#34023: Analgesic Overdose

Unless it is certain that acetaminophen has not been ingested, an acetaminophen level should be measured in all patients who have taken medications with the intent or a suspected intent to cause self-harm. The toxic amount of acetaminophen for adults and children 6 years of age or older is ≥10 grams or ≥200 mg/kg, whichever is less. [11] The amount of acetaminophen that is potentially toxic for children younger than 6 years of age is ≥200 mg/kg [11].

The pediatric criteria appear to be universally accepted and used, but there is less clarity and agreement concerning what constitutes a toxic amount for adults [12]. Early research indicated that the toxic amount of acetaminophen for adults was between 15 and 16 grams [13,14]. Poison control centers in the United States usually, but not always, use ≥200 mg/kg or ≥10 grams, whichever is less, as the standard toxic amount for adults [11]. In other areas of the world, a dose of at least 12 grams is considered a toxic amount for adults [15,16].

Every effort should be made to determine the details of the ingestion, including the time, amount, formulation, and pattern of ingestion. It is usually unwise to depend on the patient's account of the overdose. Patients are often emotionally upset and may not remember how much was taken or when or may deliberately provide inaccurate information. It is also possible that the patient may have taken other medications and does not consider acetaminophen dangerous or worth mentioning. Unrecognized and unreported acetaminophen ingestions, some potentially dangerous, are relatively common (up to 18% of all acetaminophen overdose cases), and in the context of a deliberate overdose, a patient's reporting or not reporting of an ingestion of acetaminophen is not considered reliable [16,17,18,19,20].

The initial signs and symptoms of acetaminophen toxicity are gastrointestinal, specifically nausea and vomiting. These are usually mild in severity and will resolve within 12 hours of the ingestion. Many patients are asymptomatic. The exception to this is a massive acetaminophen overdose. Patients who take 75–100 grams of acetaminophen may quickly develop coma, metabolic acidosis, and abnormal vital signs. However, these cases are very uncommon, and unless a massive overdose was taken or a co-ingestant was involved, the patient will have normal temperature, pulse, and blood pressure and will be awake, alert, and oriented. If a patient has taken an overdose of acetaminophen and is clinically unstable, it is prudent to first determine if other medications were taken.

A serum acetaminophen measurement should be obtained four hours or later from the time of ingestion. The level is plotted on the Rumack-Matthew nomogram (Figure 1), and depending on where on the nomogram the level falls, it will be considered toxic or non-toxic. Measuring the serum acetaminophen level and using the nomogram is the most reliable way of determining if a patient has ingested a toxic amount of the drug.

RUMACK-MATTHEW NOMOGRAM

Figure 1

Source: [19]

The Rumack-Matthew treatment nomogram was developed over a period of years by several investigators, with the goal of establishing an accurate and reliable tool that could predict which patients were likely to develop hepatotoxicity after an acetaminophen overdose [21,22,23]. To that end, serum acetaminophen levels were measured in patients who had reportedly ingested a toxic amount of the drug. The levels were obtained at four hours or later post-ingestion, and the patients' clinical course and serum transaminases were followed until a pattern became clear. Patients with a serum acetaminophen level of 300 mg/mL or greater four hours after ingestion are at risk for probable hepatic toxicity, with the serum threshold lowering over time. Example: Patient A and Patient B each report ingesting 12 grams of acetaminophen. The time of ingestion is certain, and the serum acetaminophen levels are done four hours from that point. Patient A's level is 250 mcg/mL, Patient B's level is 30 mcg/mL. Clinical experience using the Rumack-Matthew nomogram has shown that the first patient is very likely to develop hepatotoxicity, and the second patient clearly did not ingest 12 grams four hours before the level was measured and will not develop hepatotoxicity.

The Rumack-Matthew nomogram has been proven to be highly reliable, but it has limitations and it must be used correctly. The nomogram was developed by examining patients who had an acute overdose. If the patient has ingested acetaminophen over a period of many hours or days and the overdose is chronic in nature, the nomogram cannot be used. (Chronic ingestions will be discussed later in this course.) The nomogram extends to 24 hours post-ingestion. If the patient ingested acetaminophen more than 24 hours from the time of presentation, the nomogram cannot be used.

Hepatotoxicity is defined by the nomogram as an AST level greater than 1,000 IU/L, and the nomogram is designed to predict the likelihood that a patient with a level at a certain point on the nomogram will develop an AST level greater than 1,000 IU/L. The nomogram cannot be used to predict the risk of death, the risk of developing liver failure, or response to treatment. It is highly sensitive but not highly specific, and approximately 40% of patients who have an acetaminophen level greater than the toxic line on the nomogram will not develop hepatotoxicity in the absence of antidotal therapy [23]. However, given the uncertainties surrounding many overdose cases, the potential for serious liver damage, and the success of the nomogram, overtreatment of a certain number of patients is preferable to undertreatment.

The nomogram cannot be used to interpret a level that is measured before four hours post-ingestion [24]. This time constraint is required for two reasons. First, the peak serum level can be delayed when acetaminophen is taken in large amounts. In most cases, the peak serum level will occur within two hours of the ingestion, but it may be delayed for up to four hours. Second, the nomogram begins at four hours post-ingestion, and levels taken before this time cannot be used to determine risk [24,25,26].

The acetaminophen level should be interpreted using the nomogram; the level alone is not useful. Very high levels almost certainly indicate a patient is at high risk for untoward effects, but an acetaminophen level can only be determined to be toxic/non-toxic if the time of ingestion is also known.

If a patient has ingested an extended-release preparation, a level should be done at four hours post-ingestion and another level should be taken at eight hours post-ingestion. If either level is toxic, the patient should be treated. If both levels are below the toxicity line, no treatment is needed. If there is a co-ingestant that may delay gut peristalsis, it may be wise to obtain two acetaminophen levels. In these cases, consultation with a toxicologist or the local poison control center is recommended.

Example : A physician is caring for a patient who has reportedly ingested a toxic amount of acetaminophen, but the time of the ingestion is not known. The acetaminophen level is 18 mcg/mL. This is within the normal therapeutic range, so the physician discharges the patient. However, the "normal range" of acetaminophen (10–20 mcg/mL) is a based on a therapeutic level measured after a therapeutic dose. If the patient has taken an overdose of acetaminophen, a level of 18 mcg/mL would be considered at-risk if this level was measured 16 hours or later after the ingestion.

Nomogram "failures" are situations in which the acetaminophen level is below the toxic line, but the patient develops liver damage. These have been reported, but they are very rare and almost certainly involve mistakes in determining the time of ingestion. The original toxic/non-toxic line on the nomogram was 300 mcg/mL. It has since been decreased to 200 mcg/mL to provide a safety factor [13,20,27]. As such, the nomogram is quite conservative in nature and failures when used correctly are not possible.

There are situations in which the peak serum acetaminophen level can occur later than four hours after ingestion. Antihistamines and opioids slow gut peristalsis, and there have been case reports documenting a delayed peak acetaminophen level caused by a co-ingestion of diphenhydramine or an opioid [28,29,30,31,32,33]. Delayed peak serum levels have also been reported after massive ingestions and after taking extended-release acetaminophen products [34,35,36,37,38].

The serum transaminases, AST and ALT, are commonly measured on liver function tests (LFTs), and these tests are the most sensitive marker of liver injury caused by acetaminophen poisoning. The AST and ALT levels typically begin to rise 24 hours after ingestion of a toxic amount of acetaminophen, but this elevation can occur as early as eight hours and as late as 36 hours post-ingestion [12,39,40]. AST and ALT levels greater than 10,000 IU/L following acetaminophen poisoning are not uncommon.

Therapeutic use of acetaminophen may cause mild and transitory elevations of liver transaminases. However, these doses do not cause liver damage, and when the acetaminophen therapy is stopped, the levels return to normal [41,42].

A serum salicylate level should be measured in persons with confirmed or suspected acetaminophen overdose. Some patients consider all over-the-counter analgesics to be the same and may use the terms Tylenol, aspirin, and ibuprofen interchangeably. In addition, some prescription and over-the-counter products contain both acetaminophen and aspirin.

Every patient who has intentionally taken an overdose of an over-the-counter cough and cold or allergy relief product should be assessed for acetaminophen poisoning unless the product is identified and does not contain acetaminophen.

BUN and creatinine should also be measured, as renal damage can be caused by acetaminophen poisoning. A baseline INR should be measured. Liver damage is reflected by the serum transaminases, but liver damage that causes hepatic dysfunction is reflected by the INR.

The renal parenchyma can form NAPQI, and acute renal failure occurs in approximately 1% to 10% of all cases of acetaminophen poisoning [45,46,47,48]. In patients who develop severe liver damage, evidence of acute kidney injury has been seen in 53% to 80% of cases [12,49]. Renal failure following an acetaminophen overdose may occur without evidence of liver damage or fulminant hepatic failure, but this is very unusual [50,51,52,53]. There is no reliable way to predict which patients with acetaminophen overdose will develop renal failure, although children and adolescents appear to be at a higher risk [46].

The onset of renal failure usually begins after evidence of liver damage and liver failure; peak serum creatinine levels may not be seen until four to five days after the ingestion [46,54]. Most patients have a complete recovery of renal function, but approximately 1% will require long-term hemodialysis [46].

There have been rare, sporadic reports of other organ systems being damaged by acetaminophen overdose [55,56,57,58,59,60,61]. Cardiac damage and pancreatitis have been reported, but not as isolated problems directly related to acetaminophen. Some studies suggest that acetaminophen overdose may increase the risk of congestive heart failure, coronary artery disease, and pancreatitis, but further research is needed [62,63,64]. Patients with cardiac, pancreatic, or other organ system damage after an acetaminophen overdose are likely either experiencing multi-system organ failure from a massive overdose or an exacerbation of pre-existing medical problems.

Patients who ingest what has been called massive amounts of acetaminophen can rapidly develop profound CNS depression, hypotension, and metabolic acidosis before the onset of hepatic failure, and they may be at greater risk for hepatic injury [65,66,67,68,69]. This clinical situation typically occurs following ingestion of more than 30–100 grams of acetaminophen or if the serum acetaminophen level is greater than 800 mcg/mL [65,70,71,72].

NAPQI is produced by cytochrome P450 enzymes. The activity of these enzymes may be increased, or induced, by certain drugs, ethanol, and tobacco smoke; however, there is no definitive evidence that people who drink, smoke, or take these enzyme-inducing medications are more susceptible to liver damage from acetaminophen [77]. The concern for increased risk in these situations arose from data from animal experiments and case reports, but it has not been not supported by extensive clinical experience. Susceptibility to liver toxicity in acetaminophen overdose is enhanced by older age, restricted diet, and underlying hepatic or renal disease [77].

The relationship of alcohol and acetaminophen poisoning is complex. Ethanol is a cytochrome P450 enzyme inducer, but this effect is transitory, and only recently abstinent people who take an overdose of acetaminophen would be at increased risk. Acute ingestion of ethanol together with acetaminophen appears to provide protection against liver damage after an acetaminophen overdose by inhibiting cytochrome P450 enzymes and decreasing the amount of NAPQI that is formed [12,78]. There is no evidence that people who chronically abuse alcohol have a higher risk for liver damage from acetaminophen poisoning than people who are abstinent [12].

Malnutrition and starvation decrease hepatic stores of glutathione and decrease the liver's ability to make glutathione. However, the evidence that reduced glutathione stores caused by diet, nutritional status, or chronic alcohol abuse increases the risk of liver damage is equivocal [78,79].

Animal experiments and epidemiologic studies indicate that hepatitis C increases the risk for liver damage after acetaminophen overdose, but there is very little research on the subject [80,81,82]. A review of epidemiologic data from 2008 found that patients with hepatitis C infection who were admitted to the hospital for acetaminophen overdose were more likely to progress to severe liver failure and had a higher mortality rate than those without hepatitis [74].

Children appear to be less susceptible to liver damage from acute acetaminophen overdose, even when weight-adjusted doses and serum concentrations are considered [12,83]. Almost all deaths from acetaminophen in children younger than 6 years of age have been caused by repeated, chronic therapeutic errors. It was previously hypothesized that children had an increased ability to metabolize acetaminophen by conjugation and sulfation or that they had increased glutathione stores compared with adults. These theories have been shown to be untrue. It is now known that children are inherently more resistant to acetaminophen toxicity because of the size of their livers. The liver is proportionately larger in children than it is in adults, so children have greater relative glutathione stores and metabolize acetaminophen faster [77,79,84].

NAC is the antidote for acetaminophen poisoning. It was first developed and is still used as a mucolytic. The original form of NAC was sterile but not pyrogen-free and was only available in oral formulations. Today, oral and intravenous preparations are used in the treatment of acetaminophen overdose. In 2004, a sterile, pyrogen-free form of NAC (Acetadote) was developed and made available in the United States.

A Cochrane review found that N-acetylcysteine should be given to people with paracetamol poisoning at risk of liver damage, risk is determined by the dose ingested, time of ingestion, and investigations.

(https://www.cochrane.org/CD003328/LIVER_interventions-paracetamol-acetaminophen-overdose Last Accessed: June 24, 2024)

Level of Evidence: Meta-analysis

NAC prevents liver damage from acetaminophen overdose by [3,6,89]:

Before the introduction of NAC, the incidence of hepatotoxicity after acetaminophen overdose was approximately 58%; NAC therapy reduced this to 1.6% [89]. In addition, the fatality rate from acetaminophen poisoning dropped from 5% to 0.75% after NAC treatment became the standard of care [89]. When NAC is used soon after an overdose and given correctly, fatalities from acetaminophen overdose are rare [6].

NAC is a highly effective antidote if used correctly. It is most effective if it is given within 8 to 10 hours after the ingestion of acetaminophen, and its effectiveness begins to decline after that point [6,83]. Glutathione stores are depleted to 20% to 30% of pre-exposure levels at 8 to 10 hours post-ingestion, and this appears to be the critical point at which NAPQI binds to hepatocytes.

Intravenous NAC is usually preferred, but oral NAC is still available and used. If a patient presents within the 8- to 10-hour window, there does not appear to be any difference in effectiveness between oral or intravenous NAC [3,90,91,92]. However, the dosing regimens and the clinical considerations for the two vary.

Case Study

A woman, 44 years of age, presents to the emergency department stating that she took an overdose of acetaminophen "some time yesterday" while also consuming large quantities of alcohol. The patient has a past medical history of alcohol abuse and hypertension. Her vital signs are normal, and except for nausea and abdominal pain, which she describes as mild, the exam is normal. The patient cannot remember how much acetaminophen she took or when she took it, but a family member believes the ingestion occurred between 16 and 24 hours ago. No medical records are available. The laboratory results are:

Comments and rationale : Treatment with NAC is warranted in this case. The LFTs are above the upper limit of normal, but given the probable time frame of the ingestion, it is early for this finding. The laboratory test results and the patient's physical complaints are non-specific, and both could be caused by her chronic alcohol abuse or the recent binge, though there is no way to determine if that is so. The only unequivocal data is the acetaminophen level and the patient's stated intent. The serum acetaminophen level confirms ingestion, but it cannot be interpreted because the time of ingestion is not known. NAC treatment should be started.

Oral Administration

Oral NAC is administered with a loading dose of 140 mg/kg. This is followed four hours later by a 70 mg/kg dose, which is repeated every four hours for the next 68 hours (for a total of 19 doses). The patient's LFTs, BUN, creatinine, and INR should be checked once every 24 hours while receiving oral NAC. Daily acetaminophen levels need not be measured.

Nausea and vomiting are common side effects of oral NAC. If a patient vomits within an hour of receiving a dose, the dose should be repeated. If the patient vomits more than one hour after a dose, absorption is considered complete and repeat dosing is unnecessary.

Oral NAC should be diluted with juice or soda and served cold in a cup with a lid (as the odor is noxious). Patients should be advised to sip it slowly to prevent vomiting. If necessary, NAC can be slowly infused through a nasogastric tube. Antiemetic pre-treatment with ondansetron or metoclopramide is more effective than with prochlorperazine. Contradictions to NAC use include hypersensitivity to acetylcysteine or any component of the formula, an inability or contraindication to using the gut, and persistent vomiting.

Intravenous Administration

When intravenous NAC is used, the dosing regimen is selected based on the patient's weight. If a patient weighs more than 40 kg, a loading dose of 150 mg/kg diluted in 200 mL of diluent (D5W) is infused over 60 minutes [3]. A shorter time for the loading dose infusion was used when IV NAC was first made available, but a 60-minute infusion has been found to decrease the incidence of adverse effects. The second dose of 50 mg/kg in 500 mL of diluent infused over four hours should be given immediately after the first dose is complete. When the second dose is finished, a third dose of 100 mg/kg in 1,000 mL of diluent should be infused over 16 hours; this last dose should be started as soon as the second dose is completed. In patients who weigh more than 100 kg, the maximum doses are 15 g, 5 g, and 10 g; do not use higher doses if the patient weighs more than 100 kg [3,6].

There has been research suggesting that in case of massive acetaminophen overdose (e.g., >40–50 grams or four-hour post-ingestion acetaminophen level >300 mcg/mL) the standard NAC protocol may not be effective and additional amounts of NAC may be needed [3,6,93]. At this time, the 21-hour protocol is still considered to be the standard of care, but if a very large amount of acetaminophen has been ingested and/or the acetaminophen level is >300 mcg/mL, it would be prudent to consult with a medical toxicologist or a poison control center.

Two hours prior to the end of the 16-hour infusion, serum acetaminophen level, AST, ALT, and INR should be obtained. If there is a measurable acetaminophen level or abnormally elevated LFTs or INR, consider administering additional NAC and consult with the local poison control center or a toxicologist to determine whether the therapy should be continued. The decision to stop or to continue NAC therapy with several more doses (the latter being a very common occurrence) is often not clear-cut and each case should be handled individually [4]. Serial measurements of serum acetaminophen level are unnecessary if the patient is receiving intravenous NAC, as declining levels only document metabolism of the drug, not the diminishment of risk. The acetaminophen level and LFTs only need to be remeasured two hours before the third infusion is due to be completed.

Adverse reactions to IV NAC are common, but they are usually minor (e.g., flushed skin, pruritus) and easily managed. Serious reactions (e.g., angioedema, bronchospasm, hypotension) are indicative of an anaphylactoid reaction and typically (but not always) occur when the first dose is being given. Fortunately, serious reactions are uncommon; the incidence of anaphylactoid reactions to IV NAC has been reported to be 8.2%, most of these reactions were dermal (75.4%) and occurred during the first hour of treatment (95.4%) [94]. For patients who experience flushed skin and/or pruritus during infusion, diphenhydramine may be given while continuing the infusion (and perhaps decreasing the infusion rate temporarily) and observing the patient closely. If a patient is having an anaphylactoid reaction, the NAC infusion should be halted and diphenhydramine, beta agonists, corticosteroids, and epinephrine should be given as needed. If the patient is asymptomatic after one hour, the IV NAC should be started at a slower rate [90].

LFTs, INR, and prothrombin time (PT) are measured to determine the presence of liver damage following acetaminophen overdose. It is important to remember that NAC and acetaminophen overdose can cause mild elevations in INR and PT in the absence of hepatotoxicity, but the INR should be <1.5 and the effects should slowly resolve [6,95,96]. Patients who develop rhabdomyolysis from a mixed overdose or from the circumstances of the overdose (e.g., opioid-acetaminophen overdose causing prolonged immobility) may have elevated LFTs as well.

NAC in Special Situations

It is not unusual for patients to present more than 8 to 10 hours after taking an overdose of acetaminophen or for the time of ingestion to be unknown. If a patient has taken an overdose of acetaminophen more than 8 to 10 hours before presenting for treatment and needs therapy with NAC, the standard oral or IV treatment regimens should be used. Giving NAC to these patients will significantly decrease the incidence of hepatotoxicity and mortality [89,97]. If a patient claims to have taken an overdose of acetaminophen but presents to a healthcare facility many hours after the ingestion, the standard diagnostic workup should be done. If it can be reasonably determined that the ingestion happened 12 hours or more before presentation and the serum acetaminophen level is undetectable, the LFTS, coagulation studies, and renal function studies are normal, and the patient has no clinical evidence of liver damage, there would be no need for treatment with NAC [6].

Although the standard oral and IV NAC protocols are sufficient for most patients, some patients will reach the end point of therapy with persistently elevated LFTs and/or a measurable level of serum acetaminophen. Elevated LFTs at the end of NAC therapy indicate liver damage, and it can be difficult to predict if this damage will continue and worsen. A measurable acetaminophen level indicates a potential for more NAPQI to be formed. In either case, extending the NAC protocols beyond the 72-hour or 21-hour limit may be advisable. Making this decision can be difficult, and a toxicologist should be consulted in these cases [4]. It is rare that patients receiving oral NAC would need more than 72 hours of treatment, but it is not uncommon for patients receiving IV NAC to require treatment beyond the standard 21-hour protocol; extended therapy with IV NAC has become an accepted practice. If LFTs remain elevated at the end of the 21 hours of infusion and/or there is a measurable serum acetaminophen level, strong consideration should be given to continuing NAC administered at 100 mg/kg in 1,000 mL diluent over 16 hours [4]. Two hours before this fourth infusion will be finished, re-check the LFTs and the serum acetaminophen level to determine if more NAC is necessary. At times, a fifth or sixth infusion may be necessary.

Acetaminophen can cross the placental barrier and the fetal liver can metabolize acetaminophen, so unborn children can be harmed by excess amounts of acetaminophen. The standard oral or IV NAC protocols may be used during pregnancy [6]. If a pregnant woman has taken an overdose of acetaminophen and is treated with NAC, the fetus should not be harmed and birth defects and/or an abnormal delivery are unlikely [6].

The usual dose of aspirin when used as an oral analgesic or antipyretic is 325–650 mg every four to six hours, with a maximum daily dose of 4 g [4]. When used to treat acute coronary syndromes, the dose is 162–325 mg and the tablet should be chewed. For secondary prevention in most patients with cardiovascular conditions, the daily maintenance dose is 81 mg. Oral preparations of aspirin are available as tablets of 81 mg, 325 mg, and 500 mg, and as enteric-coated tablets in doses of 81 mg, 325 mg, 500 mg, and 650 mg. Enteric-coated aspirin tablets are designed to resist the acidic milieu of the stomach, be absorbed in the small bowel, and avoid the gastrointestinal irritation common with aspirin use. When the tablet reaches the small intestine and a local pH of 6.0, the enteric coating will dissolve and the aspirin can be absorbed. Aspirin is also available as a rectal suppository in doses of 300 mg and 600 mg [4]. In addition, it is included in combination formulations with acetaminophen and other over-the-counter or prescription drugs and in topical preparations that contain methyl salicylate.

There are several other forms of salicylic acid, including homosalate and octyl salicylate, compounds used in sunscreens; trolamine salicylate, a component of topically applied creams used for pain relief; methyl salicylate, used in topical analgesics; and choline magnesium subsalicylate, which is found in antacid preparations (Table 1) [102]. One of the more common of these compounds is bismuth salicylate, which is used in over-the-counter antacid preparations such as Pepto Bismol. A dose of 0.5 mg bismuth salicylate is approximately equivalent to 1 mg of aspirin [102]. Toxicity from dermal preparations of aspirin or the less common salicylates (aside from bismuth salicylate and methyl salicylate) is very uncommon.

Absorption of aspirin through the stomach and small bowel is rapid. Dermal absorption of salicylate is very limited unless the surface of the skin is compromised. An estimated 50% to 75% of an ingested dose reaches the systemic circulation, with peak serum level reached in approximately one to two hours, and the action of the drug is typically four to six hours. A serum level of 10–30 mg/dL is considered therapeutic. The majority of each dose (80% to 90%) is protein-bound.

Aspirin is primarily metabolized in the liver. In therapeutic doses, it is metabolized by first-order kinetics: the higher the dose, the more active the metabolizing enzymes. The half-life is three hours after a standard dose, but the half-life increases as the dose increases. Aspirin is excreted in the urine, with approximately 10% excreted unchanged as salicylic acid.

Gastrointestinal Effects

Aspirin can be very irritating to the gut, and gastrointestinal bleeding, anorexia, nausea, and vomiting are common effects of aspirin toxicity. Aspirin also directly stimulates the chemoreceptor in the medulla, another cause of nausea and vomiting. These gastrointestinal effects are in part the source of the fluid and electrolyte losses that are common after aspirin poisoning [103].

Otic Effects

Aspirin adversely affects the hair cells of the cochlea. As a result, tinnitus is a well-known and commonly reported direct toxic effect of aspirin use and overdose. Hearing loss can occur, but fortunately this is rarely a permanent effect [103,104].

Pulmonary Effects

Salicylates stimulate the respiratory center in the medulla and cause hyperventilation and tachypnea, which can result in a respiratory alkalosis [103,105]. Salicylate poisoning can also cause noncardiogenic pulmonary edema, perhaps by increasing pulmonary capillary permeability [105,106]. Noncardiogenic pulmonary edema can happen in both acute and chronic aspirin poisoning [103].

Neurologic Effects

Aspirin is directly toxic to the brain and the CNS [95,98]. It also has more complex effects on the neurologic system, which will be discussed later in this course.

Cellular and Metabolic Effects

An overdose of aspirin disrupts oxidative phosphorylation, and this is perhaps its most important toxic effect [103,105,107]. Oxidative phosphorylation is the aerobic mechanism by which mitochondria in the cells make energy in the form of adenosine triphosphate (ATP). In high doses, aspirin interferes with or "uncouples" oxidative phosphorylation and energy must be produced by anaerobic metabolism, and this greater dependence on anaerobic metabolism has several important consequences. Increased amounts of lactate are produced, and the metabolic rate is dramatically increased. Because anaerobic metabolism is relatively inefficient at producing energy, fatty acids are used for fuel, resulting in the creation of ketone bodies. The results of these metabolic derangements are far-reaching and profound. The acid-base disturbances (metabolic acidosis and respiratory alkalosis), fever, changes in glucose and fatty acid metabolism, fluid and electrolyte derangements, and other clinical effects that characterize aspirin poisoning are directly or indirectly caused by the disruption of oxidative phosphorylation. Understanding how aspirin disrupts normal metabolism is vital for understanding aspirin poisoning.

When a large amount of aspirin is taken, the absorption of the drug can be significantly delayed for several reasons. Aspirin is known to cause pylorospasm, which can delay the absorption of the drug [103,110]. Large amounts of aspirin can also form a bezoar, a concretion of foreign material in the gut [103,112]. This phenomenon is particularly common after an overdose of enteric-coated aspirin or when a patient has a gastric outlet obstruction [112].

When a normal dose of aspirin is taken, the peak serum level occurs within one to two hours. In an overdose, the peak serum level is typically seen after five or more hours post-ingestion, and there are case reports describing peak serum levels of aspirin up to 67 hours after ingestion [103,108,111,113,114,115]. The half-life of aspirin after an overdose is increased to as long 30 hours [103].

The volume of distribution of a drug describes the distribution of a drug between plasma and body tissues. When an overdose of aspirin is taken, the volume of distribution is increased, with greater drug levels located in the tissues [104]. This increases the risk of direct and cellular/metabolic poisoning and makes elimination of aspirin more difficult.

All drugs have some affinity for being bound to proteins in the plasma (e.g., albumin, lipoprotein), and it is the amount of drug that is not bound to plasma proteins that is pharmacologically active. When aspirin is taken in therapeutic doses, 80% to 90% of the drug is protein-bound, but in overdose, the concentration of protein-bound aspirin is decreased to less than 75% [104].

Therapeutic doses of aspirin are metabolized in the liver by first-order kinetics—the higher the concentration of the drug, the greater the activity of the metabolizing enzymes. When an overdose of aspirin is taken, several of the hepatic enzyme systems that metabolize the drug become saturated and aspirin is metabolized by zero-order kinetics. This means that metabolism of aspirin is independent of the amount of drug that is ingested, and elimination of the drug by the renal route becomes more important [104].

Drugs that are placed in solution (e.g., in the liquid environment of the gut) dissociate and give up protons, thus becoming ionized. Ionization of drugs in solution depends on the pH of the solution and on the acid-dissociation constant, or pKa. When the pKa is relatively low and pH is high, a drug can easily become ionized; this is the case with aspirin. Salicylic acid is a weak acid with a pKa of 3.0, so if the pH is less than 3.0, more aspirin will be non-ionized. As pH rises above 3.0, more aspirin will be ionized.

Aspirin poisoning can cause a metabolic acidosis, and a reduced serum pH results in a greater proportion of aspirin in the non-ionized form. Non-ionized aspirin can cross the blood-brain barrier, so acidosis increases CNS tissue saturation of aspirin.

Tachypnea is a common effect of aspirin overdose [103,105]. In addition, patients may have an elevated temperature because of the increased metabolic rate and dehydration, but a high fever is not common. Blood pressure should be normal, and the pulse is usually normal or mildly elevated.

Hyperventilation and tachypnea cause many patients to initially present with respiratory alkalosis. As the clinical course progresses and more aspirin is absorbed, the compensatory ability of the kidneys and the lungs become overwhelmed. In addition, the disruption of oxidative phosphorylation and changes in glucose and fatty acid metabolism become more pronounced and metabolic acidosis can occur [103,105]. This a very serious concern, because it affects aspirin pharmacokinetics and it also adversely affects cardiovascular functioning and neurological status [107,116]. The low serum pH of metabolic acidosis increases the amount of aspirin that is non-ionized, allowing aspirin to cross the blood-brain barrier and enter the CNS tissues and to be more easily reabsorbed by the kidney tubules. A mixed acid-base disturbance—metabolic acidosis with respiratory compensation—is also commonly seen.

Nausea and vomiting are very common [103,105]. The resulting fluid losses increase the serum concentration of aspirin and make its renal excretion more difficult.

Dehydration is a common result of aspirin poisoning due to the gastrointestinal, pulmonary, and metabolic effects. Patients with aspirin poisoning often have decreased oral intake due to anorexia and loss of fluids from vomiting, and tachypnea causes fluid loss from the lungs. The increased metabolic rate caused by disruption of oxidative phosphorylation increases the production of body heat and causes a low-grade fever, further dehydrating the patient.

Hypokalemia or hyperkalemia may also be seen after an aspirin overdose. Respiratory alkalosis increases renal excretion of bicarbonate and potassium, and metabolic acidosis shifts potassium from the intracellular space to the extracellular space.

The change from aerobic to anaerobic metabolism causes glycogenolysis and gluconeogenesis. Hyperglycemia may be seen early in cases of aspirin poisoning, but in the later stages, hypoglycemia is possible as glucose stores are depleted.

As noted, tinnitus is common as a result of aspirin's effects on the cochlea. Hearing loss can occur but is almost always temporary. CNS depression is an ominous sign, as it indicates the presence of metabolic acidosis, movement of salicylate into the CNS, and/or possible cerebral edema [103]. Seizures may occur, possibly from a direct toxic effect of salicylate on the brain, hypoxia, or a low glucose concentration in the CNS [103]. Seizures can obviously worsen metabolic acidosis and decrease respiratory effectiveness, and seizures are a grim prognostic sign.

As noted, hyperventilation and tachypnea are common signs of aspirin toxicity. Noncardiogenic pulmonary edema can develop, typically in older patients who have been chronically ingesting large amounts of aspirin, but it can also occur after acute ingestions [103].

Aspirin crosses the placenta, and acute or chronic aspirin ingestion can cause birth complications and aspirin poisoning in newborns [94].

Specific therapeutic interventions may be used for aspirin poisoning, but there is no antidote. If there are serious derangements in the patient's ABCs, symptomatic and supportive care should be initiated immediately. Most patients with aspirin poisoning are dehydrated, so fluid resuscitation should also be started.

The initial physical assessment should focus on the patient's neurologic and pulmonary status. CNS depression, tachypnea, and low oxygen saturation are specific indications that the patient has a serious poisoning. Intubation and mechanical ventilation may be needed to stabilize the patient, but this is a potentially dangerous procedure when attempted in patients with aspirin overdose. If airway control is necessary, a high tidal volume and rapid respiratory rate are essential to allow the normal compensatory hyperventilation [103,105,116]. However, this is difficult to accomplish, and a worsening acidosis is a definite possibility. It is not part of the physical exam, but metabolic acidosis indicates the potential for serious toxicity.

It is also important to determine how much aspirin was consumed and when the ingestion occurred. A toxic dose of aspirin is ≥150 mg/kg, and a fatal dose has been estimated to be 10–30 grams in adults [103,117]. The patient's medical history and any medications he or she has been prescribed should be determined. The patient or friend/family member should be questioned regarding any co-ingestions; many people who take medications with intent to cause self-harm will take several different drugs.

Gastric decontamination techniques may be used to remove drugs before they are absorbed. The decontamination technique of choice for aspirin poisoning is activated charcoal.

Activated charcoal binds to aspirin well and can prevent systemic absorption of the drug. A dose of activated charcoal should be given if all the following apply:

The patient's bowel sounds should be assessed, and any medical conditions that are contraindications for activated charcoal should be noted.

Research has shown that activated charcoal is most effective if it is given within an hour of ingestion of a drug [118]. However, the absorption of aspirin may be delayed following overdose due to the toxicokinetics of the drug and possibly the formation of bezoars. So, strong consideration should be given to extending the one-hour time limit for activated charcoal in patients who have taken an overdose of aspirin [103,119]. The use of multiple doses of activated charcoal may be helpful, as well; the patient can be given 25 grams every two hours for three doses, or 50 grams every four hours for two doses, after the initial dose of activated charcoal has been administered [103].

Gastric lavage should not be used in cases of aspirin poisoning. This approach is invasive, difficult, and time-consuming to perform correctly, and it is very doubtful that it is effective for treating any acute overdose [120]. Whole bowel irrigation can be used if it is suspected that the patient has a large a number of tablets in her/his gut [105].

Patients with known or suspected aspirin overdose should have serum aspirin level, arterial blood gas, BUN, creatinine, electrolytes, serum glucose, and serum acetaminophen level measured. Assessment of the salicylate level, electrolytes, and arterial blood gas should be repeated; the timing and frequency should be determined by assessment of the patient's clinical status and the results of previous tests.

An acetaminophen level should be measured in every patient who has taken an overdose. As discussed, patients may confuse the names of over-the-counter analgesics, and unrecognized and unreported acetaminophen ingestions are relatively common [121,122].

A salicylate level greater than 30–40 mg/dL is often cited as an indicator for specific treatment [103]. A serum level greater than 100 mg/dL following an acute ingestion or greater than 60 mg/dL following chronic ingestion is considered potentially very serious and is typically considered an indication for treatment with hemodialysis [103,105]. The units of measurement may vary among laboratories. Though most report serum salicylate as mg/dL, some use mg/L, a 10-fold difference, making it important to always confirm the units of measurement.

Salicylate levels should be interpreted carefully, taking into consideration the possibility of significantly delayed peak levels. Serial levels that document a progressive decline may indicate that the aspirin is being excreted or that the patient has developed metabolic acidosis and the aspirin is moving out of the serum and into the CNS. In many cases, a higher serum salicylate level is correlated with a greater risk, though the latter is also accompanied by neurological and pulmonary changes. However, salicylate levels do not consistently correlate with toxicity, and fatalities have been reported in patients with levels of 50–70 mg/dL [123].

Serial salicylate levels should be measured every two hours until at least two successive levels are noted to be within or below the normal range and are decreasing. However, serial measurements of aspirin alone should not be used for determining whether the patient is or is not at risk. The patient's acid-base status should be evaluated, and a physical exam performed every two hours to determine the level of risk and the patient's progress. Salicylate levels should be interpreted in the context of the patient's acid-base and neurologic status. Periodic measurements of serum glucose and potassium should also be done, as hypokalemia and changes in serum glucose are common in aspirin overdose.

An elevated anion gap is common in cases of aspirin overdose, but a normal anion gap in this clinical situation can occur [103]. Aspirin is excreted by the kidneys, and enhanced elimination of aspirin requires normal renal function, so the patients BUN and creatinine should be measured.

Older references may recommend using the Done nomogram, a tool like the Rumack-Matthew nomogram, to predict toxicity. However, the Done nomogram is now considered unreliable and of limited value and should not be used [103,124].

An abdominal x-ray may detect an aspirin bezoar, but the results are not always conclusive or accurate for this purpose [125,126]. If there is a suspicion that a patient has developed a bezoar, a radiologist or the local poison control center should be consulted.

Urinary alkalinization is the primary therapeutic intervention for treating mild-to-moderate aspirin overdoses [103]. Increasing the serum pH and creating an alkaline environment will ionize aspirin, preventing it from crossing the blood-brain barrier and being re-absorbed by the renal tubules. This effect is called "ion trapping," and it lowers serum aspirin levels, changes concentration gradients, moves aspirin out of the tissues, and increases the renal excretion of the drug. In addition, the urinary excretion of salicylate is dependent on urine pH; increasing the urine pH from 5.0 to 8.0 will dramatically increase renal clearance.

Ion trapping and increasing urine pH have been the traditional explanations for the efficacy of urinary alkalinization in lowering serum salicylate levels, but it is not entirely clear how urinary alkalinization works. There are no randomized trials that have investigated its use—the evidence for its clinical effectiveness comes from case reports and animal studies—and there is no agreed upon definition of mild-to-moderate aspirin poisoning or universally accepted standards on how to achieve urinary alkalinization.

Despite these uncertainties, urinary alkalinization remains a standard of care for treating mild-to-moderate aspirin overdose, and it is indicated for patients who are hemodynamically stable and have [103,105,127]:

The usual formula for urinary alkalinization is to give the patient an IV bolus of 50% sodium bicarbonate, 1–2 mEq per kg, and then begin a continuous infusion with three 50-mL ampules of 50% sodium bicarbonate in 1,000 mL of 5% dextrose in water [103,105]. Some sources recommend that 40 mEq of potassium chloride be added to the continuous infusion fluid, but alkalinization will not work if the patient is hypokalemic or if she/he is dehydrated. So hypokalemia and volume depletion should be corrected before or during alkalinization [103,105]. The solution should be infused at 1.5 to 2 times the patient's basic fluid requirement, at least, and the primary goals of this therapy are to attain a urinary pH of ≥7.5 and to ensure a good urine output [103,105,116]. Done correctly, urinary alkalinization can increase the urinary excretion of aspirin 10-fold [116]. Urine pH should be checked every one to two hours and the infusion rate adjusted as needed. Therapy should be continued until successive serum salicylate levels are less than 30–40 mg/dL and the patient has no clinical or laboratory evidence of salicylate poisoning [103].

The literature conflicts slightly in recommendations for urinary alkalinization. However, these differences could reasonably be considered insignificant, and the basic methods and goals of urinary alkalinization are the same: maintaining a normal serum potassium level and good urine output and creating an alkaline urine pH.

Possible complications of urinary alkalinization include alkalemia, hyperkalemia, and fluid overload. The process should be used cautiously and with close monitoring if the patient is at risk for cerebral or pulmonary edema.

Hemodialysis is an effective method of treating severe cases of aspirin overdose. Indications for the use of hemodialysis in these cases are [103,105,116]:

The serum salicylate level is the least reliable of these criteria for identifying patients who require hemodialysis. A level ≥90 mg/dL is used empirically as a criterion, but acid-base status and the clinical condition of the patient are better indicators of the need for hemodialysis, particularly in cases of chronic salicylate poisoning [116].

The recommended adult dose of ibuprofen is 200–800 mg every four to eight hours, with a maximum 24-hour dose of 3,200 mg. The pediatric dose (up to 11 years of age) depends on body weight and age.

Individuals with chronic kidney disease should use ibuprofen with caution. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend that if the patient's estimated glomerular filtration rate is <30 mL/minute/1.73 m2, ibuprofen should not be used [4].

Over-the-counter ibuprofen tablets are 200 mg, and over-the-counter liquid preparations are available as 1 mL/40 mg, 1.25 mL/50 mg, and 5 mL/100 mg. Prescription tablets are available in doses of 400 mg, 600 mg, and 800 mg. There are two IV preparations of ibuprofen: Neoprofen (1 mL/10 mg) and Caldor (4 mL/400 mg) [4].

Less than 100 mg/kg of ibuprofen is considered nontoxic, and ingestions of more than 400 mg/kg are potentially serious [129,149,150,151]. Reports of serious morbidities like coma, metabolic acidosis, and renal failure have all involved ingestions of more than 20 grams or 400 mg/kg (e.g., 600 mg/kg, 1,200 mg/kg, 72 grams, 100 grams) [135,152,153,154,155].

The initial care of a patient who has taken an overdose of ibuprofen involves the assessment and stabilization of the ABCs. Ibuprofen overdose can cause acidosis, coma, and hypotension, but these effects are rare. If a patient with a reported but unwitnessed and unconfirmed ibuprofen overdose is seriously ill, it is prudent to investigate the possibility that the patient may have either not taken ibuprofen or has taken a co-ingestant.

If the patient is awake, alert, oriented, and hemodynamically stable, a physical examination should be performed. Time should be taken to determine the details of the ingestion and to gather information about the patient's medical history.

Following these steps, a dose of activated charcoal may be considered if the patient is stable and alert, presents within one hour of ingesting a toxic amount of ibuprofen, has an intact gag reflex, and has not ingested any other medications that could induce rapid CNS depression. Before administration of the charcoal, one should be certain that the patient has no contraindications to its use. Gastric lavage and whole bowel irrigation should be avoided.

Blood should be obtained to assess serum acetaminophen level, salicylate level, BUN, creatinine, and serum electrolytes; other laboratory studies can be done as needed. Indications for laboratory studies are situationally dependent (e.g., acetaminophen and salicylate levels would not be needed if the patient is a small child and it was certain that only ibuprofen had been ingested). Ibuprofen levels cannot be obtained in a timely manner, and they are of no value in either predicting risk or making management decisions [149]. Other laboratory tests and diagnostic tests (e.g., electrocardiogram, computed tomography scan) may be obtained if indicated by the patient's condition and medical history.

Patients who have taken a potentially toxic amount of ibuprofen should be observed for at least four to six hours [129,149]. Treatment is symptomatic and supportive; there is no antidote for ibuprofen poisoning. Depending on the patient's clinical condition, age, and prior medical history, IV hydration may be administered. At the end of the observation period, it may be prudent to measure BUN, creatinine, and serum electrolytes again. Patients who are very young or who have or are at risk for renal disease may require longer periods of observation and more frequent measurements of acid-base status and renal function.

Complete recovery should be expected, even after severe poisoning; death from ibuprofen overdose is very rare. Despite the large number of ibuprofen overdoses, there have been fewer than 10 recorded deaths and many of these involved confounding factors. Most patients who have taken an overdose of ibuprofen have mild and temporary gastrointestinal distress and nothing more. At the end of the observation period, if the patient's clinical status is normal, the laboratory test results are within normal range, and there were no co-ingestants, further care is not required.