37: Nonsteroidal Antiinflammatory Drugs

In the late 1800s, acetylsalicylic acid, aspirin, was shown to have antiinflammatory properties similar to those of corticosteroids when used in high doses in patients with rheumatoid arthritis. In a quest to develop a compound with antiinflammatory properties equivalent to corticosteroids but chemically nonsteroidal, Dr. Stewart Adams discovered and developed 2-(4-isobutylphenyl) propionic acid, now known as ibuprofen, and in the process created a new class of drugs designated as nonsteroidal antiinflammatory drugs (NSAIDs).³⁵ Ibuprofen was initially marketed in the United Kingdom in 1969 and was introduced to the US market in 1974. Ibuprofen became available without a prescription in the United States in 1984.

In addition to the numerous benefits of NSAIDs, some deleterious and life-threatening effects are associated with both their therapeutic use and overdose. In an attempt to circumvent some of these adverse effects, selective cyclooxygenase-2 (COX-2) inhibitors were developed, and in 1999, the first selective COX-2 inhibitor, rofecoxib, was approved by the US Food and Drug Administration (FDA), but it was withdrawn from the market in 2004 after postmarketing surveillance concluded an increase in myocardial infarctions and cerebrovascular accidents were associated with its use.

NSAIDs are considered among the most commonly used and prescribed medications in the world.^10,72 An estimated one in seven patients with rheumatologic diseases is given a prescription for NSAIDs, and another one in five people in the United States use NSAIDs for acute common complaints.⁹⁴

Ibuprofen, naproxen, and ketoprofen are currently the only nonprescription NSAIDs in the United States. NSAIDs are also contained in cough and cold preparations and in prescription combination drugs (eg, ­ibuprofen with hydrocodone) and have occasionally been found as adulterants in herbal preparations.⁶²

The American Association of Poison Control Centers (AAPCC) compiles data regarding potentially toxic exposures called into participating poison centers throughout the United States using the National Poison Data System (NPDS) (Chap. 136). Beginning in 2006, a list of substances associated with the largest number of fatalities was reported annually, and since then NSAIDs have consistently been included in the top 25 substances.

The term NSAID used in this chapter does not refer to salicylates, which are unique members of the NSAID class and are covered in Chap. 39.

These chemically heterogeneous compounds can be divided into carboxylic acid and enolic acid derivatives and COX-2 selective inhibitors (Table 37–1). They all share the ability to inhibit prostaglandin (PG) synthesis. PG synthesis begins with the activation of phospholipases (commonly, phospholipase A₂) that cleave phospholipids in the cell membrane to form arachidonic acid (AA). AA is metabolized by PG endoperoxide G/H synthase, otherwise known as COX, to form many eicosanoids, including PGs and the prostanoids, prostacyclin (PGI₂) and thromboxane A2 (TXA₂). AA can also be metabolized by lipoxygenase (LOX) to form hydroperoxy eicosatetraenoic acid (HPETE), which is converted to many different leuko-trienes (LTs) that are involved in creating a proinflammatory environment (Fig. 37–1).

The COX enzyme responsible for PG production exists in two isoforms termed COX-1 and COX-2. COX-1 is constitutively expressed by virtually all cells throughout the body but is the only isoform found within platelets. This enzyme produces eicosanoids that govern “housekeeping” functions, including vascular homeostasis and hemostasis, gastric cytoprotection, and renal blood flow (RBF) and function.^11,75 COX-2, on the other hand, is rapidly induced (within 1–3 hours) in inflammatory tissue by laminar shear (or mechanical) forces and cytokines, producing PGs involved in the inflammatory response. COX-2 is also upregulated by several cytokines, growth factors, and tumor promoters involved with cellular differentiation and mitogenesis, suggesting a role in cancer development.^11,30,80

Glucocorticoids can inhibit phospholipase A (PLA) and downregulate the induced expression of COX-2, which decreases the production of eicosanoids and PGs, respectively, but oral steroids are clinically not the first choice for an antiinflammatory drug regimen given their extensive adverse side effect profile, which includes osteoporosis, hyperglycemia, hypertension, glaucoma, muscle weakness, fluid retention, and mood swings. Most NSAIDs nonselectively inhibit the COX enzymes in a competitive or time-dependent, reversible manner, unlike salicylates, which irreversibly acetylate COX (Chap. 39). Inhibiting COX-1 can interrupt tissue homeostasis, leading to deleterious clinical effects. In what may seem advantageous, some NSAIDs (eg, etodolac, meloxicam, and nimesulide) preferentially inhibit COX-2 over COX-1, while others were specifically designed to selectively inhibit COX-2 (eg, celecoxib).⁹² As will be discussed later in this chapter, many of the selective COX-2 inhibitors (sometimes referred to as coxibs) were removed from the market in the United States because of their increased risk of adverse cardiovascular events.

NSAIDs do not directly affect LOX enzyme or the production of LTs; however, some data suggest that blocking the COX enzymes allows AA to be shunted toward the LOX pathway, increasing the production of proinflammatory and chemotactic-vasoactive LTs.^54,94

Most NSAIDs are organic acids with extensive protein binding (>90%) and small volumes of distribution of approximately 0.1 to 0.2 L/kg. Oral absorption of most NSAIDs occurs rapidly and near completely, resulting in bioavailabilities above 80%. Time to achieve peak plasma concentrations can vary widely (Table 37–1).¹⁶

Some NSAIDs possess unique characteristics regarding their sites of action and accumulation within the body. For example, whereas indomethacin, tolmetin, diclofenac, ibuprofen, and piroxicam achieve significant synovial concentrations, fenamates and indomethacin have both peripheral and central effects.¹⁶ NSAIDs have the ability to cross the blood–brain barrier, but the specific pharmacologic and physicochemical properties facilitating this ability are not well defined.^3,55 Ketorolac and diclofenac have topical activity and are both used in ophthalmologic solutions, and diclofenac is also used in dermal preparations.¹⁶

Plasma half-lives in therapeutic dosing vary from as short as 1 to 2 hours for diclofenac and ibuprofen, to 50 to 60 hours for oxaprozin and piroxicam (Table 37–1). Most NSAIDs undergo hepatic metabolism with renal excretion of metabolites. Diclofenac undergoes extensive first-pass metabolism, only 10% to 20% of indomethacin and ketorolac are excreted unchanged in the urine. Variable amounts of NSAIDs are recovered in the feces.¹⁶

The kinetics of NSAIDs may change in overdose, depending on the particular xenobiotic. Therapeutic and supratherapeutic doses of naproxen (250 mg–4 g) result in the same half-life and time to peak plasma concentration, but the clearance and volume of distribution increase ­proportionately.^65,74 When plasma protein binding of naproxen becomes saturated, the free drug concentration increases more rapidly than the total drug concentration, resulting in increased urinary excretion.⁷⁴ Overdoses of oral ibuprofen do not appear to prolong its elimination half-life.^36,56,95

Gastrointestinal (GI) toxicity is the most common adverse effect from NSAID use (Table 37–2). Normally, the COX-1 enzyme expressed in the gastric epithelial cells leads to the production of PGs (PGE₂ and PGI₂), which are responsible for maintaining GI mucosal integrity by increasing mucous production and decreasing acid production. NSAIDs not only inhibit the production of these cytoprotective PGs and platelet aggregatory TXA₂ but also have a direct cytotoxic effect, increasing the risk of gastric and duodenal ulcers, perforations, and hemorrhage.^23,68,72 Esophageal and small intestinal ulcers and strictures are also associated with NSAID use. Small intestinal diaphragms (or webs) are concentric weblike septa arising from submucosal fibrosis that can eventually cause a small bowel ­obstruction. These diaphragms rarely occur but are considered pathognomonic for NSAID use.²³

Selective COX-2 inhibitors decrease the incidence of significant GI toxicity compared with some nonselective NSAIDs, a benefit that is lost in patients concomitantly taking warfarin or low-dose aspirin.^4,12,30,93 Although Helicobacter pylori and NSAID use both individually increase the risk of gastroduodenal ulcers, there are conflicting data regarding the relationship between the two, given the wide array of study designs, individual responses to infection and treatments, and different gastric acid suppressants. Current evidence suggests that the risk of GI toxicity may be decreased by eradicating H. pylori before initiating NSAID therapy in NSAID-naïve patients.^10,18,23,72

The kidney produces locally homeostatic PGs largely via COX-1, including PGI₂, PGE₂, and PGD₂, that maintain adequate glomerular filtration rate (GFR) and RBF and function by augmenting renal vasodilation, inhibiting sodium chloride absorption, and antagonizing the action of antidiuretic hormone (vasopressin). NSAIDs oppose this homeostatic renal vasodilation and augment sodium reabsorption, blunting the ­anti­hypertensive effect of thiazide and loop diuretics. NSAIDs also decrease renin synthesis, a mechanism shared by β-adrenergic antagonists, rendering this antihypertensive therapy less effective.^30,94 Patients with volume contraction (salt and water depletion) or poor cardiac output (congestive heart failure) have elevated concentrations of renal vasoconstrictor substances from stimulation of both the renin–angiotensin–aldosterone axis and the sympathetic nervous system, so NSAID use in these patients inhibits the synthesis of compensatory vasodilatory PGs, resulting in unopposed renal vasoconstriction and causing decreased RBF and GFR. This effect may lead to medullary ischemia and possibly acute kidney injury, particularly in elderly adults.⁷⁰ This vasoconstrictive effect is also associated with COX-2 selective inhibitors and appears to be reversible upon discontinuation of therapy.^61,70,94

Normal platelet function depends partly on endothelial-derived PGI₂ (largely via constitutively expressed COX-1), which blocks platelet activation and causes vasodilation, allowing blood to flow freely within vessels. At the site of vascular injury, platelets are activated by binding to collagen-bound von Willebrand factor and synthesize and release TXA₂, a potent platelet stimulator and vasoconstrictor. The antiplatelet activity of NSAIDs stems from their ability to inhibit COX-1, thereby inhibiting platelet-­stimulating TXA₂ synthesis. Selective COX-2 inhibitors also decrease PGI₂ and TXA₂ synthesis but affect TXA₂ synthesis to a lesser degree, creating a more prothrombotic environment, which is the predominant theory of how selective COX-2 inhibitors increase the risk of adverse cardiovascular events (see below for further discussion).⁷⁵

Prostaglandins play a major role during the initiation of parturition. Administration of exogenous PGF_2α and PGE₂ is used to induce uterine activity, and indomethacin has been used successfully as a tocolytic agent by blunting PG-mediated uterine stimulation. However, a major clinical drawback in using NSAIDs as tocolytics is their potential to cause premature constriction or closure of the ductus arteriosus in utero. Vasodilatory PGs are required to keep the fetal ductus arteriosus patent, and inhibiting these PGs causes fetal ductal constriction, leading to pulmonary hypertension and persistent fetal circulation after birth.⁵⁹

Atherosclerosis is a dynamic process of thrombus formation and inflammation involving numerous tissue factors and inflammatory mediators.³¹ Given the ability to inhibit synthesis of proinflammatory PGs, selective COX-2 inhibitors would be expected to be antithrombotic; however, their ability to inhibit endothelial-derived PGI₂ combined with their relative inability to inhibit platelet-activating TXA₂ (a predominantly COX-1 effect) may shift the balance toward thrombus formation.⁶⁰

In 2000, the Vioxx Gastrointestinal Outcomes Research (VIGOR) study reported a slightly higher incidence of myocardial infarction in patients taking rofecoxib compared with those taking naproxen (0.4% vs. 0.1%). This was thought to be because of a substantial number of patients who were not taking daily aspirin but should have been (based on FDA criteria) and that naproxen may have had a cardioprotective effect.^12,57,60

In 2004, Merck pharmaceutical company withdrew rofecoxib from the worldwide market given the prepublication results of a study demonstrating an undisputed elevated cardiovascular risk.¹⁴ Results from a meta-analysis⁴⁴ spawned controversy within the medical literature regarding the extent of delay before the withdrawal of rofecoxib from the market.^26,42,48,86 Several other studies addressing selective COX-2 inhibitors had similarly increased risk of adverse cardiovascular events, suggesting this to be a class effect.^26,66,81 Valdecoxib has subsequently been removed from the market, leaving celecoxib as the only selective COX-2 inhibitor available; however, it carries an FDA alert on a possible increased cardiovascular risk.⁸¹

The data on nonselective NSAID use and cardiovascular risk remain controversial. Many of the currently published studies and meta-analyses use large databases and are unable to exclude significant confounding factors, including smoking, body mass index, chronic disease, concurrent aspirin use, and socioeconomic status.⁹¹ Some of the nonselective NSAIDs that show a trend toward elevated cardiovascular risk include diclofenac, meloxicam, indomethacin, and, to a lesser extent, ibuprofen.^33,57,77,91 In 2005, the FDA asked manufacturers of all nonprescription NSAIDs to revise their package inserts to provide more information on the potential cardiovascular risks pending further investigation.

NSAIDs are a heterogeneous class of drugs, some carrying a unique toxicity profile. Fortunately, most nonselective NSAIDs behave similarly in overdose, although much of the medical literature specifically describes ibuprofen. Regardless of the particular NSAID ingested, symptoms typically manifest within 4 hours after ingestion.^{36,37,38,53,56,90}

Initial clinical manifestations are usually mild and predominantly include GI symptoms, such as nausea, vomiting, or abdominal pain, or neurologic symptoms, such as drowsiness, headache, tinnitus, blurred vision, diplopia, and dizziness. More moderate and severe findings are rare and include coma, seizures, central nervous system (CNS) depression, metabolic acidosis, hypotension, hypothermia, rhabdomyolysis, electrolyte imbalances, cardiac dysrhythmias, and acute kidney injury.^{19,36,37,53,56,58,90} Massive NSAID ingestions may lead to multisystem organ failure and death.^{21,41,79,88,95}

Neurologic Effects

The neurologic effects of NSAID use vary from the mild drowsiness, headache, and dizziness with therapeutic dosing to the more life-threatening CNS depression, coma, and seizures in overdose. The mechanism associated with the decreased level of consciousness is unknown; however, several animal studies suggest a relationship with opioid receptors, and a human case report documents a dramatic return of consciousness in a child after intravenous (IV) administration of high-dose naloxone.²⁷ Other reported neurologic manifestations of toxicity include optic neuritis, amblyopia, color blindness, transient diplopia, other visual disturbances, transient loss of hearing, acute psychosis, and cognitive dysfunction.^39,67

Drug-induced aseptic meningitis is reported with several NSAIDs, including tolmetin, rofecoxib, naproxen, sulindac, piroxicam, and ­diclofenac, but ibuprofen is more commonly implicated, perhaps because of its widespread use.⁶⁴ Clinical findings include fever and chills, headache, meningeal signs, nausea, vomiting, and altered mental status; cerebrospinal fluid findings include pleocytosis, elevated protein, and normal glucose.⁶⁴ Studies suggest an immunologic mechanism behind NSAID-induced aseptic meningitis because it appears to be more common in patients with systemic lupus erythematosus (SLE) or mixed connective tissue disease.^39,64,67

Muscle twitching and generalized tonic-clonic seizures are described with mefenamic acid overdose and usually occur within 7 hours after ingestion.² Seizures are also associated with ibuprofen overdose,⁶⁹ although the specific mechanism for NSAID-induced seizures is unknown.

Renal and Electrolyte Effects

Both acute overdose and chronic therapeutic dosing of NSAIDs may have deleterious effects on kidney function, most of which are reversible. These include sodium retention and edema, hyperkalemia, acute kidney injury (AKI), membranous nephropathy, nephrotic syndrome, interstitial nephritis, and both acute and chronic renal papillary necrosis.^39,71,94 General risk factors for NSAID-induced AKI include congestive heart failure, volume depletion, diabetes mellitus, underlying kidney disease, SLE, cirrhosis, diuretic therapy, and advanced age.⁵⁴ There is also growing concern over the potential development of AKI with NSAID use in patients who are concurrently taking multiple antihypertensive medications, such as diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers.⁵⁰

Acute tubulointerstitial nephritis (ATIN) is one of the more common forms of NSAID-induced renal impairment, and it may occur with short-term therapeutic dosing.^24,54 Many cases of ATIN probably go undiagnosed because clinical symptoms usually do not appear until significant renal impairment occurs.^24,73 Significant elevations in blood urea nitrogen (azotemia) may occur in elderly patients within 5 to 7 days of initiating NSAID therapy and usually return to baseline within 2 weeks of discontinuation.³⁴

Analgesic abuse nephropathy is a condition whose pathogenesis is not well defined, but it develops from excessive, chronic therapeutic consumption of NSAIDs. This results in AKI manifested by renal papillary necrosis, often requiring hemodialysis.^78,94 Analgesic abuse nephropathy was originally described with the use of analgesic combinations including phenacetin and aspirin in addition to caffeine and has decreased in prevalence after the removal of phenacetin from many world markets.

Anion gap metabolic acidosis, with and without AKI, complicates many acute, massive ibuprofen ingestions and may be profound.^25,41,95,96 The cause of the acidosis in this setting is most likely multifactorial, involving profound hypotension and tissue hypoperfusion with elevated lactate concentrations and the accumulation of ibuprofen and its two major metabolites, all weak acids.⁵³ An elevated anion gap metabolic acidosis with elevated lactate concentrations is also described after naproxen overdose, suggesting this to be a class effect given that all NSAIDs are acid derivatives.¹³

Use of NSAIDs by pregnant women is associated with reversible oligohydramnios and is used therapeutically as a treatment modality for polyhydramnios. Decreased fetal urine output and neonatal acute and chronic kidney failure, including transient oligoanuria, are associated with gestational NSAID use, commonly indomethacin.^5,29,45

Gastrointestinal Effects

Although the most common adverse GI effect of therapeutic NSAID use is dyspepsia, most patients with dyspepsia do not have ulcers.²³ To help prevent the development of ulcers associated with NSAID therapy, concomitant use of misoprostol (a PGE₁ analog), an H₂-blocker, or a proton pump inhibitor (PPI) is often used; however, PPIs may be superior for both ­preventing and healing gastroduodenal ulcers resulting from chronic NSAID therapy.⁷² The most serious adverse GI effect is ulcer formation, which has the potential for life-threatening perforation and hemorrhage, and numerous studies reported an increased risk of these effects with therapeutic use of NSAIDs.^32,51,68 The relative risk of developing gastroduodenal perforation, ulcer, or hemorrhage during chronic, therapeutic NSAID therapy ranges from 2.7 to 5.4, with ketorolac posing the greatest risk.^68,87 Acute NSAID overdoses cause bloody emesis, fecal occult blood loss, and severe, life-­threatening GI hemorrhage.

NSAID-induced hepatotoxicity is a well-known adverse effect that has prompted the removal of several NSAIDs from the market. Hepatotoxicity occurs with an incidence of less than 0.1% and can be quite difficult to diagnose because many patients on chronic NSAID therapy have underlying conditions, such as SLE or rheumatoid arthritis, which may cause hepatotoxicity. NSAID-induced hepatotoxicity is an idiosyncratic reaction primarily causing hepatocellular injury and does not depend on the chemical class. Diclofenac and sulindac are most commonly implicated.⁸⁵

Immunologic and Dermatologic Effects

The nonimmunologic anaphylactoid and the IgE-mediated anaphylactic reactions that are reported with the use of NSAIDs are clinically indistinguishable from one another, producing flushing, urticaria, bronchospasm, edema, and hypotension.⁷ Evidence for anaphylactic reactions includes the presence of NSAID-specific IgE antibodies, positive wheal-and-flare skin reactions, and lack of cross-reactivity with oral challenges of aspirin and other NSAIDs.⁷ The proposed mechanism of NSAID-induced anaphylactoid reactions involves the inhibition of COX-1, which not only inhibits the production of PGE₂ (which causes bronchodilation and inhibits the release of histamine from mast cells and basophils) but also shunts the AA metabolism to increased production of bronchoconstricting LTs.

The term aspirin-sensitive asthmati c is a bit of a misnomer because it refers to anaphylactoid reactions that may occur with any COX-1 inhibiting NSAID, not only aspirin.^7,83 Selective COX-2 inhibitors cause similar clinical reactions but with an unclear mechanism. There appears to be very little cross-reactivity between NSAIDs and selective COX-2 inhibitors, and reports of reactions to one COX-2 inhibitor and not another suggest a predominant IgE-mediated mechanism.^7,47,83

The most common skin reactions include angioedema and facial swelling, urticaria and pruritus, bullous eruptions, and photosensitivity.³⁹ Although rare, toxic epidermal necrolysis and Stevens-Johnson syndrome are reported.³⁹

Hematologic Effects

As a class, NSAIDs are frequently implicated in the development of drug-induced thrombocytopenia and cause adverse effects on most other cell lines and function, including agranulocytosis, aplastic anemia, hemolytic anemia, methemoglobinemia, and pancytopenia.^{22,39,46,63,89} Specifically, phenylbutazone in chronic, therapeutic doses was associated with agranulocytosis and aplastic anemia,⁷⁹ prompting its removal from the US market in the 1970s. The inhibitory effect of NSAIDs on granulocyte adherence, activation, and phagocytosis, along with the potential for masking signs and symptoms, has been suggested as the mechanism responsible for the association between NSAID use and necrotizing fasciitis.⁴⁰

The ability of a particular type of NSAID to inhibit platelet aggregation and affect bleeding time depends on the dose and half-life because NSAIDs reversibly inhibit COX. One dose of ibuprofen prolongs the bleeding time within 2 hours and persists for up to 12 hours; however, this increase in bleeding time usually remains within the upper limit of normal range. This is in contrast to aspirin, which irreversibly inhibits COX, and typically doubles the bleeding time within 12 hours, returning to normal within 24 to 48 hours.⁷⁵ Compared with placebo, flurbiprofen and indobufen clinically inhibit platelet function, thereby decreasing vascular reocclusion after angioplasty and preventing thromboembolic complications.^9,15 The concern over whether ketorolac has clinically significant effects on postoperative bleeding remains controversial.^1,20

NSAID use may also potentiate bleeding in patients already at higher risk. These patients include those with thrombocytopenia, coagulation factor deficiencies, or von Willebrand disease and those ingesting alcohol or on warfarin therapy.⁷⁵

Cardiovascular Effects

Although no evidence supports a direct cardiotoxic effect of NSAIDs or their metabolites, acute and massive NSAID overdoses may be complicated by persistent and severe hypotension; myocardial ischemia; and cardiac conduction abnormalities and dysrhythmias, including bradycardia, ventricular tachycardia or fibrillation, and prolonged QT interval.^25,41,95 The cause of these findings is yet to be elucidated, although these effects are reported only in severely ill patients with acid–base abnormalities and multisystem organ involvement (see Cardiovascular Risk earlier).

Pulmonary Effects

Although there is no evidence of direct pulmonary toxicity, some case reports describe the development of acute respiratory distress syndrome similar to the clinical manifestations of salicylate toxicity, suggesting an NSAID class mechanism based process.^25,41,52,58 Although chest radiographic findings such as bilateral pulmonary infiltrates appear to resolve rapidly, one study reported persistent clinical abnormalities associated with exertional dyspnea one month later (see Immunologic Effects earlier).⁵⁸

Diagnostic Testing

Serum concentrations of most NSAIDs can be determined but usually only by a specialty laboratory requiring several days to report results. Although ibuprofen nomograms were constructed in an attempt to correlate serum concentrations with clinical toxicity,^36,43 the utility of these nomograms proved limited.^38,56

Laboratory measurements, including complete blood count, serum electrolytes, blood urea nitrogen, and creatinine, should be obtained for all symptomatic patients, patients with intentional ingestions, ibuprofen ingestion of greater than 400 mg/kg in a child, or ibuprofen ingestion of greater than 6 g in an adult.³⁸ For patients presenting with significant neurologic effects, such as CNS depression, further evaluation of acid–base and ventilatory status by blood gas, hepatic aminotransferases, and prothrombin time should be obtained. A computed tomography scan of the head and a lumbar puncture may be clinically indicated in cases of suspected aseptic meningitis or when structural or infectious etiologies are suspected. An acetaminophen (APAP) concentration should always be determined in patients with intentional ingestions and in patients presenting with an unclear history because many people mistake APAP for NSAIDs because of confusing labeling and packaging or unawareness that they are completely different types of analgesics. For similar reasons, obtaining a salicylate concentration may also be considered.

Management of a patient with an NSAID overdose is largely supportive and guided by the clinical signs and symptoms. Most asymptomatic patients with intentional overdose and those with normal vital signs require observation for 4 to 6 hours and a serum APAP concentration before being medically cleared. Children with ibuprofen ingestions of less than 100 mg/kg can be observed at home, but those who ingest greater than 400 mg/kg are at high risk for toxicity and require medical evaluation.³⁸ GI decontamination with activated charcoal (AC) should be considered for an asymptomatic patient with the potential for a large ingestion, symptomatic patients, and children with a history of ibuprofen ingestion greater than 400 mg/kg.^38,49 Serum concentrations of ibuprofen continue to increase even after the time of emergency department arrival, so gastric lavage for massive overdose followed by AC should be considered, and multiple-dose AC may be useful for patients with massive overdoses of sustained-release preparations.⁹⁵

Patients who develop severe, life-threatening manifestations usually present with lethargy or unresponsiveness.^{25,41,58,69,95} Aggressive, supportive care is indicated in these patients, including stabilization of the airway and IV fluid therapy. An early electrocardiogram is essential to detect any significant electrolyte abnormalities or conduction disturbances. Electrolyte imbalances should be corrected and sodium bicarbonate therapy considered for life-threatening metabolic acidosis. Hypotension should be treated initially with IV fluid therapy followed by direct-acting vasopressors if necessary. Electrocardiograms should be monitored for the development of any life-threatening electrolyte imbalances or cardiac conduction abnormalities.

Given their high protein binding, NSAIDs do not appear to be amenable to extracorporeal removal methods; however, in cases of refractory metabolic acidosis or kidney failure, hemodialysis or continuous renal replacement therapies may be useful to correct the acid–base status.^6,52 Patients with seizures, which are characteristic of mefenamic acid overdose,² should be treated with IV benzodiazepines.

• NSAIDs are among the most commonly used drugs in the world.

• Most patients with NSAID overdoses develop nonspecific symptoms, including nausea and abdominal discomfort, requiring little clinical management other than psychiatric assessment.

• Patients with large ingestions may require GI decontamination and treatment of metabolic acidosis and kidney failure.

• In all cases of intentional NSAID ingestion, APAP coingestion should be excluded.

Acknowledgment

Martin G. Belson, MD, and William A. Watson, PharmD, contributed to this chapter in previous editions.

References