How Do I Diagnose and Manage Patients Admitted to the ICU After Common Poisonings?

Patients who are critically poisoned present significant diagnostic and therapeutic challenges to critical care staff. Unfortunately, there is no universally accepted management algorithm to aid in the evaluation despite the presence of so many harmful agents. The history is often unavailable, and providers must rely on physical examination, knowledge of toxidromes, and laboratory data to guide diagnosis and management.

In this chapter, we review diagnostic strategies using toxidromes and laboratory testing, describe acetaminophen (paracetamol, or N -acetyl- p -aminophenol [APAP]) and salicylate (acetylsalicylic acid [ASA]) toxicity in moderate detail, clarify the appropriate use of N -acetylcysteine (NAC) as an antidote for acetaminophen overdose, review the evidence behind urine alkalinization for salicylate overdose, and present the evidence behind various decontamination strategies.

Diagnosis

Toxidromes

Toxidromes are constellations of signs and symptoms consistent with a specific group of xenobiotics and their unique effects on neuroreceptors ( Table 79-1 ). The benefit of using toxidromes is that the correct management can be started without knowing the specific agent involved. For example, drugs that block acetylcholine at the muscarinic receptors can result in the anticholinergic toxidrome, which presents with tachycardia, dry skin, hypoactive bowel sounds, urinary retention, mydriasis, and in more severe cases, delirium. Regardless if it was caused by antihistamines, antipsychotics, or plants such as Jimsonweed, these symptoms should improve with the administration of physostigmine. The sympathomimetic toxidrome occurs after activation of norepinephrine and dopamine receptors by stimulants such as cocaine or amphetamine. These patients have tachycardia, diaphoresis, mydriasis, and delirium; regardless of the ingested agent, they will improve when treated with benzodiazepines (BZs). The anticholinergic and sympathomimetic toxidromes may initially appear similar; however, anticholinergic patients are “dry as a bone,” whereas sympathomimetic patients are usually diaphoretic. The cholinergic toxidrome is the opposite of the anticholinergic and results from overstimulation of muscarinic and nicotinic receptors. It manifests as diaphoresis, salivation, lacrimation, urination, defecation, and miosis, with bradycardia, bronchospasm, and bronchorrhea being the life-threatening symptoms. Regardless of which organophosphate or carbamate caused these symptoms, atropine is the treatment. The opioid toxidrome results from overstimulation of the mu, kappa, and delta opiate receptors and presents with pinpoint pupils, respiratory depression, and decreased mental status. Antagonists of the opioid receptors, such as naloxone, reverse these symptoms. The sedative/hypnotics toxidrome is similar to that of opioids but has no pupillary changes and significantly less respiratory depression. There is no antidote for most of the causative agents except for flumazenil reversing BZ-related toxicity.

Table 79-1

Toxidromes: Clinical Presentations

Toxidrome	Vital Signs	Signs
Anticholinergic	HR ↑	Bowel sounds ↓ Delirium ^∗ Dry mouth Mydriasis or normal skin—dry, flushed
Sympathomimetic	HR ↑ BP ↑	Agitated Delirium ^∗ Mydriasis Skin—diaphoretic
Opioid	RR ↓ and/or shallow	Bowel sounds ↓ Mental status ↓ Miosis
Sedative-hypnotic	RR normal or ↓ ^†	Mental status ↓
Cholinergic	HR ↓	Bronchoconstriction Bronchorrhea Diaphoresis Lacrimation Miosis Salivation Urination

BP, blood pressure; HR, heart rate; RR, respiratory rate; ↑, increased; ↓, decreased.

∗ If severe.

† If combined with other sedatives.

Correctly identified toxidromes can help guide antidote administration and improve the clinical picture without knowing the exact agent involved. However, poisoned patients often ingest many different agents that stimulate/block receptors that conflict with each other, thus clouding the presenting toxidrome.

Laboratory

Most hospitals offer urine drug screens; however, their routine use has not been shown to alter patient management or outcomes. Interpretation can be difficult because different urine assays vary as to which agents, within a class, will be detected. Thus the false positives and false negatives from the assays will vary from institution to institution. Some general points can be made, though. A “positive” screen does not reflect current intoxication because clinical symptoms are generally gone long before the screen becomes “negative.” For example, the tetrahydrocannabinol screen for marijuana can remain positive for weeks after an acute exposure and months after chronic exposure. BZ assays often yield false-negative results because not all of the BZs are biotransformed to the same detectable metabolite. Amphetamines are often associated with false-positive results because of their structural similarity to many legal medications such as pseudoephedrine.

Quantitative serum levels are available for some medications. Measured levels that most commonly affect patient care in a setting of an ingestion are acetaminophen, salicylate, lithium, digoxin, methanol, and ethylene glycol. Phenytoin, valproic acid, and carbamazepine levels are often ordered to help with therapeutic dose monitoring. In an overdose, though, the presence of an elevated measurement is best used to confirm the drug’s presence but rarely affects management because patients are observed until clinical improvement and not laboratory normalization.

Dangerous Poisonings: Two Important Agents

Most toxic exposures in the United States are nonfatal. According to the 2012 report from the American Association of Poison Control Centers’ National Poison Data System, only 0.1% of the reported exposures resulted in death. However, acetaminophen and acetaminophen-containing products accounted for 8.0% of deaths (206 of the 2576 exposure related fatalities) and salicylates for 2.4% (61 of the 2576). Errors occur in the evaluation and treatment of both of these common exposures. For example, a 2008 Maryland Poison Center study suggested that intravenous (IV) NAC administration errors for acetaminophen poisoning occur in approximately one third of cases and include incorrect doses, incorrect rate, interruption of therapy, and unnecessary administration of NAC. In addition, these agents are at times confused because they are commonly used over-the-counter analgesics. Thus the following section details the treatment of acetaminophen and salicylate overdose.

Acetaminophen

Most acetaminophen (APAP) is glucuronidated and sulfated to inactive, harmless metabolites in the liver ( Fig. 79-1 ); however, approximately 5% to 10% is oxidized by the cytochrome P450 system into the hepatotoxic N -acetyl- p -benzoquinoneimine (NAPQI). NAPQI is detoxified via conjugation with glutathione, which produces a nontoxic species that is renally eliminated. After an APAP overdose, the glutathione supply is rapidly depleted, resulting in free NAPQI and subsequent hepatotoxicity. Hepatitis (as defined by aspartate aminotransferase [AST] > 1000 IU/L) occurs after an ingestion of 150 mg/kg, and higher doses can lead to acute liver failure (ALF).

Because APAP toxicity has no early symptoms, a level is obtained in all cases of possible overdose. NAC is a partial antidote to APAP poisoning and acts to maintain or replenish depleted glutathione reserves in the liver. The Rumack-Matthew nomogram guides the use of NAC in acute (single-exposure) overdoses when the time of ingestion is known. The treatment line is based on a 4-hour half-life starting with a toxic 4-hour serum concentration of 150 μg/mL. This screening tool has a sensitivity of almost 100% when strictly applied. Levels before 4 hours after exposure generally do not guide therapy. Except in the setting of very large overdoses (>80 to 100 tablets) or co-ingestants that slow down gastrointestinal motility, serial APAP levels are unnecessary because of APAP’s predictable absorption and elimination half-life. In cases of massive APAP ingestion, not only is complete absorption delayed but elimination half-life can also be prolonged to as much as 20.3 hours.

A toxic level was traditionally treated with oral NAC for 72 hours (140 mg/kg followed by 70 mg/kg every 4 hours for 17 doses) in the United States. In Europe, Canada, and other territories, IV NAC has been used for decades. Acetadote, a pyrogen-free IV form of NAC, was approved in the United States in 2004. Acetadote is recommended for patients who were seen within 8 to 10 hours of acute ingestion and is administered with a 21-hour protocol: 150 mg/kg of NAC in 200 mL of 5% dextrose in water (D5W) over 1 hour, then 50 mg/kg in 500 mL of D5W over 4 hours, and then 100 mg/kg in 1000 mL of D5W over 16 hours. A recent cost analysis showed that an Acetadote regimen was less expensive than the generic oral NAC because of shortened hospital stay. Both regimens are equally effective when started early ; however, one meta-analysis showed that for treatment started more than 18 hours after ingestion (late presenters), the 72-hour oral NAC formulation was more effective at preventing hepatotoxicity than the IV Acetadote. This difference was attributed to the oral NAC protocol’s larger cumulative dose (1330 mg/kg vs. 300 mg/kg) and longer duration of treatment (72 hours vs. 21 hours). Furthermore, late presenters who had already developed ALF had lower mortality and less progression to grade III/IV encephalopathy when given NAC compared with those who had not. On the basis of these data, many toxicologists advocate giving additional NAC (i.e., Acetadote bag #3: 100 mg/kg in 1000 mL of D5W over 16 hours) in addition to the 21-hour infusion for anyone who has continuously rising AST and for those with ongoing hepatitis (AST > 1000 IU/L). This is true even in situations when the APAP level becomes undetectable because it is its unmeasured metabolite, NAPQI, that is causing the liver injury.

Salicylates

Salicylate (ASA) poisoning is very common because of its availability in many stand-alone and combination products for analgesia and fever and in liniments. The salicylate toxidrome includes vomiting, hyperpnea, diaphoresis, dizziness, and hearing changes such as muffled hearing or tinnitus. Arterial blood gas shows mixed respiratory alkalosis and anion-gap metabolic acidosis. In chronic ingestion, patients often have an altered mental status and mimicking infection, and it is referred to as “pseudosepsis.”

Serum salicylate concentrations are most commonly reported in milligrams per deciliter. Therapeutic levels range from 10 to 30 mg/dL. Toxicity results from tissue distribution and not from the salicylate in the blood; thus serum levels and toxicity do not always correlate. For example, a serum salicylate level could be decreasing because salicylate is either being distributed into tissues (and the patient is becoming clinically sicker) or being eliminated by the kidneys (and the patient is clinically improving). Toxicity is considered to be resolving if (1) serial salicylate levels are no longer toxic (<30 mg/dL) and are decreasing and (2) the patient is clinically improving. It must be emphasized that salicylate evaluation is very different from that of APAP (in which treatment is primarily dictated by laboratory results) because ASA management depends on serial serum levels in conjunction with symptomatology.

Treatment of salicylate toxicity is focused on increased excretion ( Fig. 79-2 ). Urine alkalinization enhances salicylate elimination by “trapping” the ASA ion in the renal tubules and improving its removal. In Prescott’s study, urine alkalinization was achieved by adding three 50-mEq ampules of sodium bicarbonate into 1 L of D5W with 40 mEq of potassium chloride and infusing this mixture at 375 cc/hr (1.5 L total) for 4 hours (isotonic sodium bicarbonate preparations are commercially available in some territories). The mean urine pH in these patients was 8.1 and resulted in a significant increase in urinary salicylate excretion. Forced diuresis was shown to be ineffective at improving elimination. Hypokalemia must be avoided because intercalated cells in the distal tubules secrete hydrogen ions in exchange for potassium, thus preventing urine alkalinization and causing retention of salicylate.