Strychnine poisoning

INTRODUCTION — Strychnine, an alkaloid derived from seeds of the tree Strychnos nux vomica, was first used as a rodenticide in Germany in the early 16^th century. By the early 1900s, strychnine became widely available in cathartic pills, and caused a significant number of fatalities from suicidal and unintentional ingestions in the United States. In the early 1900s, strychnine toxicity was a major cause of toxicologic death in children [1,2]. The number of strychnine exposures in the United States has fallen significantly since its elimination from nonprescription preparations in 1962 [1].

This topic review will discuss the basic pharmacology, clinical presentation, and management of strychnine poisoning. Discussions of the general approach to the management of poisoned patients and detailed management of other toxins are found elsewhere.

●(See "General approach to drug poisoning in adults".)

●(See "Initial management of the critically ill adult with an unknown overdose".)

●(See "Approach to the child with occult toxic exposure".)

SOURCES OF EXPOSURE — Although rare, most strychnine poisonings today result from the adulteration of street drugs (eg, cocaine, heroin), as well as herbal medications and homeopathic remedies [3-5]. Rarely, cases of poisoning occur in which a strychnine-containing rodenticide is implicated [6-8]. (See "Overview of rodenticide poisoning".)

PHARMACOLOGY AND CELLULAR TOXICOLOGY — The seeds of Strychnos nux vomica contain 1.1 to 1.4 percent of strychnine and brucine, another toxic alkaloid [9]. Commercial rodenticide preparations typically contain between 0.3 to 5.0 percent strychnine [2,10]. Strychnine is typically formulated as a relatively odorless and tasteless white powder [6]. While brucine (2,3-dimethoxystrychnine) is the lesser alkaloid, lethal ingestion of brucine alone has been reported [11].

Lethal doses of strychnine are generally accepted as 1 to 2 mg/kg [12], although death has been reported at lower doses, and survival has been documented with significantly higher doses [13].

Strychnine is a competitive antagonist of glycine, an important inhibitory neurotransmitter in the spinal cord, brainstem, and higher centers [14]. Strychnine's toxicity is attributed to action at the postsynaptic receptor in the motor neurons of the spinal cord's neural horn [9]. There, it antagonizes inhibitory tone, resulting in powerful and uncontrollable muscle contractions. Additional mechanisms have been proposed, including agonism of excitatory N-methyl-D-aspartate (NMDA) receptors and antagonism of gamma amino butyric acid (GABA), another inhibitory neurotransmitter [15,16].

KINETICS — Strychnine is rapidly absorbed from all routes [8,17]. The onset of symptoms occurs within 10 to 20 minutes of ingestion, while injection or inhalation may result in more rapid development of symptoms, and dermal exposure may produce a delayed onset [18,19]. Strychnine displays little protein binding and is rapidly redistributed from the blood to the tissues. Its volume of distribution is 13 L/kg [1,2,20]. Elimination follows first-order kinetics with an elimination half-life of approximately 10 to 16 hours [18,21,22].

Hepatic metabolism eliminates approximately 80 percent of ingested strychnine [23-25]. Inducers of hepatic microsomal enzyme activity can enhance strychnine metabolism, while deacetylation can reduce the drug's biologic activity [8]. Up to 20 percent of ingested strychnine may be eliminated in the urine [2,18,25,26]. However, in massive ingestions urinary excretion appears to play a lesser role, accounting for the excretion of as little as 1 percent of the amount ingested [26]. Strychnine is also concentrated and excreted in the bile [25].

CLINICAL FEATURES OF OVERDOSE

History — It is important to know the amount of strychnine ingested and whether other drugs or substances were taken. Lethal doses of strychnine are generally accepted as 1 to 2 mg/kg [27], although death has been reported at lower doses, and survival has been documented with significantly higher doses [28].

The patient's history should include a detailed description of events leading up to presentation. The clinician should ask about depression, intentional self-injury, exposure to dietary supplements, occupational exposure to pesticide, and use of illicit drugs. Additional history regarding trauma, past medical history, and current medications will help to narrow the differential diagnosis and identify coingestants.

The onset of symptoms from strychnine poisoning usually occurs within 10 to 20 minutes of ingestion, but injection or inhalation may result in more rapid development, and dermal exposure may produce a delayed onset.

Presentation and physical examination — Prodromal signs may include mydriasis, hypervigilance, anxiety, hyperreflexia, clonus, and stiffness of the facial and neck muscles [29]. Spontaneous vomiting following oral exposure is unusual in strychnine poisoning [2].

The sine qua non of strychnine toxicity is the "awake" or "spinal" seizure, in which the patient demonstrates tonic-clonic seizure activity but remains fully alert throughout and afterwards. Characteristic muscle spasms may include opisthotonos (truncal rigidity and back arching), as well as marked grimacing (risus sardonicus, or sardonic smile) [18]. Muscle contractions typically follow a waxing and waning course, with minutes of tetanic contraction followed by up to two minutes of muscle relaxation, or even flaccidity [3,25]. Stimulation may provoke or worsen the spasms [30,31].

Tetanic contraction of skeletal muscle produces rigidity, tachycardia, and hyperthermia [9]. Rhabdomyolysis and compartment syndrome can result. Patients may also develop a severe lactic acidosis from uncontrolled muscle activity [32]. Involvement of thoracic and diaphragmatic musculature leads to respiratory paralysis, the most common cause of death in strychnine toxicity. Prognosis is generally favorable if the patient survives beyond five hours from the onset of symptoms [2]. Neuromuscular sequelae are rare among survivors; however, prolonged weakness, myalgia, myoedema, and anterior tibial compartment syndrome have been reported [2,8,17]. (See "Rhabdomyolysis: Clinical manifestations and diagnosis" and "Acute compartment syndrome of the extremities".)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of strychnine toxicity includes tetanus, epilepsy, dystonic drug reactions, infections of the neck, hypocalcemia, picrotoxin exposure, and psychogenic disorders.

●Tetanus ‒ Tetanus classically presents with trismus, followed by diffuse spasms of the neck and extremities [17]. Tetanospasmin blocks the release of glycine from inhibitory neurons, producing hyperexcitability more slowly than strychnine [8]. Symptoms of tetanus generally progress over days. A history of recent penetrating injury and inadequate immunization status support this diagnosis. (See "Tetanus".)

●Generalized seizure ‒ True generalized tonic-clonic seizures can be distinguished from strychnine toxicity by the presence of an altered level of consciousness and a postictal period. The finding of an altered sensorium in a patient with involuntary muscle activity should prompt a search for etiologies other than strychnine. (See "Convulsive status epilepticus in adults: Classification, clinical features, and diagnosis".)

●Dystonic drug reaction and neck infection ‒ Dystonic drug reactions and infections of the neck may mimic facial grimacing seen with strychnine, with less of the diffuse tonic-clonic activity. A history of exposure to an antipsychotic or antiemetic medication and improvement with anticholinergic therapy support the diagnosis of dystonia. (See "Schizophrenia in adults: Maintenance therapy and side effect management", section on 'Dystonia'.)

●Hypocalcemia ‒ Hypocalcemia may present with hyperexcitability, tetany, focal numbness, and diffuse muscle spasms. Typically the findings are not as severe as in strychnine toxicity, and a serum calcium level quickly reveals the diagnosis. (See "Clinical manifestations of hypocalcemia".)

●Clenbuterol toxicity Clenbuterol, a beta-agonist commonly used to adulterate heroin, typically causes tachycardia, tremor, anxiety, and vomiting. However, cases of clenbuterol toxicity presenting with agitation, muscle spasm, hyperreflexia, and elevated serum creatine kinase concentrations have been reported. The authors specifically note the similarity in presentation to strychnine toxicity [33,34].

●Picrotoxin toxicity ‒ Picrotoxin inhibits the action of gamma-aminobutyric acid (GABA) leading to convulsions that develop more slowly than with strychnine poisoning [8]. This outdated analeptic is not widely available.

Psychogenic causes for involuntary muscle contractions should be considered a diagnosis of exclusion.

LABORATORY EVALUATION — Although identification and measurement of strychnine in blood and urine has been described, rapid laboratory tests specific for detecting and quantifying strychnine are unavailable in most clinical settings. Close correlation between strychnine levels and clinical toxicity has not been demonstrated. Clinical features guide management; the main value of laboratory analysis lies in confirmation of the exposure and identification of complications, such as rhabdomyolysis [32].

Routine laboratory evaluation of any acutely poisoned patient should include the following:

●Fingerstick glucose, to rule out hypoglycemia as the cause of any alteration in mental status.

●Acetaminophen and salicylate levels, to rule out these common coingestions.

●Electrocardiogram, to rule out conduction system poisoning by coingestants that affect the QRS or QTc intervals.

Other potentially useful laboratory studies in the setting of strychnine poisoning include: complete blood count; basic electrolytes, including potassium and calcium; creatinine and BUN; creatine phosphokinase; and urinalysis. With strychnine toxicity, a leukocytosis may develop, and a lactic acidosis can occur due to the intensity of muscle activity. Hypokalemia has been reported in the setting of strychnine exposure [35]. Creatine phosphokinase and myoglobinuria are useful markers of rhabdomyolysis, and early assessment of renal function is indicated as renal failure may result.

MANAGEMENT

Initial stabilization — As with any poisoning, management begins with rapid assessment of the patient's airway, breathing, and circulation. Oxygen is administered, intravenous access established, and continuous cardiac monitoring employed. Fingerstick serum glucose is immediately obtained. Prompt recognition of the poisoning and initiation of treatment is critical [32]. The patient should be managed in a quiet, dark room to avoid all extraneous stimuli; excessive manipulation and loud noises may precipitate paroxysms of muscle activity secondary to reflex hyperexcitability.

Given their rarity and complexity, all cases of suspected strychnine toxicity should be managed in conjunction with a poison control center or medical toxicologist. (See 'Additional resources' below.)

Control of muscle activity — Aggressive control of muscle activity is the cornerstone of successful management of strychnine poisoning [2]. High-dose benzodiazepines are the mainstay for controlling muscle activity. In adults, treatment can be initiated with 5 to 10 mg of diazepam or 2 to 3 mg of lorazepam. These doses may be re-administered every 15 minutes, until control of rigidity is obtained. Patients must be re-assessed frequently, and medications titrated rapidly to effect (improvement or cessation of rigidity). Amounts as large as 1 mg/kg of diazepam have been used [27,36]. In children, diazepam may be dosed at 0.2 mg/kg and lorazepam at 0.04 mg/kg. In cases where intravenous access cannot be established initially, the first doses may be given intramuscularly (IM). However, benzodiazepines should only be given IM when absolutely necessary, as absorption by this route is erratic.

In the presence of benzodiazepines, gamma amino butyric acid (GABA) has increased affinity for its receptor, causing increased inhibitory tone at the level of the motor neuron [1]. Because strychnine affects glycine receptors, not GABA receptors, benzodiazepines may not provide adequate pharmacologic reversal in severe strychnine toxicity [8]. Lack of improvement after serial doses of benzodiazepines indicates that treatment with other medication classes is necessary.

Barbiturates may also be efficacious, and provide synergy with benzodiazepines in refractory cases [2]. If more than 0.5 mg/kg of diazepam, or 0.1 mg/kg of lorazepam, are given without significant improvement in the patient's condition, we suggest the addition of a barbiturate to further control muscle activity. Intravenous phenobarbital may be administered to adults at in slow intravenous boluses of 100 mg (no faster than 50 mg/min), with a 24 hour limit of 600 mg [37,38]. The dosing for intravenous phenobarbital in children is not well-defined; however, doses as high as 30 mg/kg have been recommended intravenously for status epilepticus in children [39]. A loading dose of 10 to 20 mg/kg can be given, followed by additional doses of 5 to 10 mg/kg every 20 minutes. Concurrent use of barbiturates and benzodiazepines usually necessitates tracheal intubation due to the significant and synergistic central nervous system (CNS) and respiratory depression caused by this combination therapy.

Propofol is another reasonable alternative should treatment with high-dose benzodiazepines prove ineffective. Treatment with propofol requires tracheal intubation. Propofol can be initiated with a 125 to 300 mcg/kg continuous infusion and titrated to effect. Propofol should not be used routinely in children under the age of two.

Involuntary muscle contractions can be extremely painful, and appropriate analgesia should be given. In the non-intubated patient, opioids should be titrated carefully to avoid hypoventilation; a short-acting agent, like fentanyl, may be most appropriate in critical patients. Fentanyl can be administered in intermittent doses at 0.5 to 1.5 mcg/kg IV; further doses may be repeated every 5 to 15 minutes as needed.

Airway management and paralysis — Most deaths result from respiratory compromise, and emergent airway management is often necessary with a significant acute ingestion [2]. Sedation, paralysis, and endotracheal intubation are necessary in the setting of uncontrollable motor activity, severe acidosis (pH <7.1), or significant hyperthermia (core temperature above 40ºC).

Etomidate 0.3 mg/kg IV is an appropriate induction agent for use in rapid sequence intubation (RSI). Propofol and midazolam are good alternative induction agents. We prefer rocuronium 1.2 to 1.5 mg/kg IV or another nondepolarizing neuromuscular blocking agent if RSI is performed in the strychnine-poisoned patient, given the potential for transiently increased muscle activity with the use of succinylcholine. (See "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care" and "Rapid sequence intubation in adults for emergency medicine and critical care".)

Benzodiazepines or propofol may be used for sedation following intubation. It is imperative that the patient be well sedated while paralyzed. Long-acting nondepolarizing agents may be used after intubation (eg, vecuronium, cisatracurium), particularly in the setting of hyperthermia. While additional evaporative cooling methods may be used, paralysis is the most rapid and effective means for reversing hyperthermia and acidosis in these patients. Succinylcholine has no role in the long-term paralysis of these patients, given its potential to cause hyperkalemia and hyperthermia, and to worsen rhabdomyolysis. (See "Neuromuscular blocking agents in critically ill patients: Use, agent selection, administration, and adverse effects".)

IV fluid, activated charcoal, and other interventions — Supportive care and monitoring for complications is crucial. Intravenous fluids should be given in sufficient amounts to maintain brisk urine output (above 1 mL/kg per hour), as rhabdomyolysis, metabolic acidosis, and acute renal failure are well-known complications [2,21]. Serial examinations and appropriate surgical consultation for compartment syndrome are necessary [2]. (See "Rhabdomyolysis: Clinical manifestations and diagnosis".)

There is no role for ipecac or gastric lavage in strychnine toxicity. Multidose activated charcoal may be beneficial as the high-strychnine concentration found in the hepatobiliary system suggests enterohepatic recirculation, but benefit is unproven. The use of charcoal should be avoided in any patient with a tenuous airway or altered mental status [2,25]. There is no demonstrated role for hemodialysis in enhancing elimination [28]. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Multidose activated charcoal'.)

PEDIATRIC CONSIDERATIONS — Strychnine poisoning in the pediatric population parallels that in adults; pathophysiology and clinical manifestations are the same. However, diagnosing strychnine poisoning in children can be difficult. Young children may be unable to communicate vague symptoms; adolescents may be reluctant to disclose their use of recreational drugs, which may be adulterated with strychnine.

As with adults, the key to management is controlling involuntary muscle activity, administering supportive care, and treating complications. The approach to medical therapy for controlling muscle activity is unchanged in children. Benzodiazepines are first line treatment. The starting dose of diazepam in children is 0.1 mg/kg, with rapid titration to effect. Medical therapy is described in detail above. (See 'Control of muscle activity' above.)

Supportive care is of the utmost importance and includes: administration of oxygen and intravenous fluids, continuous cardiac monitoring, and correction of vital signs. Vigilance for signs of respiratory muscle fatigue is essential. End-tidal CO₂ monitoring may be a useful adjunct for early identification of hypoventilation. Children must be managed in a center with expertise in pediatric emergency airway management. Complications of rhabdomyolysis, metabolic acidosis, renal failure, and compartment syndrome should be treated aggressively. (See "Rhabdomyolysis: Clinical manifestations and diagnosis" and "Carbon dioxide monitoring (capnography)".)

Pediatric exposures to strychnine occur worldwide, often in the developing world where use of strychnine as a pesticide continues. Some rodenticide formulations of strychnine are sold as bright pink tablets, making them appealing to small children [16].

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General measures for acute poisoning treatment".)

SUMMARY AND RECOMMENDATIONS

●Sources of exposure – Strychnine poisoning is rare and generally results from the adulteration of street drugs (eg, cocaine, heroin), small amounts found in herbal medications and homeopathic remedies, and strychnine-containing rodenticides. (See 'Sources of exposure' above.)

●Pharmacology – Strychnine's toxicity antagonizes inhibitory tone in motor neurons of the spinal cord's neural horn, resulting in powerful and uncontrollable muscle contractions. (See 'Pharmacology and cellular toxicology' above.)

●Kinetics – Strychnine is rapidly absorbed from all routes. The onset of symptoms from strychnine poisoning usually occurs within 10 to 20 minutes of ingestion, but injection or inhalation may result in more rapid development, and dermal exposure may produce a delayed onset. (See 'Kinetics' above.)

●Clinical features – The sine qua non of strychnine toxicity is the "awake" seizure, in which the patient demonstrates tonic-clonic activity but remains fully alert throughout and afterwards. Characteristic muscle spasms may include truncal rigidity and back arching, as well as marked grimacing. Muscle contractions typically follow a waxing and waning course, with minutes of tetanic contraction followed by up to two minutes of muscle relaxation, or even flaccidity. (See 'Presentation and physical examination' above.)

●Differential diagnosis – The differential diagnosis of strychnine toxicity includes tetanus, epilepsy, dystonic drug reactions, infections of the neck, hypocalcemia, picrotoxin exposure, and psychogenic disorders. (See 'Differential diagnosis' above.)

●Laboratory evaluation – Rapid laboratory tests specific for detecting and quantifying strychnine are not available in most clinical settings. The main value of laboratory analysis lies in confirmation of the exposure and identification of complications, such as rhabdomyolysis. Laboratories indicated in the management of strychnine poisoning are described above. (See 'Laboratory evaluation' above.)

●Management – In a patient with muscle contractions from strychnine, we suggest treatment with high-dose benzodiazepines (Grade 2C). Aggressive control of muscle activity is the cornerstone to successful management. Barbiturates may also be efficacious and provide synergy with benzodiazepines in refractory cases. Propofol is another alternative treatment. (See 'Control of muscle activity' above.)

Most deaths result from respiratory compromise, and emergent airway management is often necessary with a significant acute ingestion. Sedation, paralysis, and endotracheal intubation are necessary in the setting of uncontrollable motor activity, severe acidosis (pH <7.1), or significant hyperthermia (core temperature above 40ºC). For rapid sequence intubation, we use rocuronium for paralysis. (See 'Airway management and paralysis' above.)