSE

1) Follow loading dose with infusion of 50 mcg/kg/min for 4 minutes.
2) EVALUATION OF RESPONSE: If inadequate response to initial loading dose and 4 minute maintenance dose, repeat loading dose (infuse 500 mcg/kg for one minute) followed by a maintenance infusion of 100 mcg/kg/min for 4 minutes. Reevaluate therapeutic effect.
3) If response is inadequate, repeat loading dose and increase the maintenance dose by increments of 50 mcg/kg/min, administered as above.
4) END POINT OF THERAPY: As the desired heart rate or blood pressure is approached, omit loading dose and adjust maintenance infusion as required.

d) USUAL ADULT DOSE: 25 to 200 mcg/kg/min.
e) MAXIMUM ADULT DOSE: 300 mcg/kg/min.
f) CAUTIONS

1) Esmolol is a short acting beta-adrenergic blocking agent with negative inotropic effects. Esmolol may be hazardous in patients with bronchospastic disease (asthmatics, COPD) or myocardial depression.

2) LIDOCAINE

a) Dysrhythmias refractory to propranolol or esmolol may respond to lidocaine.
b) LIDOCAINE/INDICATIONS

1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).

c) LIDOCAINE/DOSE

1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.

a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).

2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).

d) LIDOCAINE/MAJOR ADVERSE REACTIONS

1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).

e) LIDOCAINE/MONITORING PARAMETERS

1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).

f) CASE REPORT: Graham et al (1988) found that a 100 mg bolus of lidocaine followed by a lidocaine infusion (4 mg/min) was NOT as effective as propranolol at eliminating ventricular dysrhythmias.

C) TORSADES DE POINTES

1) SUMMARY

a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).

2) MAGNESIUM SULFATE

a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).

3) OVERDRIVE PACING

a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).

4) POTASSIUM REPLETION

a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).

5) ISOPROTERENOL

a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

6) OTHER DRUGS

a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).

7) AVOID

a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

D) HYPOTENSIVE EPISODE

1) Infuse 10 to 20 mL/kg of isotonic fluid and place in Trendelenburg position. Consider central venous pressure monitoring to guide further fluid therapy. If hypotension persists consider administering dopamine or norepinephrine. CAUTION: Catecholamines may precipitate ventricular dysrhythmias in patients with chloral hydrate overdose (Ludwigs et al, 1996). Monitor ECG continuously.
2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

E) FLUMAZENIL

1) ADVERSE EFFECTS: Short et al (1988) attempted to reverse the respiratory depression and coma induced by an overdose of an unknown quantity of oxazepam and chloral hydrate with an intravenous dose of 0.5 mg flumazenil.

a) This rapidly precipitated multifocal ventricular ectopic beats with ventricular tachycardia.
b) The patient had a 9 year history of physical dependency to benzodiazepines and may have suffered an acute withdrawal reaction following the dose of flumazenil (Short et al, 1988).

2) CASE REPORT: Donovan & Fisher (1989) reported that flumazenil 200 mcg followed by 3 additional 100 mcg doses, at one minute intervals, reversed the respiratory depression, hypotension, and miosis induced by a 10 gram overdose of chloral hydrate (Donovan & Fisher, 1989).

Enhanced Elimination

A)

1) Hemodialysis has been advocated and may be useful in a patient unresponsive to normal supportive care or in whom acid-base or fluid and electrolyte problems may become uncontrollable.
2) CASE REPORT

a) Hemodialysis begun 7.5 hours postingestion resulted in a decrease of blood trichloroethanol levels of 5 to 1.6 mg/dL over 6 hours and was associated with improvement of ventricular dysrhythmias and mental status (Vaziri et al, 1977).
b) A total of 5.79 grams was removed during 4.5 hours of hemodialysis in a patient who had ingested 38 grams (Stalker et al, 1978). The trichloroethanol half-life was 34 and 35 hours before and after hemodialysis and 6.1 hours during dialysis.

3) Dialysis is not recommended for treatment of chlorobutanol toxicity since renal excretion of this compound is minimal.

B)

1) Removes trichloroethanol at a rate similar to hemodialysis (Gerretsen et al, 1979 (Suppl); Buur et al, 1988).

C)

1) Buur et al (1988) report the combined use of hemodialysis and charcoal hemoperfusion for 4 hours to treat a severe intoxication involving chloral hydrate 20 grams, diazepam 400 mg, and clomipramine 500 mg.

a) During combined hemodialysis and charcoal hemoperfusion, the half-life of trichloroethanol was 3.2 hours during treatment and 12.8 hours after termination of treatment.
b) Trichloroacetic acid half-life was 4.3 hours (reported average half-life is 67 hours). The clearance by hemoperfusion was found to decrease with time (Buur et al, 1988).
c) The patient received the treatment 12 hours after ingestion, but remained comatose. A second treatment was given 22 hours postingestion; at termination of treatment the patient was responding to speech and was fully lucid within hours (Buur et al, 1988).

D)

1) Forced diuresis is NOT recommended.

E)

1) May be useful following overdose in a small infant/neonate who continues to clinically deteriorate despite conventional supportive therapy.
2) Mowry et al (1983) reported the use of 3 double volume exchange transfusions in a 29-week, 1300 gram infant who had ingested 400 to 450 mg chloral hydrate (Mowry et al, 1983).

a) Clearance averaged 2.30 +/- 0.78 mL/min. In their opinion, substantial amounts of trichloroethanol were not removed.

3) A 2-volume exchange transfusion, performed 33 hours after stoppage of chloral hydrate, reduced trichloroethanol levels from 208 to 175 mg/L in a 2-month-old infant (Anyebuno & Rosenfeld, 1991).

Abstracts

Case Reports

A)

1) Ludwigs et al (1996) reported the case of a 29-year-old man who ingested approximately 70 grams of chloral hydrate in a suicide attempt. The patient presented to the ICU with coma, hypotension (systolic BP 60 mm Hg), and hypothermia (34 degrees Celsius). ECG showed sinus bradycardia with ST-segment depression and T-wave inversion. The patient received fluid replacement and catecholamines, which resulted in ventricular arrhythmias, which were treated with defibrillation, lidocaine, and metoprolol. After treatment with hemoperfusion and hemodialysis and supportive therapy, the patient recovered and was awake 8 hours later (Ludwigs et al, 1996).
2) Bloom (1966) reported a case of a 23-year-old man who ingested 2 to 3 oz of chloral hydrate syrup and developed ventricular fibrillation of a 1 hour 10 minute duration and dilated pupils which were fixed for 10 minutes. In addition, the patient's SGOT and LDH were elevated for 1 day. Subsequent to cardiac resuscitation the patient recovered completely; the myocardium showed no subsequent evidence of damage despite the fact that external cardiac massage was employed for 70 minutes (Bloom, 1966).
3) Vellar et al (1972) reported a 25-year-old woman who ingested 200 mL of chloral hydrate syrup (20 grams of chloral hydrate). On admission 24 hours postingestion coma, hypothermia, and pulmonary edema were present. The following day severe generalized peritonitis was found, as well as necrosis and perforation of the gastric fundus. Over the next 3 weeks several massive upper GI hemorrhages occurred. Two weeks later a stricture at the level of the esophagogastric anastomosis was demonstrated (Vellar et al, 1972).
4) Gleich et al (1967) reported a 66-year-old woman who ingested 18 grams of chloral hydrate and presented comatose 2 hours later. Hypotension and ventricular tachycardia occurred 12 hours post-ingestion; blood pressure was unobtainable 3 hours later with runs of ventricular fibrillation. Pneumonitis occurred on the third day and gastrointestinal bleeding on the eleventh day. Esophageal stricture subsequently developed (Gleich et al, 1967).

B)

1) Mindham (1968) reported a case of a 6-year-old boy who was inadvertently given 8 g instead of 600 mg of chloral hydrate. He became comatose but awoke 18 hours later with no ill effects. SGOT and SGPT rose transiently to 350 Units but no liver damage occurred (Mindham, 1968).
2) A term infant was intubated at delivery and was started on chloral hydrate 44 milligrams/kg every 6 hours on day 14 to control agitation and irritability. Chloral hydrate was increased to 50 mg/kg every 6 hours on day 17. Severe lethargy, decreased deep tendon reflexes, marked abdominal distension, absent bowel sounds, and diminished spontaneous urine output were noticed on day 21 and the need for ventilatory support to increased. An echocardiogram revealed poor myocardial contractility. Chloral hydrate was discontinued. A trichloroethanol (TCE) level, obtained 6.5 hours following the last oral dose, was 250 mg/L. A 2-volume exchange transfusion, performed 33 hours later, reduced TCE levels from 208 to 175 mg/L and a significant improvement in the infants sensorium and motor activity ensued. Neurologic, cardiac, gastrointestinal, and renal status continuously improved and spontaneous voiding of urine and resolution of gastrointestinal ileus occurred when TCE level reached 86 mg/L. The infant was extubated 2 weeks later and discharged home on day 70 after birth (Anyebuno & Rosenfeld, 1991).

Range Of Toxicity

Summary

A)

B)

Therapeutic Dose

7.2.1)

A) SPECIFIC SUBSTANCE

1) CHLORAL HYDRATE -

a) The usual adult hypnotic dose is 0.5 to 2 grams and, as a sedative, 250 milligrams three times daily up to a maximum single or daily dose of 2 grams (Sweetman, 2002).

2) CHLOROBUTANOL -

a) Chlorobutanol is available in concentrations of 0.5% as a preservative in pharmaceutical ophthalmic, parenteral, and otic preparations (Sweetman, 2002).

3) DICHLORALPHENAZONE -

a) Dichloralphenazone is used in combination with other medications (isometheptene mucate and acetaminophen) for relief of tension and vascular headaches. Each red capsule contains Isometheptene Mucate 65 milligrams, Dichloralphenazone 100 milligrams, and Acetaminophen 325 milligrams (Prod Info Midrin(R), isometheptene mucate, dichloralphenazone, and acetaminophen, 2001).

1) FOR RELIEF OF MIGRAINE HEADACHE - 2 capsules at once, followed by 1 capsule every hour until relieved; maximum of 5 capsules within a 12-hour period (Prod Info Midrin(R), isometheptene mucate, dichloralphenazone, and acetaminophen, 2001).
2) FOR RELIEF OF TENSION HEADACHE: 1 or 2 capsules every 4 hours up to 8 capsules a day (Prod Info Midrin(R), isometheptene mucate, dichloralphenazone, and acetaminophen, 2001).

7.2.2)

A) SPECIFIC SUBSTANCE

1) CHLORAL HYDRATE

a) SEDATION FOR PROCEDURES

1) 25 to 100 mg/kg orally or rectally 30 to 60 minutes prior to procedure (Litman et al, 2009; Layangool et al, 2008; Taghon et al, 2006; Krauss & Green, 2006; Hopkins et al, 1999; Bhatt-Mehta & Rosen, 1998; Algren & Algren, 1996; Greenberg et al, 1993); may repeat 25 mg/kg after 30 minutes if needed up to 100 mg/kg. .
2) Maximum single dose 1 gram: maximum total dose 2 grams or 100 mg/kg, whichever is less (Krauss & Green, 2006; Hopkins et al, 1999; Bhatt-Mehta & Rosen, 1998; Prod Info SOMNOTE(R) oral capsules, 2004).

2) DICHLORALPHENAZONE -

a) Ages 6 to 12 years - Usual hypnotic dose is 450 to 900 milligrams (JEF Reynolds , 1992).
b) Ages 1 to 5 years - Usual hypnotic dose is 225 to 450 milligrams (JEF Reynolds , 1992).
c) Up to 1 year of age - Usual hypnotic dose is 112 to 225 milligrams (JEF Reynolds , 1992).

Minimum Lethal Exposure

A)

1) CHILD: A 4-year-old child became unresponsive approximately 6 hours after receiving chloral hydrate 900 mg (70 mg/kg) prior to dental extraction. Emergency personnel administered cardiopulmonary resuscitation (CPR) prior to emergency department (ED) presentation. At the ED, the patient was asystolic and had a Glasgow Coma Scale score of 3. Arterial blood gases revealed severe acidosis. CPR continued with immediate intubation and vasopressor administration. Despite continued aggressive cardiac resuscitative efforts, the patient remained unresponsive with pupils fixed and dilated. Approximately 12 hours post-arrival, the patient died after experiencing another cardiopulmonary arrest episode and could not be resuscitated (Nordt et al, 2014).
2) ADULT: Ingestion of 40 grams of chloral hydrate by a 33-year-old woman (Gerretsen et al, 1979 (Suppl)) and 35 grams by a 35-year-old woman (King & England, 1983) resulted in death.

Maximum Tolerated Exposure

A)

1) Response to overdose amounts of chloral hydrate can be quite variable. Since overdose patients generally vomit, it is difficult to know exactly how much has been retained. Individuals with known cardiac dysfunction are highly susceptible to toxicity.
2) As with most drugs, it is difficult to predict precise toxicity because of the many variables concerned with absorption and metabolism. Patients rarely demonstrate any findings if they have not presented with toxicity prior to 2 to 3 hours following ingestion.

B)

1) PEDIATRIC: Significant toxicity (cardiac arrhythmias) was reported in a 2-year-old child after ingestion of 1500 milligrams(Nordenberg et al, 1971).

a) Significant toxicity and survival have occurred in children with doses as high as 38 grams of chloral hydrate (Pershad et al, 1999).
b) Doses of 80 to 100 mg/kg have been given to children less than 5 years old with no toxicity other than sedation (Pershad et al, 1999; Vade et al, 1995).

2) ADULT and PEDIATRIC: Ingestions of the following amounts has resulted in severe toxicity (coma, arrhythmias) with survival:

ADULTS
AGE	AMOUNT	REFERENCE
32 yr	20 g	Gerretsen (1979)
39 yr	25 g	Gerretsen (1979)
41 yr	12.5 g	Gerretsen (1979)
25 yr	20 g	Vellar (1972)
19 yr	17.5 g	Vaziri (1977)
48 yr	18 g	DiGiovanni (1969)
29 yr	15 g	Marshall (1977)
64 yr	10 to 20 g	Marshall (1977)
66 yr	18 g	Gleich (1967)
38 yr	38 g	Stalker (1978)
39 yr	30 g	Gustafson (1977)
51 yr	25 g	Gustafson (1977)
21 yr	20 g	Gustafson (1977)
67 yr	30 g	Bowyer (1980)
29 yr	10 g	Brown (1980)
36 yr	37.5 g	Brown (1980)
57 yr	22.5 g	Brown (1980)
30 yr	15 g	Young (1986)
26 yr	15 g	Graham (1988)
CHILDREN
AGE	AMOUNT	REFERENCE
8 yr	8 g	Mindham (1968)
2 yr	1.5 g	Nordenberg (1971)
10 mo	500 mg/kg/d	Hirsch (1986)
5 mo	283 mg/kg/d	Hirsch (1986)

3) INFANT: An 8-month-old infant became unresponsive and developed hypothermia, hypotension, esophageal burns, and hemorrhagic gastritis after inadvertently receiving 8 grams of chloral hydrate orally for sedation prior to an ophthalmic exam instead of the prescribed 0.4 gram. The chloral hydrate was also insufficiently diluted with only 15 mL of water (diluted concentration of 53%, pH 3.45; normal diluted concentration is 10%). With supportive care, the infant recovered without sequelae (Lin & Ma, 2006).
4) INFANT: A 28-day-old infant developed agitation, hypersalivation, and respiratory depression with hypoxia after inadvertently receiving a single oral chloral hydrate dose of 250 mg/kg (a total of 1000 mg) instead of the prescribed dose of 50 mg/kg. A chest X-ray was normal and all serum electrolyte concentrations, and renal and liver function tests were within normal limits. The patient spontaneously recovered approximately 7 hours post-ingestion (Kirimi et al, 2002).
5) CHILD: A 3-year-old boy became unresponsive after receiving 6,000 mg (400 mg/kg) of chloral hydrate prior to a dental procedure, instead of the prescribed 500 mg (50 mg/kg). Vital signs of the patient revealed persistent sinus tachycardia (120 to 130 bpm) and hypotension (91/55 mmHg). His Glasgow Coma Scale score was 3, and cardiac monitoring indicated dysrhythmias (ventricular bigeminy and trigeminy, and episodes of non-sustained ventricular tachycardia). With supportive treatment, the patient gradually recovered and was discharged home without neurologic sequelae (Nordt et al, 2014).
6) CHILD: A 15-month-old girl, with severe neurodevelopmental deficits, experienced stridorous respirations (respiratory rate 18 breaths/min), followed by cyanosis and apnea with O2 saturation of 64% approximately 25 minutes after administration of 1,200 mg chloral hydrate (100 mg/kg) for sedation prior to an ophthalmic evaluation. Assisted bag-valve-mask ventilation with 100% oxygen was performed, resulting in improvement in respiratory status. She was then maintained on oxygen 6 L/min by facemask, gradually weaning to room air over a 45-minute period. Following observation for 12 hours, the patient was discharged home without sequelae (Nordt et al, 2014).
7) ADULT: A healthy 25-year-old woman developed coma, hypotension, and recurrent ventricular tachycardia after ingesting 12.5 g chloral hydrate; she recovered with intensive supportive care (Laurent et al, 2006).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) GENERAL

a) THERAPEUTIC RANGE -

1) The THERAPEUTIC RANGE in adults for chloral hydrate is 1 to 2 milligrams percent (as trichloroethanol). Approximately 1000 mg of chloral hydrate taken orally by an average adult should yield a trichloroethanol plasma level of 1 to 2 milligrams percent (Bochner et al, 1978).
2) Other authors have reported therapeutic trichloroethanol levels range from 0.2 to 1.2 milligrams percent (Levine et al, 1985).
3) Chronic ingestion can produce physical dependence and tolerance to higher levels and withdrawal symptoms on termination of drug (Graham et al, 1988).

b) TOXIC LEVELS -

1) Are listed by some sources as 10 milligrams percent, with 25 milligrams percent lethal. These probably represent trichloroethanol since chloral hydrate is not readily detected (Winek, 1985).
2) Chlorobutanol levels of 75 to 100 micrograms/milliliter have been associated with somnolence, dysarthria, and respiratory depression (DeChristoforo et al, 1983; Borody et al, 1979).

2) CASE REPORTS

a) POSTMORTEM LEVELS -

1) Postmortem examination of a 22-year-old woman that received an uncertain amount of chloral hydrate revealed a trichloroethanol blood concentration of 7.09 milligrams percent.

a) Attempts at resuscitation with epinephrine may have aggravated the toxic effects of chloral hydrate (Jastak & Pallasch, 1988).

2) Postmortem levels of up to 170 milligrams percent have been found (Levine et al, 1985).
3) An unknown amount ingested by a 35-year-old adult produced death and postmortem levels of 127 milligrams/liter (blood) and 128 milligrams/liter (urine). Acetaminophen and oxycodone were also found (Heller et al, 1992).

Pharmacology Toxicology

Pharmacologic Mechanism

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Toxicologic Mechanism

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CHLORAL HYDRATE AND RELATED AGENTS

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