Because activated charcoal is an inert substance, it is thought that lung injury after aspiration of activated charcoal is caused by gastric contents. Aspiration of gastric contents causes neutrophils to release neutrophil elastase, which increases pulmonary vascular permeability.¹¹ In comparison, intratracheal administration of activated charcoal does not increase elastase in the bronchoalveolar fluid.¹² Activated charcoal can activate alveolar macrophages, which are a potent source of oxygen radicals, proteases, and other inflammatory mediators. Charcoal also causes obstruction of small distal airways Overdistention of alveolar segments in areas not occluded by charcoal leads to volutrauma in those areas, which increases microvascular permeability.¹³ Although case reports reveal long-term pulmonary pathology after aspiration or instillation of activated charcoal,^14,¹⁵ the true incidence of chronic problems after charcoal aspiration is unknown.

Position Statement

Single-dose activated charcoal should not be administered routinely in the management of poisoned patients. The effectiveness of charcoal decreases with time; the greatest benefit is obtained within the first hour after ingestion. Administration of activated charcoal may be considered if a patient has ingested a potentially toxic amount of poison (that is known to be adsorbed to charcoal) not longer than 1 hour before treatment. There is no evidence that the administration of activated charcoal improves outcome.^10,¹⁶

Cathartics

Position Statement

Administration of a cathartic alone has no role in the management of poisoned patients. Routine use of a cathartic in combination with activated charcoal is not endorsed.¹⁷

Whole-Bowel Irrigation

Whole-bowel irrigation consists of administration through a nasogastric tube of an osmotically balanced, polyethylene glycol–based electrolyte solution to decontaminate the entire gastrointestinal tract by physically expelling intraluminal contents. As much as 1500 to 2000 mL/h can be administered to an awake patient. Negotiations to let the patient attempt to drink the solution only cause delay, because patients are unable to drink at a constant rate. Contraindications include bowel pathology, unprotected or compromised airway, hemodynamic instability, and intractable vomiting. Complications are nausea, vomiting, and abdominal cramps.¹⁸

Position Statement

Whole-bowel irrigation should not be used routinely in the poisoned patient. Whole-bowel irrigation should be considered for potentially toxic ingestions of sustained-release or enteric-coated drugs. There are insufficient data to support or exclude the use of whole-bowel irrigation for toxic ingestions of lithium, iron, lead, zinc, or packets of illicit drugs.¹⁸

Clinical Implications of Gastrointestinal Decontamination

There is no role for syrup of ipecac in the hospital setting. Gastric lavage may be considered for obtunded patients if it can be instituted within one hour after the ingestion. Single-dose activated charcoal should not be routinely administered to patients with mild to moderate degrees of poisoning. Whole-bowel irrigation should be considered for awake patients within the first hours after ingestion of a sustained-release preparation, ionic compounds (e.g., lithium), or packets of illicit drugs.

These guidelines refer to the routine management of poisoned patients. Cellular toxins require special consideration. The physician should always call the Poison Center (1-800-222-1222 in the United States) to discuss a patient with a potentially life-threatening ingestion.

Enhanced Elimination

Multiple-Dose Activated Charcoal

Multiple-dose activated charcoal is the repeated oral administration of activated charcoal to enhance drug elimination. If the drug concentration in the gut is lower than that in the blood, the drug will passively diffuse back into the gut. The concentration gradient, intestinal surface area, permeability, and blood flow determine the degree of passive diffusion. As the drug passes continuously into the gut, it is adsorbed onto the charcoal particles, a process called gastrointestinal dialysis. Multiple-dose activated charcoal also interrupts the enterohepatic and enterogastric circulation of drugs. Drugs with a prolonged elimination half-life, a small volume of distribution (less than 1 L/kg), and little protein binding are the most amenable to this sort of management.¹⁹

The initial dose of charcoal is 50 to 100 g, and this treatment is followed every 1, 2, or 4 hours by a dose equivalent to 12.5 g/h. More frequent, smaller doses may prevent vomiting. Addition of a cathartic (e.g., sorbitol) can be considered for the initial one or two doses. Continuous use of a cathartic can cause diarrhea and fluid and electrolyte imbalances. Multiple-dose activated charcoal can be continued until the patient improves clinically. Contraindications include an unprotected airway, intestinal obstruction, and an anatomically abnormal gastrointestinal tract. Complications include bowel obstruction and vomiting with subsequent aspiration.¹⁹

Position Statement

Multiple-dose activated charcoal should be considered if a patient has ingested a life-threatening amount of carbamazepine, dapsone, phenobarbital, quinine, or theophylline. With all of these drugs, data confirm enhanced elimination, although no controlled studies have demonstrated clinical benefit.¹⁹

Urinary Alkalinization

Urinary alkalinization is the administration of intravenous (IV) sodium bicarbonate to produce urine with a pH ≥ 7.5. The objective of treatment is pH manipulation, not forced diuresis. Hypokalemia is the most common complication. Alkalemia also can occur.²⁰

Position Statement

Urinary alkalinization should be considered as first-line treatment in patients with moderately severe salicylate poisoning who do not meet the criteria for hemodialysis. Urinary alkalinization also should be considered for patients with severe poisoning due to 2,4-dichlorophenoxyacetic acid or mecoprop (MCPP) poisoning. Urinary alkalinization is not recommended as first-line treatment for cases of phenobarbital poisoning, because multiple-dose activated charcoal is superior.²⁰

Selected Antidotes

Stabilization of the patient always should precede administration of antidote(s). The effects of the toxin can outlast the effects of the administered antidote. Patients receiving antidotes should be observed in a critical care setting.

Dextrose

Up to 8% of patients with altered mental status are hypoglycemic.²¹ Hypoglycemia can be a result of drug or toxin exposure, nutritional deprivation, or a medical complication (e.g., sepsis, hyperthermia). Glucose should be checked at the bedside for all patients with altered mental status.

Naloxone

Endogenous and exogenous opiates produce their effects by binding at one or more opiate receptors. Naloxone, nalmefene, and naltrexone are competitive opioid antagonists that bind at the mu (µ), kappa (κ), and delta (δ) receptors and competitively prevent the binding of endogenous and exogenous opiates at these receptors. The duration of action of naloxone is 15 to 90 minutes. Its clinical effects depend on the dose and route of naloxone administration as well as the dose and rate of elimination of the opiate agonist. Naloxone can be administered by IV, intramuscular, intratracheal, or sublingual routes. After IV administration, naloxone rapidly enters the central nervous system (CNS). In patients with opiate poisoning, consciousness is restored and respiration improves within 1 to 2 minutes. Meiosis, inhibition of baroreceptor reflexes, laryngospasm, and decreased gastrointestinal motility are also reversed.²²

Certain nonopiate drugs can cause release of endogenous opiates, contributing to CNS and respiratory depression as well as hypotension. Alternatively, nonopiate drugs and naloxone can compete for an unidentified nonopiate receptor that contributes to CNS depression and hypotension. Naloxone can reverse the toxicity caused by drugs that are not opioids, such as clonidine, angiotensin-converting enzyme inhibitors, and sodium valproate. Naloxone should be administered to all patients with altered mental status or coma of unknown cause. Opiate-dependent patients should receive only small doses in an effort to prevent rapid withdrawal. If a patient is not opiate dependent, a reasonable starting dose is 2 mg, increasing to 10 mg (in increments) if there is no response. Large doses of naloxone may be necessary to reverse the effects of nonopiate drugs or of opiate drugs with high affinity for the δ and κ opiate receptors.

If respiratory depression returns, the initial dose of naloxone may have to be repeated or a constant infusion of naloxone initiated. The starting dose for a constant infusion of naloxone is hourly administration of about one-half to two-thirds of the bolus dose that reversed the opiate effects. If withdrawal is precipitated, it is short lived and not life threatening. Complications of naloxone administration are very rare.²³

Flumazenil

Flumazenil competitively antagonizes the pharmacologic effects of drugs that act on the benzodiazepine receptor (e.g., all drugs in the benzodiazepine class). Receptor occupancy follows the law of mass action, and antagonism is dose dependent. The duration of action of flumazenil is variable and depends on the type of benzodiazepine ingested, relative doses of agonist and antagonist, presence of ongoing benzodiazepine absorption, and relative receptor binding affinities. Flumazenil also antagonizes the sedative effects of drugs other than benzodiazepines, such as zolpidem (Ambien), cannabis, ethanol, promethazine, chlorzoxazone, and carisoprodol. These drugs may have differing affinities for the γ-aminobutyric acid A (GABA_A) receptor, implying that the dose of flumazenil required to reverse the effects depends on the affinity of the specific drug for the receptor.²⁴

Flumazenil is safe and effective for reversing conscious sedation after short procedures such as endoscopy. This safety has been generalized to imply that flumazenil also is safe for patients with a multidrug overdose and that reversal of benzodiazepine-induced sedation prevents morbidity from procedures such as endotracheal intubation or computed tomography. However, many patients have experienced single or multiple seizures after flumazenil administration. Status epilepticus has been precipitated, leading to death. The data are insufficient to determine whether morbidity or mortality is increased as a result of flumazenil-precipitated seizures.^25,²⁶

Flumazenil administration can precipitate seizures in patients with an overdose who have ingested both a benzodiazepine and a pro-convulsant drug or just a pro-convulsant drug. Flumazenil also can precipitate seizures in patients who have a history of seizures, chronic benzodiazepine ingestion, or head injury. Identification of patients at risk for seizures is difficult.²⁷ Before administering flumazenil to a patient with an ingestion, it is reasonable to first obtain an electrocardiogram (to rule out exposure to pro-convulsant tricyclic antidepressants) and a urine drug screen. Re-sedation occurs after 18 to 120 minutes in approximately half of patients awakened by flumazenil. Therefore, either continuous IV infusion or observation for a number of hours is required.²⁸

Administration of flumazenil to patients with an overdose should be limited to the following situations: iatrogenic overdose with known patient history, obtundation in a toddler secondary to ingestion of benzodiazepine, and reversal of a paradoxical response to benzodiazepine.

Physostigmine

Physostigmine inhibits acetylcholinesterase, the enzyme responsible for the metabolism of acetylcholine (ACH). ACH is an endogenous neurotransmitter that mediates action by binding to muscarinic and nicotinic receptors. Accumulation of ACH stimulates cholinergic nerve endings. In the poisoned patient, physostigmine is most frequently administered to treat anticholinergic toxicity. Clinical signs of anticholinergic toxicity are recognized by the mnemonic, “Blind as a bat, Red as a beet, Hot as a hare, Dry as a bone, Mad as a hatter.” Physostigmine administration should be considered if life-threatening clinical signs of anticholinergic peripheral effects (hypertension, tachycardia, and seizures) or central effects (painful psychosis) are present. However, it is extremely difficult to balance cholinergic and anticholinergic forces. Complications of cholinergic crises (caused by excessive doses of physostigmine) include hypertension, arrhythmia, asystole, bronchorrhea, bronchoconstriction, seizures, and status epilepticus. Contraindications to physostigmine administration include reactive airway disease, peripheral vascular disease, intestinal or bladder obstruction, and treatment with a depolarizing neuromuscular blocking agent (e.g., succinylcholine). An acceptable dose of physostigmine is 2 mg IV over 10 minutes. This drug should be administered in the presence of a physician because of the potential for precipitation of life-threatening cholinergic effects.²⁹

Hypotension in the Poisoned Patient

Hypotension in the poisoned patient is most frequently caused by receptor blockade, drug-induced myocardial depression, or drug-induced vasodilatation. Clinicians reflexively initially treat hypotension by infusing IV fluids; however, unless the poisoned patient is hypovolemic, large volumes of fluid can predispose patients to the development of acute respiratory failure.

Catecholamines are the pressors of choice for treatment of hypotension in most intensive care unit (ICU) patients who are older, chronically ill, or acutely ill from an infectious process. The causative factors in sepsis-induced vasodilation and myocardial depression/ischemia are different from the factors that cause drug-induced vasodilation, myocardial depression, or ischemia. Treatment approaches must address the cause of the hypotension and not assume that all hypotensive patients should be treated in a similar manner.

Poisoned patients who are young and healthy respond to hypotension with an outpouring of endogenous catecholamines. Adrenergic receptors are sensitive in young patients. Administration of exogenous catecholamines is unlikely to be of much benefit, because catecholamine receptors are already maximally stimulated by endogenous catecholamines. Agents that must be considered for the treatment of hypotension in the poisoned patient are sodium bicarbonate (for a sodium channel-blocking agent), glucagon, and insulin/glucose.

Glucagon

The cardiovascular effects of glucagon are mediated by myocardial glucagon receptors which are catecholamine independent. Stimulation activates adenylate cyclase, leading to increased intracellular levels of the second messenger, cyclic adenosine monophosphate (cAMP). This cyclic nucleotide increases myocardial calcium uptake. Both the slope of phase zero of the action potential and the conduction velocity through the atrioventricular node are increased. Glucagon increases heart rate and stroke volume, thereby increasing cardiac output. After IV administration, augmented inotropy is seen within 1 to 3 minutes, with a peak effect in 5 to 7 minutes.³⁰

Glucagon should be considered early in the treatment of hypotensive poisoned patients. Treatment regimens vary. An acceptable regimen is 10 mg of glucagon given over 10 minutes (rapid administration causes vomiting), followed by 1 to 3 mg/h. If the patient wretches, the hourly dose of glucagon should be decreased. Elderly patients may be more sensitive to the emetic effects of the drug.

Insulin and Glucose

Insulin improves contractility in anoxic rat hearts and improves cardiac index after cardiopulmonary bypass surgery. During drug-induced shock, insulin shifts myocardial fatty acid oxidation to carbohydrate oxidation, which increases contractility, left ventricular pressure, and rate of change of developed pressure. Enhanced fatty acid oxidation, such as occurs after epinephrine administration, transiently increases contractility at the expense of increased myocardial oxygen consumption.³¹

In hypotensive poisoned patients, a reasonable dose of insulin is 10 units of regular insulin and 50 mL of 50% dextrose solution. These priming doses should be followed by infusion of 6 units of insulin per hour, with concurrent administration of sufficient glucose to maintain euglycemia. Hourly serum glucose checks are mandatory because hypoglycemia occurs frequently.

Cardiac Arrhythmias

ICU treatment regimens assume that a diseased heart is the cause of most cardiac arrhythmias. This assumption is invalid in poisoned patients. Treatment of the arrhythmia must take into consideration the pharmacology of the toxin causing the arrhythmia.

Acute Renal Failure

In poisoned patients, acute renal failure (ARF) is most frequently the result of a decrease in extracellular fluid volume and renal hypoperfusion caused by drug- or chemical-induced vasodilation, drug-induced myocardial depression, or rhabdomyolysis. Attempts to prevent ARF are important because there is no specific therapy once ARF is established. Studies evaluating the efficacy of low-dose dopamine (0.5-3.0 mg/kg/min) in preventing ARF have not demonstrated any benefit, but the patient populations in these studies consisted of critically ill patients with established ARF or at high risk for developing ARF.³² The efficacy of administration of low-dose dopamine after periods of hypotension in poisoned patients who typically are younger and without chronic disease has not been evaluated. When dopamine is administered to normal human subjects, there is a dose-dependent increase in renal blood flow, sodium excretion, and glomerular filtration rate.³³ Low-dose dopamine also limits adenosine triphosphate (ATP) utilization and oxygen requirements in nephron segments at risk for ischemia.³⁴ Although there are no studies regarding the efficacy of low-dose dopamine in cases of drug-induced hypotension, one may consider administration in previously healthy poisoned patients who have adequate vascular volume and remain oliguric or anuric despite maximal diuretic therapy.

Seizures

Blood pH can be as low as 7.17 at 30 minutes and 7.20 at 60 minutes after resolution of a 30- to 60-second seizure.³⁵ Acidosis decreases cardiac output, oxygen extraction, and left ventricular end-diastolic pressure and impairs myocardial contractility. If a patient has ingested a cardiotoxic drug (e.g., a tricyclic antidepressant) that causes significant myocardial depression, the consequences of acidosis can increase the toxicity of the drug. Ictal increases in plasma epinephrine levels can add to the potential risk for cardiac arrhythmias. Additionally, airway reflexes are inhibited postictally, which adds to the potential for aspiration.³⁶

Whether seizures increase morbidity and mortality in poisoned patients is difficult to ascertain. Deaths of poisoned patients who sustain seizures are usually attributed to the toxicity of the drug. Because of the number of variables, it is impossible to know whether the risk for mortality is influenced by the presence of convulsions. Accordingly, the physician should take an aggressive approach toward terminating seizures in poisoned patients. Benzodiazepines are the drugs of choice to quickly terminate seizures, because they are lipophilic and rapidly enter the CNS.