The phrase "poisoned patient" is often used to describe patients exhibiting clinical signs and symptoms that result from an exposure to a pharmaceutical agent, an illicit drug or an environmental toxin. Poisonings may occur for many different reasons: intentional harm (e.g., suicide), intentional misuse (recreational drug abuse), unintentional (ingestions by small children exploring their environment) and therapeutic error. In the year 2006, over two million exposures to toxins were reported to Poison Centers in the United States.(1) These calls probably represent a minority of actual exposures.

Frequently, the physician may not know exactly which agents are responsible for the clinical symptoms. In these situations, the use of a few general guidelines and management principles will help to provide optimal supportive care. Specific antidotes for some agents are available and may be helpful in situations where a specific toxic syndrome (toxidrome) is identified. However, for the large majority of patients, optimal management may be provided with supportive care alone.

Initial Management

Initial management of the poisoned patient should always begin with a rapid assessment of airway patency, breathing (including depth and rate of ventilation) and circulation (including heart rate, blood pressure and an estimation of tissue perfusion by assessing level of consciousness, capillary refill time, presence of skin pallor and an assessment of urinary output). Consideration should be given to external decontamination if there is a potential for ongoing absorption or a suspicion of an exposure that could potentially cause harm to others, for example, an organophosphate insecticide or cyanide.

Careful evaluation during a secondary examination may yield useful clues to identify the general class of agents responsible for symptoms. Examples include pupil size (large in both anticholinergic and adrenergic toxicity and small in opioid and cholinergic toxicity) and skin texture (moist/wet skin is found in cholinergic and adrenergic toxicity and in sedative-hypnotic withdrawal; dry, flushed skin is found in anticholinergic toxicity). All patients with altered mental status should have an immediate bedside glucose determination and, if low, they should receive intravenous dextrose 0.5-1 g/kg.

A rapid 12-lead electrocardiogram should be performed in all patients, with particular attention given to interval duration (QRS and QTc). A QRS interval >100 msec suggests a sodium channel blockade that results from a variety of agents, such as tricyclic antidepressants, where QRS duration is an established predictor of toxicity.(2) A bolus of hypertonic sodium bicarbonate (1-2 mEq/kg) should be immediately administered to all patients who exhibit a QRS prolongation >100 msec on the ECG in the setting of a toxic exposure, and this should be followed by an infusion, which is typically made of 150 mEq (3 amps) of sodium bicarbonate in one liter of D₅W, infused at a rate of two to three times the patient's maintenance rate. A repeat ECG should be obtained immediately after the administration of sodium bicarbonate to assess the response to therapy. Patients treated with this therapy should have careful attention paid to their serum potassium concentration, as bicarbonate therapy results in intracellular shift of potassium, which my result in clinical hypokalemia.

Hypotension

Hypotension, defined as a blood pressure that is inadequate to perfuse tissues, occurs commonly in poisoned patients and can result from several different factors -- volume depletion secondary to dehydration (from gastrointestinal, urinary and insensible losses), cardiac dysrhythmias, coexisting hypoxia or acidosis, or anaphylaxis.(3) Hypotension may also be a direct result of the exposure. Many agents cause hypotension by various mechanisms such as vasodilation, negative inotropy and impaired conduction. Initially, all hypotensive patients should be given intravenous (IV) crystalloid fluids at a 10-20 mL/kg bolus, with further fluid administration titrated accordingly.(4)

Hypotension refractory to IV fluids may require vasopressor support. Many different vasopressors are available, classified as direct-acting (they act directly on an adrenergic receptor), indirect-acting (they increase the concentration of norepinephrine or epinephrine and subsequently stimulate the receptor) or mixed-acting [a sympathomimetic drug which increases norepinephrine (NE) and also directly activates receptors].(5)

No single recommendation can be made for choosing a vasopressor to correct hypotension for all poisoned patients -- many variables should be considered and the choice should be individualized. However, it should be noted that many poisoned patients may already be on antidepressant medications that block the reuptake of neurotransmitters into the nerve terminal (serotonin and NE) and will thus have relative depletion of NE available in the terminal for release. In these situations, a direct-acting vasopressor, such as NE, which predominantly stimulates the alpha1 receptor resulting in vasoconstriction, will likely be the preferred choice over dopamine, a mixed-acting drug.(5)

GI Decontamination

All poisoned patients who present with an oral overdose should be considered candidates for GI decontamination. The philosophy of GI decontamination centers on the concept of a dose response relationship -- the effect of a toxin changes with concentration. In theory, if the amount of toxin to which a patient is exposed is decreased, then the resulting clinical effect will be lessened. Several methods exist for gastrointestinal decontamination of poisoned patients such as administering activated charcoal, orogastric lavage and whole bowel irrigation. Each method has associated risks and benefits. Since the demonstration of clinical benefit for these modalities in actual poisoned patients has proven to be difficult, controversy exists over the clinical indications for each method.

Orogastric lavage (OGL) is performed by passing a large bore orogastric tube (36-40F) into the stomach with subsequent instillation and then removal of fluid in attempts to empty stomach contents. Since OGL is highly invasive and has many potential complications such as aspiration, esophageal perforation and dysrhythmias,(6)(7)(8) it is not recommended for the routine management of poisoned patients. However, in certain circumstances such as a recent ingestion of a potentially life-threatening substance, OGL may be considered. OGL is contraindicated in patients with unprotected airways.(9) One randomized study showed a clinical benefit for OGL in a small sub-group of obtunded patients presenting within one hour of ingestion(10) but this could not be confirmed in a subsequent study.(11) However, many such studies have limitations including small sample size, methodological selection bias and subjective interpretation of outcomes.(12)(13)

Activated charcoal (AC) is prepared by the pyrolysis of carbonaceous products, which are subsequently heated to increase their adsorptive surface area. It is the most common form of gastrointestinal decontamination used in the management of poisoned patients.(14) AC is given by mouth or nasogastric tube to adsorb the toxin while in the GI tract, thus minimizing its subsequent systemic absorption. Several volunteer studies have been performed to assess the clinical benefit of administering AC. Though there is variability in drug studied, as well as in the amount of charcoal given, the greatest amount of adsorption is consistently obtained when charcoal is administered within one hour.(14) Despite these data, AC may be effective after one hour, especially with sustained release products.(15)

Though the use of AC in routine care of the overdose patients is discouraged by consensus guidelines,(14) consideration should be made on a case by case benefit, as situations may arise where AC is potentially beneficial. Single dose AC given to patients after ingestion of citalopram was associated with a lower incidence of prolonged QT.(16) Similarly, a randomized trial showed decreased morbidity and mortality when multiple-dose activated charcoal was given to patients who intentionally ingested yellow oleander seeds to attempt suicide.(17) AC is contraindicated in patients who have an unprotected airway or following ingestion of substances that have a high risk of aspiration (hydrocarbons).(14) AC should not be used if endoscopy is planned in patient evaluation (e.g., corrosives), as it may obscure view.

Whole bowel irrigation (WBI) requires the administration of large volumes of an osmotically balanced polyethylene glycol electrolyte lavage solution (PEG-ELS) into the bowel in an attempt to mechanically flush out substances and decrease their time in the GI tract. Unlike the use of water or normal saline, the presence of PEG-ELS and electrolytes prevents significant changes in fluid or electrolyte balance.(18) Although volunteer studies demonstrate decreased bioavailability of ingested drugs, no clinical controlled trials have been performed and there is no conclusive evidence that WBI improves outcomes in poisoned patients.(19)(20)(21) However, WBI should be considered when patients ingest life-threatening amounts of sustained release or enteric coated tablets, or substances not well adsorbed to charcoal (such as iron and lithium).(21) WBI should also be considered for removal of packets of intentionally ingested drugs, as in the case with body-packers.(22) Contraindications to WBI include known bowel perforation obstruction, significant GI bleeding, unprotected airways and hemodynamically unstable patients.(21)

Though clinical studies have not shown a strong benefit to gastrointestinal decontamination in poisoned patients, consideration should be given to the difficult nature in studying this topic. In vivo, animal and human volunteer studies are controlled environments that use doses that are minimally toxic. These circumstances do not necessarily mimic the real-life poisoned patient, who may ingest multiple substances, each with different pharmacokinetic properties, and present at different times after ingestion. While most clinical trials do not show convincing evidence that decontamination shows a benefit, this is not true in all circumstances and the principles of decontamination should not be abandoned. Management of the possibly poisoned patient should always be individualized, with the risk of the ingested substance considered along with the risk of the GI decontamination. If the toxin involved will potentially cause substantial clinical impairment, decontamination should be considered, especially if the patient presents early after exposure.

Laboratory Testing

Basic laboratory tests including serum chemistries and liver function tests may aid in the evaluation and management of the poisoned patient. Additional serum drug concentrations and urine drug abuse assays may also be available, depending on the resources of the facility. In general, however, obtaining routine drug and urine screens in the absence of specific clinical indications is costly, time-consuming and unnecessary.

In contrast, all patients presenting after a suicidal ingestion must have a serum acetaminophen concentration measured. Acetaminophen is a popular over-the-counter product and a common ingredient in combination products for cough, cold or pain remedies. Acetaminophen may, therefore, be readily available in many households. Because it is so common, it may not even be viewed by patients as a medication, may not be perceived as potentially harmful and, therefore, may not be reported as an ingested substance on medical interview.

Approximately 1 in 500 patients presenting with ingestions after attempted self harm but not reporting an exposure to acetaminophen have been found to have a potentially toxic acetaminophen concentration.(10)(23) Toxic acetaminophen levels may be obtained with no or non-specific symptoms -- when treated early, the prognosis is excellent(24) Other serum drug concentrations such as salicylates, lithium, methanol, ethylene glycol, lithium, digoxin, may be clinically useful in guiding therapy in specific situations, but should only be obtained when specific clinical indications are present.

Urine screens for drugs of abuse are not very helpful for the acute assessment and management of the overdosed patient. Unlike serum drug concentrations, which directly measure the presence of a substance, urine screens are qualitative assays, simply interpreted as a positive or negative, depending on the presence of the drug or its metabolite. Specific drugs assayed on a particular screen vary between institutions but most common assays include amphetamines, cannabinoids, cocaine, opioids and phencyclidine. Unexpected positive results found on drug screens seldom change management and almost never affect outcome.(25)(26)(27)

Additionally, urine drugs screens have several important limitations. Qualitative drug screens only detect a small range of drugs; they are not comprehensive screens and, therefore, negative drug screens do not exclude all drug exposures. Positive screens may represent clinically insignificant concentrations or be a false-positive resulting from structural similarity between compounds.(28) Moreover, since drugs can be found in the urine long after symptoms have passed, the qualitative presence of a drug in the urine does not necessarily indicate that it contributed to the current clinical presentation. This effect frequently misleads the physician to attribute symptoms to a drug when there is another diagnosis to be made (e.g., lethargy may be attributed to a positive benzodiazepiene screen when in fact the patient has a meningitis). Drug screening may be of value in the documentation of suspected cases of malicious poisoning or confirmation of the presence of substances in cases of suspected child abuse or neglect.

Seizures

Seizures may occur with exposure to some drugs. Since the central nervous system relies on a fine balance of excitatory and inhibitory neurotransmission, alterations in this balance may results in seizures. Drugs that alter the production of GABA, the primary inhibitory neurotransmitter of the brain, or, alternatively, drugs that antagonize the GABA receptor, can result in seizures. Antagonism of the adenosine receptor, an endogenous anticonvulsant, can produce severe and protracted seizures. This frequently follows significant ingestions of caffeine or theophylline. Seizures may also occur as the result of an electrolyte disturbance such as hyponatremia or alterations in glucose metabolism.

Regardless of etiology, all seizures should be approached in the same manner. Immediate care should be treated with a benzodiazepine (lorazepam 0.05-0.1 mg/kg IV or IM, or diazepam 5-10 mg IV/PR); hypoglycemia and hypoxia should be excluded. If seizures continue despite initial therapy, consideration should be given to empiric pyridoxine therapy (70 mg/kg to a maximum dose of 5 g), particularly if there is an exposure to INH or hydrazines. A second line agent, such as propofol or a barbiturate, should be added as needed. Phenytoin should not be used in the management of toxicologic seizures, as it has been demonstrated to be either ineffective or harmful for most toxin-related seizures (TCAs, theophylline).(29)(30)

Hyperthermia

Hyperthermia, defined as a core body temperature above 39°C, may occur as a result of an exposure to many different medications or drugs of abuse. For example, malignant hyperthermia, serotonin syndrome, neuroleptic malignant syndrome, thyrotoxicosis, cocaine/sympathomimetic exposure and alcohol withdrawal may all result in hyperthermia.

Neuroleptic malignant syndrome (NMS) is an idiopathic, potentially life-threatening syndrome that may occur when there are abrupt reductions in central dopminergic neurotransmission in the hypothalamus leading to alterations in thermoregulation and autonomic dysfunction.(31) This most frequently occurs with exposure to neuroleptic medications (e.g., haloperidol) which block the D₂ dopamine receptor but also may occur with withdrawal of dopamine agonists (e.g., levadopa/carbidopa) used in the treatment of Parkinson's disease. Risk factors for NMS include young age, male gender, exposure to high potency neuroleptics, depot preparations and rapid dose escalation in dose, dehydration, agitation, preexisting abnormalities of CNS dopamine activity or receptor function.(31)(32)

While many different criteria for diagnosis of NMS exist, there is no gold standard. However, good criteria include a combination of altered mental status, motor symptoms (typically lead-pipe rigidity) and hyperthermia in the context of exposure to a precipitant.(31)(32) Laboratory values are not specific for the diagnosis and may instead reveal sequelae such as rhabdomyolysis and multi-organ failure. Signs and symptoms of NMS occur slowly and may develop over a period of several days.

Serotonin syndrome (SS) is a clinical syndrome that occurs in situations of excess serotonin. While there are many serotonin receptors located throughout the CNS, excess stimulation of the 5-HT_2A receptor and, in some cases, the serotonin 5-HT_1A, receptor, has resulted in serotonin syndrome.(33)(34) This has been reported to occur with a large number of medication and drug exposures, including monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), meperidine, antibiotics, weight-reduction agents, antiemetics, antimigraine agents, drugs of abuse (cocaine, MDMA, etc.) and herbal products.(35)

Like NMS, no gold standard criteria exist for the diagnosis but it is well recognized that serotonin syndrome is a spectrum of clinical findings that includes hyperthermia, muscle rigidity, tremors, hyperreflexia, clonus, altered mental status and autonomic instability, together with a history of exposure to an agent that increases serotonin concentration. Clonus is the most important finding in establishing the diagnosis of serotonin syndrome.[FN:35:8387]]

Regardless of etiology, the optimal management of the patient with drug-induced hyperthermia is initially the same: rapid cooling, IV hydration, removal of the precipitating agent and good supportive care. Sedation is frequently required, as agitation and muscle rigidity prevent rapic cooling. Other adjuncts to therapy such as bromocriptine for NMS or cyproheptadine for SS should be considered in consultation with a medical toxicologist.

Conclusion

Poisoned patients may present with an array of clinical findings depending on the type of drug as well as the amount of drug they were exposed to. While some antidotes exist and may aid in management, initial evaluation and management should begin with adherence to some basic toxicological principles. Clinicians are strongly encouraged to contact their local Poison Control Center for consultation and additional guidance when caring for poisoned patients.