Analgesics and Antidepressants

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Chapter 79 Analgesics and Antidepressants

Aaron B. Skolnik, MD , Susan R. Wilcox, MD

1 What are the signs and symptoms of salicylate poisoning?

Supratherapeutic levels of salicylate produce characteristic tinnitus. Salicylate poisoning induces a central nervous system (CNS)–mediated respiratory alkalosis, while producing a metabolic acidosis. Aspirin in particular is highly irritating to the gastrointestinal tract, and patients may present with nausea, vomiting, abdominal pain, or hematemesis. Severe poisoning can induce hypoglycemia and hyperthermia due to uncoupling of oxidative phosphorylation and may also cause acute respiratory distress syndrome. Aspirin significantly inhibits platelet function, and any salicylate-containing product can inhibit vitamin K–dependent clotting factors when taken in overdose. The most serious poisonings involve the CNS and may present with confusion, agitation, delirium, hallucinosis, seizures, coma, or death.

2 When patients die of salicylate poisoning, of what do they usually die?

Usually, they die of cerebral edema or refractory shock with terminal arrhythmias. Their shock, in turn, is often related to severe and refractory acidemia.

3 What constitutes a toxic dose of aspirin?

Acute ingestion of greater than 150 mg/kg of aspirin or equivalent is sufficient to produce toxicity that may include gastrointestinal symptoms, metabolic disturbances, tinnitus, and tachypnea and/or hyperpnea. Acute ingestion of greater than 300 mg/kg of aspirin may be lethal. Be aware that chronic salicylate toxicity may also develop in elderly patients, dehydrated patients, or those taking carbonic anhydrase inhibitors. This can happen even at stable therapeutic dosing depending on the patient’s underlying health status and salicylate clearance.

4 What are the initial steps in treating salicylate poisoning?

image First, delay and prevent absorption of salicylate. Early initial management of an acute ingestion should include administration of activated charcoal, when possible. Multiple dose activated charcoal may also be considered.

image Patients should also be resuscitated.

image Patients with moderate or severe poisoning are typically volume depleted, and intravenous fluids should be administered via bolus.

image It is important to remember that salicylate-poisoned patients have a very high minute ventilation, both from primary respiratory alkalosis and to compensate for metabolic acidosis. Physicians must be especially cautious in administering sedation or initiating mechanical ventilation so as not to worsen acidosis.

5 What is the role of bicarbonate in the treatment of salicylate poisoning?

Alkalinization of serum is important in limiting the distribution of salicylate into tissues, especially the CNS. The ensuing urinary alkalinization traps salicylate in its ionized form in the urine and enhances renal clearance. Sodium bicarbonate solutions (typically dextrose 5% with 150 mEq/L sodium bicarbonate) should be infused to a goal serum pH of 7.5 to 7.55. Administration of intravenous bicarbonate will also help to alkalinize the urine, with a goal urinary pH of 8. To maintain alkaluria, potassium must also be replaced. Often, 40-50 mEq/L of potassium chloride is added to sodium bicarbonate infusions to maintain normokalemia.

6 What laboratory values are important in salicylate toxicity?

To guide therapy, arterial pH, serum electrolytes, and urinary pH must be measured frequently and high urine output maintained. As salicylate’s absorption from the gastrointestinal tract can be erratic, salicylate levels must also be checked serially, as often as every 1 to 2 hours in the most severely poisoned patients.

7 What are the indications for hemodialysis in salicylate poisoning?

Patients with renal failure, hemodynamic instability, any sign of CNS toxicity, or rising serum salicylate levels despite maximal medical therapy should undergo hemodialysis. Most patients with any salicylate level more than 100 mg/dL will require hemodialysis at some point in their treatment. Hemodialysis should be also considered for those with salicylate levels greater than 80 mg/dL on the basis of their clinical status. Failure to initiate hemodialysis promptly for neurotoxic patients is a common error in management, and salicylate-poisoned patients can very rapidly decompensate.

8 What are the signs and symptoms of acetaminophen poisoning?

The challenge of recognizing and treating acetaminophen toxicity is that patients are often asymptomatic after acute acetaminophen ingestion. Nausea, vomiting, anorexia, and/or lethargy may occur within hours of ingestion. Very rarely, massive overdose can cause altered mental status and metabolic acidosis within 6 hours of an overdose. Twenty-four to 48 hours after overdose, hepatic injury with transaminitis may develop or even acute or hyperacute liver failure with accompanying hyperbilirubinemia, jaundice, coagulopathy, and encephalopathy. Acute renal failure, which is probably multifactorial in origin, may also occur. Acetaminophen toxicity should be considered in any patient with unexplained liver failure.

9 What is the mechanism of acetaminophen-induced hepatotoxicity?

Acetaminophen’s hepatotoxicity is due to a reactive metabolite called N-acetyl-p-benzoquinone imine (NAPQI). Under therapeutic dosing conditions, most acetaminophen is metabolized in the liver by glucuronidation and sulfation. A tiny amount is excreted unchanged in the urine, and about 4% is metabolized by the cytochrome system (mostly cytochrome P 2E1) into NAPQI. NAPQI is then safely detoxified by the antioxidant effects of hepatic glutathione. However, under overdose conditions, hepatic glutathione stores become depleted, allowing NAPQI to bind to and cause death of hepatocytes.

10 How is the Rumack-Matthew acetaminophen treatment nomogram used?

The Rumack-Matthew treatment nomogram is used to identify patients who have taken a single, acute acetaminophen overdose and who are at risk for hepatotoxicity and require treatment. To use the nomogram, the time of ingestion must be known and a serum acetaminophen level must be drawn at a known time at least 4 hours after ingestion. The time after ingestion is plotted on the x-axis and the acetaminophen level on the y-axis. If the intersection point of these two values falls above the treatment line, the patient is treated with N-acetylcysteine (NAC). In the United States, this treatment line is labeled “possible hepatic toxicity” and corresponds with a 4-hour postingestion acetaminophen level of 150 mcg/mL (Fig. 79-1).

image

Figure 79-1 The Rumack-Matthew nomogram identifies patients with a single ingestion of acetaminophen at risk for hepatotoxicity.

(From Heard KJ: Acetylcysteine for acetaminophen poisoning. N Engl J Med 359:285–292, 2008.)

11 How does NAC work?

NAC works by replenishing hepatic glutathione stores and acting as a glutathione substitute, allowing the detoxification of NAPQI. This prevents the resulting NAPQI-induced hepatocyte damage and death. It also increases sulfation of acetaminophen, thereby reducing NAPQI formation.

12 Which is better: intravenous or oral NAC?

Two common regimens exist for treatment and prevention of acetaminophen-induced hepatotoxicity, a 72-hour regimen of oral NAC and a 20-hour regimen of intravenous NAC. On the basis of the literature at the time of this writing, both regimens seem to have good safety profiles for patients, though more anaphylactoid reactions occur when NAC is administered intravenously and more gastrointestinal intolerance when administered orally (NAC smells like rotten eggs). No good, prospective data at this time suggest that either IV or oral NAC is superior in preventing clinically significant hepatotoxicity (i.e., that resulting in liver failure or need for transplantation). Intravenous NAC has the advantage of parenteral administration in patients unable to take or tolerate oral NAC and necessitates a shorter hospital stay. Many toxicologists favor a patient-tailored approach, wherein one of the above protocols is initiated and the final duration of NAC therapy is based on the patient’s laboratory values and clinical course.

13 What are the receptor effects and clinical effects of tricyclic antidepressant (TCA) poisoning?

TCAs have seven pharmacologic effects. Understanding these effects is helpful in remembering the associated clinical syndrome of TCA toxicity (Table 79-1).

Table 79-1 Pharmacologic Effects of Tricyclic Antidepressants

Mechanism Effect
Presynaptic biogenic amine reuptake inhibition (norepinephrine and serotonin) Therapeutic antidepressant effect
Early sympathomimesis
Myoclonus
Hyperreflexia
Fast sodium channel influx blockade QRS duration prolonged
PR interval prolonged
Right axis deviation
Bundle branch blockade
Ventricular dysrhythmias
Negative inotropy
Potassium channel efflux blockade QTc prolongation
Muscarinic acetylcholine receptor blockade Tachycardia
Mydriasis
Decreased sweating
Hyperthermia
Flushing
Ileus
Urinary retention
Histaminic receptor blockade Sedation
Alpha receptor blockade Sedation
Orthostatic hypotension
Miosis
Reflex tachycardia
GABA-A receptor blockade Seizures
Status epilepticus

GABA-A, γ-Aminobutyric acid-A.

14 What value is the electrocardiogram in patients with TCA poisoning?

The electrocardiogram is the best early screen for TCA toxicity. Electrocardiographic findings usually manifest within the first few hours of poisoning and allow this potentially fatal diagnosis to be made early. The combination of the following classic electrocardiographic findings in a patient with an unknown ingestion strongly suggests TCA poisoning. These findings include the following:

image Sinus tachycardia

image PR prolongation

image Widened QRS complex (greater than 100 milliseconds)

image QTc prolongation

image Terminal R complex in aVR greater than 3 mm in height

In addition, electrocardiographic features are predictive of the clinical course and guide treatment in severe toxicity. The risk of seizures increases if the QRS duration is greater than 100 milliseconds, and a terminal R wave greater than 3 mm in aVR predicts an increased risk of both seizures and ventricular dysrhythmias. The presence of either of these findings warrants immediate treatment.

15 How is cardiovascular toxicity of TCAs treated?

Cardiovascular toxicity of TCAs is treated first with sodium bicarbonate therapy, titrating initial bolus therapy to resolution of QRS prolongation and following this with continuous infusion of bicarbonate solution to alkalinize the serum and provide a loading dose of sodium ions. If the patient continues to have QRS prolongation or significant right axis deviation, despite alkalemia to pH of 7.55, hypertonic saline solution can also be administered. Lidocaine is the historical second-line agent in treating dysrhythmias, but the physician must be aware that lidocaine is also a sodium channel blocker and administration could potentiate seizures. Synchronous cardioversion should be used in patients with TCA overdose on the basis of current advanced cardiac life support guidelines when indicated. Torsades de pointes can be treated with magnesium sulfate infusion. Despite the QTc prolongation associated with TCA use, the tachycardia due to the antimuscarinic effects of TCAs often limits the likelihood of “R-on-T” phenomena. Finally, in recent years, lipid emulsion rescue has emerged as an antidotal treatment in life-threatening poisoning by lipophilic drugs. All TCAs are highly lipophilic, given their therapeutic targets in the CNS, and animal and human data suggest that TCAs and related compounds respond well to lipid rescue. Patients with known or suspected TCA cardiotoxicity and hemodynamic instability or malignant dysrhythmias are candidates for lipid emulsion therapy, discussed in more detail in Chapter 81 on cardiovascular drug toxicity.

Key Points Analgesics and Antidepressantsimage

1. Patients with salicylate toxicity should start alkalinization therapy and have serum salicylate levels checked every 1 to 2 hours.

2. Hemodialysis should be initiated promptly in any patient with salicylate levels over 100 mg/dL or those with levels greater than 80 mg/dL with significant clinical deterioration or neurotoxicity.

3. Acetaminophen levels may be plotted on the Rumack-Matthew nomogram only if the patient has had a single, acute ingestion of acetaminophen at a known time at least 4 hours before presentation.

4. Any suspected or confirmed acetaminophen-toxic patient should immediately start receiving NAC, by either the oral or IV route.

5. Sodium bicarbonate is the treatment of choice to prevent seizures and arrhythmias in TCA overdose and should be administered as boluses until the QRS is <100 milliseconds.

Bibliography

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