Case Presentation by Dr. Eugene Rozen
Suicide attempt by pill ingestion
History is provided by the patient and her parents.
This is a 15-year-old female that arrived via ambulance to the emergency department at Children’s Hospital of Michigan 2½ hours after intentionally ingesting an unknown quantity of aspirin and acetaminophen in a suicide attempt. She denies taking any other pills of any kind. She denies having ingested any alcohol or recreational drug. At presentation she is complaining of abdominal discomfort with nausea, and has had several episodes of non-bloody, non-bilious vomiting. She denies headache, dizziness, alterations in vision, tinnitus, LOC, dyspnea, chest pain, or palpitations.
Neurologic: No dizziness or headaches
HEENT: No changes in vision or tinnitus
Respiratory: No dyspnea
Cardiovascular: No chest pain or palpitations
Gastrointestinal: Negative except as stated in HPI
Musculoskeletal: No weakness, no trauma
Genitourinary: No dysuria, no hematuria
Integumentary: No rashes
Psychiatric: Initially wanted to commit suicide but presently denies suicidal ideation and regrets what she has done
Vitals: T 36.5ºC, HR 108, RR 24, BP 109/80, O2 Sat 100% ORA
General: In NAD on stretcher.
Head: Normocephalic, atraumatic
Eyes: PERRL 5mm, Non-icteric, non-injected, EOMI
ENT: TM intact, No rhinorrhea, no nasal flaring, no pharyngeal erythema
Respiratory: Tachypneic with clear, bilateral air entry and no retractions
Cardiovascular: Tachycardic. Regular rhythm, S1, S2 with no murmur. Radial and pedal pulses are strong and symmetric
Abdomen: Soft, non-tender, non-distended. BS normal in 4 quadrants.
Musculoskeletal: Full passive range of motion in all joints. No tenderness or swelling.
Neurologic: No focal deficits, cranial nerves intact.
Psych: Awake, alert and interactive.
APAP @ 4 hours: 40
ASA @ 4 hours: 55 mg/dL
UDS: Negative except APAP, aspirin
ABG: pH 7.43, pCO2 27.6, Bicarb 19.1, pO2 100 (RA)
CBC: w 18.5 (85%N, 10%L 5%M); h/h 13.4/39.4; p 340
ALT 65, AST 45
UA: Clear, Yellow, pH 6.0, SG 1.023, Blood 1+, Bac 2+, RBC 5-10, otherwise normal
ECG: Sinus tachycardia, otherwise normal
CXR: No acute cardiopulmonary process
1. Which of the following is most representative of an ABG in a patient with moderate ASA toxicity?
a) pH 7.34 pCO2 33 HCO3 16
b) pH 7.38 pCO2 30 HCO3 20
c) pH 7.32 pCO2 52 HCO3 27
d) pH 7.29 pCO2 52 HCO3 16
2. Which of the following is an absolute indication for hemodialysis in acute ASA toxicity?
a) pH >7.45 on ABG
b) Salicylate level of 65mg/dL
d) New crackles on lung auscultation
3. Which of the following is true regarding acute and chronic salicylate ingestion?
a) Chronic ingestion carries a significantly lower mortality than acute ingestion
b) Hemodialysis is indicated at a higher ASA level in chronic ingestion than in acute ingestion
c) ASA toxicity may present in a nearly therapeutic level of ASA in chronic ingestions
d) Chronic aspirin ingestion is common in children
The metabolic manifestations of ASA ingestion are mixed metabolic acidosis and respiratory alkalosis. Although they reciprocate, they are actually independent processes. Answer choice B shows a primary metabolic acidosis. When compensation is calculated (either by Winter’s formula, HCO3+15, or the comparing the pCO2 and after-decimal digits of the pH) this option shows a superimposed respiratory alkalosis. Option A is incompletely compensated metabolic acidosis, Option C is respiratory acidosis and Option D is mixed respiratory and metabolic acidosis.
Hemodialysis is a therapeutic measure taken either in the presence of symptoms indicating severe toxicity or in patients who have failed other treatments. The absolute indications in acute toxicity are a salicylate level >75mg/dL, pulmonary edema, central nervous system symptoms, renal failure, severe acidosis and increasing salicylate levels despite other treatments.
An alkalotic pH may be from bicarbonate therapy or from hyperventilation, but in either event it is likely a good sign, as severe toxicity is associated with acidosis. Hyperventilation is a symptom seen in mild toxicity that can be treated with more conservative therapy. In chronic salicylate toxicity, a serum level >50mg/dL is an absolute indication for hemodialysis.
Even in acute ingestion, ASA levels do not actually correlate with severity of disease and toxicity may persist at nearly therapeutic levels. Chronic toxicity may be difficult to identify because its symptoms mimic cardiopulmonary conditions, there may not be a history of ingestion and serum levels may even be within normal levels.
Chronic ingestion has a 25% mortality compared to 1% with acute. Hemodialysis is indicated at 50mg/dL in chronic ingestion, compared to 100mg/dL for acute. Before the association was made between Reye’s syndrome and aspirin, children would actually commonly present with chronic ingestion toxicity when treated for fevers or colds. This would be a self-propagating cycle since the symptoms of ASA toxicity may resemble the conditions the aspirin was meant to treat. These days, young children do not commonly receive ASA for fevers/viral syndromes and their presentations are usually due to acute ingestions.
Aspirin overdose is a physiology-heavy topic. The patient described in the case did not need the level of intervention that will be discussed below, but I realized during that shift and in researching this topic that she could have been critically ill and I would have been unprepared to treat her properly. I’ve made this discussion rather dense in the way of basic science, but I think that an understanding of the pathophysiology in this case makes the clinical portion logical and largely self-evident.
Salicylates are derived from the bark of trees from the genus Salix (as in salicylate) and Spiraea (as in aspirin) and have been used for millennia to treat pain, fevers, and inflammation. Near the end of the 19th century, the Friedrich Bayer Dye company developed a chemical synthesis for acetylsalicylic acid from Spiraea bark extracts by a reaction similar to the one for converting morphine into heroin (a product developed by the same company). Bayer AG, as it is now known, patented acetylsalicylic acid as Aspirin and began selling it in 1899. It’s other wonder drug, Heroin, continues to sell like hotcakes.
Mechanism of Toxicity
The pharmacological mechanism of acetylsalicylic acid (ASA) is irreversible inhibition of cyclooxygenase 1 and 2 (blocking the synthesis of prostaglandins, prostacyclins and thromboxanes), disruption of the kallikrein-kinin system (inhibiting polymorphonucleocyte chemotaxis and granulocyte adherence to damaged endothelium), and inhibition of interleukin-1 (a macrophage-derived mediator that causes pyrexia). Together these functions, primarily its effects on prostaglandins and thromboxanes, serve to decrease pain, fever, inflammation and thrombosis.
At low doses, the inhibition of these physiologic functions causes ASA’s common adverse effects, erosive gastritis, GI bleeding, and impaired hemostasis. At higher levels, ASA can interfere with cellular respiration, which is the principal method by which it induces toxicity, referred to as Salicylism.
Within the mitochondria, a proton gradient created by the tricarboxylic acid cycle and the electron transport chain between the intermembrane space and the mitochondrial matrix powers ATP synthesis (figure 1), this is called oxidative phosphorylation. Aspirin interferes with this cycle by buffering and transporting the protons across this membrane, thereby decreasing the potential of the gradient. When this happens, the reactions of the TCA cycle and the ETC are rendered futile, since a lesser amount of ATP is produced. This activates alternative pathways for ATP generation: anaerobic glycolysis and fatty acid oxidation. The upregulation of these two processes induces lactic acidemia and the formation of ketone bodies, respectively. The relative inefficiency of anaerobic glycolysis, which creates approximately 2 ATP molecules per glucose compared to aerobic cellular respiration, which creates approximately 32 ATP molecules per glucose, may deplete glucose stores, resulting in clinical hypoglycemia. Aspirin at high concentrations or prolonged exposure can also induce apoptosis via increased membrane permeability of mitochondria, but this is a complex process and less relevant for clinical medicine.
ASA’s toxic manifestations are dose dependent and begin in the hair cell of the ear. ASA, possibly through a mechanism similar to its effect on mitochondria, can affect the voltage-dependent membrane capacitance of outer hair cells. Through mechanisms that are beyond the scope of this discussion, tinnitus and reversible hearing loss result. These are often present in acute aspirin toxicity, but are also features of chronic ASA use. With chronic toxicity, ASA may also induce the synthesis of prestin, a membrane protein that alters the piezoelectric qualities of the hair cells, leading to hearing deficits.
At slightly higher doses, ASA begins to affect the brainstem. Most sources state that this is due to “direct stimulation” of the respiratory center in the medulla. The putative mechanism is that the locally diminished ATP and resulting acidic environment stimulates tachypnea, as would hypoxia and hypercarbia. The result of the tachypnea is a respiratory alkalosis and one of the early objective findings in these patients. The renal response to respiratory alkalosis is elimination of bicarbonate which complicates the toxicity at higher levels.
At these higher levels, the effect on the mitochondria can become systemic with accumulation of lactic acid and ketone bodies. The renal elimination of bicarbonate as a compensatory response to the primary respiratory alkalosis causes a decrease in the acid-buffering ability of the blood. An additional contribution to the systemic acidosis is made by the kidneys. ASA can result in renal damage through its inhibition of prostaglandins which normally serve to vasodilate the intrarenal vasculature. The resultant hypoxic damage can cause the kidneys to not only have diminished capacity for acid-base compensation, but to also retain inorganic acids (phosphoric and sulfuric), which are the primary mechanism by which the nephron excretes hydrogen atoms. The kidney’s ability to handle acidosis is further diminished by the inhibitory effect of ASA on alpha-ketoglutate dehydrogenase, a TCA enzyme involved in renal ammoniagenesis, a secondary mechanism of renal acid buffering. This effect is compounded by prerenal azotemia caused by volume losses in the form of vomiting and insensible losses from tachypnea and diaphoresis. The metabolic derangement seen in ASA-intoxicated patients is mixed respiratory alkalosis and metabolic alkalosis with a wide anion gap.
As the plasma levels of ASA increase further, central nervous system and pulmonary cell abnormalities result, which in turn cause edema of these tissues. These mechanisms are not fully understood but may result from both direct cellular damage and alteration in hemodynamics leading to vasoconstriction.
Principles of Treatment
There is no antidote to aspirin and the approach to management relies on managing symptoms supportively and decreasing absorption of ASA until elimination of ASA from the serum and tissues, the mainstay of therapy, is successful. The theoretical basis of the latter two will be discussed here, and supportive treatments specific to ASA intoxication will be discussed in the Clinical Approach section.
Decreasing absorption is generally of little value. Until recently, gastric lavage and induced emesis were used to cleanse the stomach of ASA but it has been commonly accepted that these treatments are not benign and that the risks posed by their implementation are not justified by the marginal benefit they produce. Activated charcoal (and its DIY alternative, burnt toast) remains controversial. The mechanism of action of activated carbon is that is has an enormous surface area (1 gram may have a surface area equal to 500-1,500m2) and a chemical milieu that promotes the non-covalent adsorption of many small organic molecules including aspirin and the salicylates (figure 2). When given orally, it can bind ASA, precluding its systemic absorption via the small intestine. It works best when given early, but ASA may come in extended release formulations and is known to not only delay gastric emptying and cause pylorospasm, but also to form gastric concretions which cannot be rapidly broken down by digestion. The result of these combined factors is that a large acute ingestion may take up to 12 hours to be fully absorbed and reach peak plasma levels – compared to 1-2 hours in regular doses – and that administration of activated charcoal later in the patient’s presentation may still be beneficial.
Elimination of ASA in mild-moderate toxicity relies on the concept of ion trapping. Acetylsalicylic acid and its main bioactive metabolite, salicylic acid, are weak acids with pKa 3.5, and 3.0, respectively. So long as they are un-ionized, i.e. protonated and uncharged, their passage through cellular membranes is facilitated. This includes peripheral tissues, the blood brain barrier, and the cellular membranes that line the nephrons. If they can pass through these cellular barriers they are more likely to cause toxicity to the tissues, most importantly the brain, and more likely to be reabsorbed in the nephrons, prolonging their time in the body.
The basis of ion trapping is that a deprotonated weak acid (its conjugate base) is a charged molecule (ion) and as such is considerably more polar; causing it to form aqueous complexes and impeding passage through non-polar cellular membranes. It is essentially trapped in the extracellular fluid which keeps it from exerting its toxic effects on the tissues and keeps it in the nephron lumen from which it is ultimately excreted with the urine.
If the Henderson-Hasselbach equation is applied to ASA at a pH of 7.1, an acidotic serum value typical of salicylate toxicity, the concentration of the ionized conjugate base is roughly 4,000 times that of the unionized acid (i.e. for every uncharged molecule, there are 4,000 ionized molecules). At a pH of 7.5, a therapeutic target value discussed later, that ratio increases to nearly 8,000. For salicylic acid, whose toxic effects are comparable to ASA’s, these values are 12,500 and 31,600, more than a 2.5-fold increase. At a pH of 8.0, the ASA ratio is increased to 30,000:1 and the salicylic acid ration is increased to 100,000:1. Having a larger fraction of the molecules in the ionized form decreases the exposure of CNS cells to the toxins and speeds the toxins’ elimination.
It is not always the case that the patient’s condition permits the time necessary for this detoxification. This elimination may also be disrupted in patients with renal impairment which, inconveniently, is a known adverse effect of chronic ASA ingestion. In these cases extracorporeal hemodialysis may be a therapeutic necessity.
The pathophysiology of ASA toxicity provides a logical framework for understanding its clinical manifestations. Evaluation of the patient can vary depending on the acuity of disease, and if the clinical situation permits it, a history should be attained that can elucidate the quantity of ingestion and the time course. The presence of comorbidities may hint at the possibility of chronic toxicity, which will affect treatment. As with the evaluation of other toxidromes, the clinician should make an effort to elicit the presence of coingestants.
Figure 3 shows the clinical manifestations of acute ASA toxicity and the serum concentrations at which they occur. It should be understood that chronic toxicity results in a more insidious onset and generally lower serum concentrations for a given symptom.
The common alterations in vital signs will be hyperthermia and tachypnea, although hyperpnea (increased depth, rather than frequency, of respirations) may be a more common finding in mild toxicity. Vomiting, hyperventilation and diaphoresis can cause hypovolemia, which may manifest with tachycardia. Hypotension is a more troubling finding and associated with more severe toxicity.
Early symptoms, as elaborated in the preceding section, are tinnitus, hearing deficits and hyperventilation. The patient may otherwise appear mildly distressed and report a history of nausea and vomiting. Symptoms of hyperpyrexia, dehydration, vomiting may initially be managed supportively in the emergency department, but the presence of pulmonary involvement and CNS effects, which may include confusion, agitation, delirium, lethargy, convulsions and coma warrant a considerably more aggressive approach to therapy as well as specialist consultations.
Managing aspirin toxicity is an intensive process in which treatments go hand in hand with lab results, and they will be discussed together. Any patient who presents with salicylism needs to have a serum aspirin level, which can be done by gas chromatography/mass spectrometry, nuclear magnetic resonance, infrared spectroscopy, enzyme specific assays or fluorescence polarization immunoassay. For immediate verification of suspicions, collect a urine specimen and add it to a solution of ferric chloride, mercuric nitrate, and hydrochloric acid, commonly known as the (largely unavailable) Trinder Reagent or Trinder spot test, to detect ASA levels greater than 30mg/dL colorimetrically with very high sensitivity. These ASA levels should be monitored regularly and are an endpoint to treatment. It is critical to recognize that complications of ASA ingestion can manifest in the face of decreasing and even near-therapeutic levels. The initial salicylate level may be misleading since absorption can be delayed, as discussed.
Acute toxicity begins to manifest at 30-50mg/dL with dose dependent increases in severity of intoxication from there on. A concentration of 100mg/dL in acute ingestion is an absolute indication for hemodialysis. At a serum concentration of 500mg/dL, ASA is uniformly lethal. The information obtained in the anamnesis is important when evaluating the ASA level because chronic ingestion has not only a higher mortality (25% vs. 1% for acute) but manifests complications at lower serum levels. In a chronically intoxicated patient, 50mg/dL is an indication for hemodialysis.
The patient’s acid base status should be regularly assessed with blood gas analysis and pH measurements of the urine. The goal of ion trapping is to administer bicarbonate solution titrated to a urine pH exceeding 7.5 while avoiding a serum pH greater than 7.55. Bicarbonate is given initially as a 1-2mEq/kg bolus and then is added to D5W at 150mEq/L (3 ampules in 1 liter) and administered at 1.5-2 times the normal maintenance requirements (calculated using the 100/50/20 rule or the 4/2/1 rule in children). Forced diuresis should be avoided in attempting to eliminate ASA, and acetazolamide should not be used to alkalinize the urine.
Patients with toxicity are likely to have multiple metabolic derangements and a full electrolyte panel should be drawn initially and as treatment progresses. Vomiting, respiratory alkalosis, ASA-induced renal tubular damage, and inhibition of the electron transport chain (needed for active ion transport) all contribute to a fall in potassium. Hypokalemia should be managed early and aggressively because the renal secretion of H+ and urine alkalization cannot properly work without adequate serum potassium.
The uncoupled oxidative phosphorylation causes a hypermetabolic state that can deplete glucose which should be regularly checked and supplemented as needed. After initial correction with dextrose bolus, maintenance fluids must contain 5% dextrose with bicarbonate. BUN and creatinine levels should be analyzed as renal failure is an absolute indication for hemodialysis and renal impairment should prompt consideration of the possibility.
Patients with severe ASA toxicity can be critically ill, and terminal complications must be identified. The three most ominous features in these patients are hypoventilation, brain edema and pulmonary edema. Most patients with ASA toxicity will present with some measure of hyperventilation. Although this is an independent pathologic process rather than a compensatory physiologic process for metabolic acidosis, it nonetheless provides some measure of serum alkalization which can balance the serum pH and trap salicylate anions. A hyperventilating patient may pose a concern for “tiring out” and being unable to sustain a respiratory effort, tempting the possibility of intubation. This becomes even more tempting if there is pulmonary edema, especially if there is a degree of hypoxia. The intubation of these patients should be avoided at all costs. The period of apnea needed during RSI, limitations of mechanical ventilation that result in relative hypoventilation, and ventilator asynchrony can all exacerbate acidemia and cause bad outcomes. Non-invasive oxygenation and non-invasive ventilation are alternatives that should be tried first. If intubated, patients must be put on hemodialysis. The best outcomes for intubation and mechanical ventilation are in those patients that are hypoventilating, in whom a high minute ventilation would be beneficial.
Hemodialysis is the last measure that can be taken in the critically ill patients. The indications for hemodialysis are an ASA level of 50mg/dL in chronic ingestions or 75 mg/dL in acute ingestions, CNS symptoms, pulmonary edema, renal or hepatic failure, severe metabolic abnormalities, rising salicylate levels during treatment, and failure of other therapies.
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