The diagnosis and treatment of poisoning often must proceed rapidly without the results of extensive toxicologic screening. Fortunately, in most cases the correct diagnosis can be made by using carefully collected data from the history, a directed physical examination, and commonly available laboratory tests.

1. History. Although frequently unreliable or incomplete, the history of ingestion may be very useful if carefully obtained.
   1. Ask the patient about all drugs taken, including nonprescription drugs, herbal medicines, dietary supplements, and vitamins. Inquire about occupation, hobbies, recent travel, and cultural practices.
   2. Ask family members, friends, and paramedical personnel about any prescriptions or over-the-counter medications known to be used by the patient or others in the house.
   3. Obtain any available drugs or drug paraphernalia for later testing, but handle them very carefully to avoid poisoning by skin contact or an inadvertent needle stick.
   4. Check with the pharmacy on the label of any medications found with the patient to determine whether other prescription drugs have been obtained there.
   5. Check the patient's cell phone for a better estimate of the time of ingestion, as patients sometimes text their contacts or loved ones just minutes before or after an ingestion.
2. Physical examination
   1. General findings. Perform serial examinations because findings in intoxicated patients invariably change over time. A carefully directed examination may uncover one of the common autonomic syndromes or “toxidromes” (see Table I-18). Note: patients may not manifest a classic toxidrome, especially in the presence of opposing effects from multiple medications or underlying medical conditions.
      1. Alpha-adrenergic syndrome. Hypertension with reflex bradycardia is characteristic. The pupils are usually dilated (eg, phenylpropanolamine and phenylephrine).
      2. Beta-adrenergic syndrome. Beta₂-mediated vasodilation may cause hypotension. Tachycardia is common (eg, albuterol, metaproterenol, theophylline, and caffeine).
      3. Mixed alpha- and beta-adrenergic syndrome (sympathetic or sympathomimetic syndrome). Hypertension is accompanied by tachycardia. The pupils are dilated. The skin is sweaty, although mucous membranes may be dry (eg, cocaine and amphetamines).
      4. Sympatholytic syndrome. Blood pressure and pulse rate are both decreased. (Exceptions: Peripheral alpha receptor antagonists may cause hypotension with reflex tachycardia; alpha₂ agonists may cause peripheral vasoconstriction with transient hypertension.) The pupils are small, often of pinpoint size. Peristalsis is often decreased (eg, centrally acting alpha₂ agonists [clonidine and methyldopa] and phenothiazines).
      5. Nicotinic cholinergic syndrome. Stimulation of nicotinic receptors at autonomic ganglia and neuromuscular junctions activates both parasympathetic and sympathetic systems, with unpredictable or biphasic results. Initial tachycardia may be followed by bradycardia, and muscle fasciculations may be followed by paralysis (eg, nicotine and the depolarizing neuromuscular blocker succinylcholine, which act on nicotinic receptors in skeletal muscle).
      6. Muscarinic cholinergic syndrome. Muscarinic receptors are located at effector organs of the parasympathetic system and in general mediate secretory functions. Stimulation causes bradycardia, miosis, sweating, hyperperistalsis, bronchorrhea, wheezing, excessive salivation, and urinary incontinence (eg, bethanechol).
      7. Mixed cholinergic syndrome. When both nicotinic and muscarinic receptors are stimulated, mixed effects may be seen. The pupils are usually miotic (of pinpoint size). The skin is sweaty, and peristaltic activity is increased. Seizures may occur. Fasciculations are a manifestation of nicotinic stimulation of the neuromuscular junction and may progress to muscle weakness or paralysis (eg, organophosphate and carbamate insecticides and physostigmine).
      8. Anticholinergic (antimuscarinic) syndrome. Tachycardia with mild hypertension is common. The pupils are widely dilated. The skin is flushed, hot, and dry. Peristalsis is decreased, and urinary retention is common. Patients may have myoclonic jerking or choreoathetoid movements. Agitated delirium is common, and hyperthermia may occur (eg, atropine, scopolamine, benztropine, antihistamines, tricyclics and other antidepressants, and some antipsychotics).
   2. Eye findings
      1. Pupil size is affected by a number of drugs that act on the autonomic nervous system. Table I-19 lists common causes of miosis and mydriasis.
      2. Horizontal-gaze nystagmus is common with a variety of drugs and toxins, including barbiturates, ethanol, carbamazepine, phenytoin, and scorpion envenomation. Phencyclidine (PCP) may cause horizontal, vertical, and even rotatory nystagmus.
      3. Hippus or pupillary athetosis refers to rhythmically dilating and contracting pupil size, and can be caused by aconitine, some hallucinogens, or seizure activity.
      4. Cranial neuropathy involving the eyes can indicate a lesion of the brain matter (eg, ischemic stroke), cranial nerves (eg, cerebral edema impinging on cranial nerve VI, causing an abducens palsy), or ocular muscles (eg, botulism presenting with ptosis or disconjugate gaze).
      5. Problems with visual acuity or papilledema fundoscopic testing suggest retinal toxins such as methanol (formic acid) or chloroquine and related antimalarials.
      6. Corneal injury can be caused by irritant or corrosive substances.
      7. Chronic digoxin toxicity can cause xanthopsia (the illusion of seeing yellow halos around objects).
      8. Hallucinations or perceptual illusions can result from recreational substances. Synesthesia (crossed sensory inputs described as “seeing sounds and hearing colors”) is typical of serotonergic hallucinogens such as LSD and DMT. Other visual changes include afterimages, trails, and intense color saturation.
   3. Neuropathy. A variety of drugs and poisons can cause sensory, motor, or cranial neuropathy, usually after chronic repeated exposure (Table I-20). Some agents (eg, arsenic and thallium) can cause neuropathy after a single large exposure.
   4. Abdominal findings. Drugs and toxins (see Table I-18) commonly affect peristalsis and secretory functions of the digestive tract.
      1. Ileus may be caused by mechanical factors such as injury to the gastrointestinal tract with perforation and peritonitis. or mechanical obstruction by a swallowed foreign body.
      2. Abdominal distension and ileus may also be a manifestation of acute bowel infarction, a rare but catastrophic complication that results from prolonged hypotension or mesenteric artery vasospasm (caused, eg, by ergot, cocaine, or amphetamines).
      3. Vomiting, especially with hematemesis, may indicate the ingestion of a corrosive substance.
      4. Diarrhea can result from GI irritation by a variety of toxins, withdrawal from opioids, or cholinergic excess (eg, organophosphate or carbamate poisoning).
      5. Bladder distention due to urinary retention is common in antimuscarinic syndrome and may require Foley catheter placement.
   5. Skin findings
      1. Sweating or the absence of sweating may provide a clue to one of the autonomic syndromes (see Table I-18).
      2. Flushed red skin may be caused by carbon monoxide poisoning, boric acid toxicity, chemical burns from corrosives or hydrocarbons, or anticholinergic agents.
      3. Pale coloration with diaphoresis is frequently caused by acute anemia or sympathomimetic agents. Severe localized pallor should suggest possible arterial vasospasm, such as that caused by ergot or some amphetamines. Jaundice or uremia can also blanch the skin tone.
      4. Cyanosis may indicate hypoxia, sulfhemoglobinemia, or methemoglobinemia.
   6. Odors. A number of toxins may have characteristic odors (Table I-21). However, the odor may be subtle and may be obscured by the smell of vomit or by other ambient odors. In addition, the ability to smell an odor may vary; for example, only about 50% of the general population can smell the “bitter almond” odor of cyanide. Thus, the absence of an odor does not guarantee the absence of the toxin.
   7. Urine.
      1. Color
         1. Red-pink or orange urine may be seen with pyridium, rifampin, or treatment with deferoxamine or hydroxocobalamin.
         2. Violet or blue urine can be caused by methylene blue or methocarbamol. Rarely, purple urine can also be seen in catheterized patients with urinary tract infections (purple urine bag syndrome).
         3. Green urine may be caused by propofol, cimetidine, promethazine and indomethacin.
         4. Brown or black urine can indicate the presence of phenol, myoglobin (eg, rhabdomyolysis), and the plant-based laxative cascara.
         5. Fluorescence under ultraviolet light (Wood lamp) suggests presence of fluorescein, which is found in most antifreeze products. However, other substances in the urine can also be fluorescent, limiting the utility of this finding.
      2. Crystals of calcium oxalate may be seen in the urine of patients with ethylene glycol poisoning (Ethylene Glycol And Other Glycols).
3. Essential clinical laboratory and diagnostic tests. Simple, readily available laboratory and diagnostic tests may provide important clues to the diagnosis of poisoning and may guide the investigation toward specific toxicology testing. When the diagnosis is obvious, broad laboratory testing may not be necessary.
   1. Routine tests. The following tests may be useful for screening of the overdose patient with an uncertain diagnosis. Note: Each test comes with limitations which are important to consider when selecting a diagnostic strategy. Like physical examination findings, laboratory values in poisoned patients are dynamic and serial assessment is often warranted in high risk or critically ill patients.
      1. Serum glucose (rapid bedside device).
      2. ECG.
      3. Serum acetaminophen level.
      4. Electrolytes for determination of the sodium, potassium, bicarbonate, and anion gap. Venous blood gases and lactate to assess acid-base status.
      5. Blood alcohol (ethanol) level.
      6. Measured serum osmolality and calculation of the osmol gap.
      7. Complete blood cell count or hemogram.
      8. Hepatic aminotransferases (AST, ALT) and synthetic hepatic function (eg, bilirubin and coagulation) tests.
      9. Blood urea nitrogen (BUN) and creatinine for evaluation of renal function.
      10. Urinalysis to check for crystalluria, hemoglobinuria, or myoglobinuria.
      11. Pregnancy test (females of childbearing age).
      12. Creatine kinase to check for rhabdomyolysis.
   2. Serum osmolality and osmol gap. Under normal circumstances, the measured serum osmolality is approximately 290 mOsm/L and can be calculated from the results of the sodium, glucose, and blood urea nitrogen (BUN) tests. The difference between the calculated osmolality and the osmolality measured in the laboratory is the osmol gap (Table I-22). Note: Clinical studies suggest that the normal osmol gap may vary from -14 to +10 mOsm/L. Thus, small osmol gaps may be difficult to interpret.
      1. Causes of an elevated osmol gap (see Table I-22)
         1. The osmol gap may be increased in the presence of low-molecular-weight substances such as ethanol, other alcohols, and glycols, any of which can contribute to the measured but not the calculated osmolality. Table I-23 describes how to estimate alcohol and glycol levels by using the osmol gap.
         2. An osmol gap accompanied by, or immediately preceding, a worsening anion gap acidosis should immediately suggest poisoning by methanol or ethylene glycol.
      2. Differential diagnosis
         1. Combined osmol and anion gap elevation may also be seen with severe alcoholic ketoacidosis or diabetic ketoacidosis, owing to the accumulation of unmeasured anions (beta-hydroxybutyrate) and osmotically active substances (acetone, glycerol, and amino acids).
         2. Patients with chronic renal failure who are not undergoing hemodialysis may have an elevated osmol gap owing to the accumulation of low-molecular-weight solutes.
         3. False elevation of the osmol gap may be caused by the use of an inappropriate sample tube (lavender top, ethylenediaminetetraacetic acid [EDTA]; gray top, fluoride-oxalate; blue top, citrate; see Table I-32).
         4. A falsely elevated osmol gap may also occur in patients with severe hyperlipidemia or hyperglobulinemia with resulting pseudohyponatremia.
      3. Pitfalls and limitations of the osmol gap
         1. Measurements of the osmolality, sodium, BUN, and glucose must be done on the same serum specimen; otherwise, the gap may be falsely low or high.
         2. Serum osmolality should be measured using a freezing point-depression osmometer. A falsely normal osmol gap despite the presence of volatile alcohols may result from using a heat-of-vaporization method to measure osmolality because the alcohols will boil off before the serum boiling point is reached.
         3. While an osmol gap >20 suggests the presence of a toxic alcohol, a normal gap does not exclude a toxic alcohol ingestion. This is especially true late in the course of ingestion when the osmotically active parent compound (eg, methanol) has been metabolized to the osmotically inactive corresponding acid (eg, formic acid).
      4. Treatment depends on the cause. If ethylene glycol or methanol poisoning is suspected, antidotal therapy (eg, fomepizole or ethanol) and hemodialysis may be indicated.
   3. Anion gap metabolic acidosis. The normal anion gap of 8-12 mEq/L accounts for unmeasured anions (eg, phosphate, sulfate, and anionic proteins) in the plasma. Metabolic acidosis is usually associated with an elevated anion gap.
      1. Causes of elevated anion gap (Table I-24)
         1. An elevated anion gap acidosis is commonly caused by an accumulation of lactic acid but may also be caused by other unmeasured acid anions, such as formate (eg, methanol poisoning), glycolate or oxalate (eg, ethylene glycol poisoning), beta-hydroxybutyrate (in patients with ketoacidosis), and pyroglutamic acid (5-oxoproline).
         2. In any patient with an elevated anion gap, especially if ketones and lactate are normal, also check the osmol gap; a combination of elevated anion and osmol gaps suggests poisoning by methanol or ethylene glycol. Note: Combined osmol and anion gap elevation may also be seen with severe alcoholic ketoacidosis and diabetic ketoacidosis.
         3. A narrow anion gap may occur with an overdose by bromide or nitrate, both of which can increase the serum chloride level measured by some laboratory instruments. Also, high concentrations of lithium, calcium, or magnesium can narrow the anion gap owing to relative lowering of the serum sodium concentration or the presence of their salts (chloride, carbonate). Finally, severe hypoalbuminemia may reduce the anion gap.
      2. Differential diagnosis. Rule out the following:
         1. Common causes of lactic acidosis such as hypoxia, ischemia, and sepsis.
         2. False depression of the serum bicarbonate and P

            CO

            ₂ measurements, which can occur from incomplete filling of the red-topped Vacutainer blood collection tube.
         3. False depression of the P

            CO

            ₂ and calculated bicarbonate measurements, which can result from excess heparin when arterial blood gases are obtained (0.25 mL of heparin in 2 mL of blood falsely lowers the P

            CO

            ₂ by about 8 mm Hg and bicarbonate by about 5 mEq/L).
         4. False elevation of the serum lactate owing to anaerobic glycolysis in the blood sample tube before separation and testing.
         5. The presence of a second, nongap acidosis (eg, respiratory acidosis due to hypoventilation) can exacerbate the clinical effects of the metabolic acidosis. In a pure metabolic acidosis, the expected P

            CO

            ₂ in a blood gas sample should be 1.5 times the serum bicarbonate level (±6-10); a value outside this range suggests a second acid-base abnormality.
      3. Treatment
         1. Treat the underlying cause of the acidosis.
            1. Treat seizures with anticonvulsants or neuromuscular paralysis.
            2. Treat hypoxia and hypotension if they occur.
            3. Treat methanol or ethylene glycol poisoning with fomepizole (or ethanol) and hemodialysis.
            4. Treat salicylate intoxication (Salicylates) with alkalinization and hemodialysis.
         2. Treatment of the acidemia itself is not generally necessary unless the pH is less than 7-7.1. In fact, mild acidosis may be beneficial by promoting oxygen release to tissues. However, acidemia may be harmful in poisoning by tricyclic antidepressants or salicylates.
            1. In a tricyclic antidepressant overdose (Antidepressants, Tricyclic), acidemia enhances cardiotoxicity. Maintain the serum pH at 7.45-7.5 with boluses of sodium bicarbonate. Note: although some sources recommend continuous bicarbonate infusions for TCA overdose, we prefer to give intermittent 1-2 mEq/kg boluses only as needed for QRS prolongation, which may help avoid excessive alkalemia.
            2. In salicylate intoxication (Salicylates), acidemia enhances salicylate entry into the brain and must be prevented. Alkalinization with a continuous infusion of sodium bicarbonate prevents acidemia and promotes salicylate elimination in the urine. A bolus of sodium bicarbonate prior to rapid sequence intubation may help blunt the effect of transient respiratory acidosis due to neuromuscular paralysis.
   4. Hyperglycemia and hypoglycemia. A variety of drugs and disease states can cause alterations in the serum glucose level (Table I-25). A patient's blood glucose level can be altered by the nutritional state, endogenous insulin levels, and endocrine and liver function and by the presence of various drugs or toxins. If insulin administration is suspected as the cause of the hypoglycemia, obtain serum levels of insulin and C-peptide; a low C-peptide level in the presence of a high insulin level suggests an exogenous source.
      1. Hyperglycemia, especially if severe (>500 mg/dL [28 mmol/L]) or sustained, may result in dehydration and electrolyte imbalance caused by the osmotic effect of excess glucose in the urine; in addition, the shifting of water from the brain into plasma may result in hyperosmolar coma. More commonly, hyperglycemia in poisoning or drug overdose cases is mild and transient. Significant or sustained hyperglycemia should be treated if it is not resolving spontaneously or if the patient is symptomatic.
         1. If the patient has altered mental status, maintain an open airway, assist ventilation if necessary, and administer supplemental oxygen (Airway).
         2. Replace fluid deficits with IV normal saline or another isotonic crystalloid solution. Monitor serum potassium levels, which may fall sharply as the blood glucose corrects, and give supplemental potassium as needed.
         3. Correct acid-base and electrolyte disturbances.
         4. Administer regular insulin, 5-10 U IV initially, followed by infusion of 5-10 U/h, while monitoring the effects on the serum glucose level (children: administer 0.1 U/kg initially and 0.1 U/kg/h (Insulin)).
      2. Hypoglycemia, if severe (serum glucose <40 mg/dL [2.2 mmol/L]) and sustained, can rapidly cause permanent brain injury. For this reason, whenever hypoglycemia is suspected as a cause of seizures, coma, or altered mental status, immediate empiric treatment with dextrose is indicated.
         1. If the patient has altered mental status, maintain an open airway, assist ventilation if necessary, and administer supplemental oxygen (Airway).
         2. Perform rapid bedside blood glucose testing: hypoglycemia is considered a “supplemental vital sign” for patients with altered mental status.
         3. If the blood glucose is low (<60-70 mg/dL [3.3-3.9 mmol/L]) or if bedside testing is not available, administer concentrated 50% dextrose, 50 mL IV (25 g). In children, give 25% dextrose, 2 mL/kg (Glucose (Dextrose)). In small infants, some clinicians use 10% dextrose.
         4. In malnourished or alcoholic patients, also give thiamine, 100 mg IM or IV, to treat or prevent acute Wernicke syndrome. Thiamine can also be given orally if the patient is awake.
         5. For hypoglycemia caused by oral sulfonylurea drug overdose (Diabetic Drugs), consider antidotal therapy with octreotide to prevent recurrence of hypoglycemic episodes.
   5. Hypernatremia and hyponatremia. Sodium disorders occur infrequently in poisoned patients (see Table I-26). More commonly they are associated with underlying disease states. Antidiuretic hormone (ADH) is responsible for concentrating the urine and preventing excess water loss.
      1. Hypernatremia (serum sodium >145 mEq/L) may be caused by excessive sodium intake, excessive free water loss, or impaired renal concentrating ability.
         1. Dehydration with normal kidney function. Excessive sweating, hyperventilation, diarrhea, or osmotic diuresis (eg, hyperglycemia or mannitol administration) may cause disproportional water loss. The urine osmolality is usually greater than 400 mOsm/kg, and the antidiuretic hormone (ADH) function is normal.
         2. Impaired renal concentrating ability. Excess free water is lost in the urine, and urine osmolality is usually less than 250 mOsm/L. This may be caused by hypothalamic dysfunction with reduced ADH production (diabetes insipidus [DI]) or impaired kidney response to ADH (nephrogenic DI). Nephrogenic DI has been associated with long-term lithium therapy as well as acute lithium overdose.
      2. Treatment of hypernatremia. Treatment depends on the cause, but in most cases, the patient is hypovolemic and needs fluids. Caution: Do not reduce the serum sodium level too quickly because osmotic imbalance may cause excessive fluid shift into brain cells, resulting in cerebral edema. The correction should take place over 24-36 hours; the serum sodium should be lowered about 1 mEq/L/h. Note: if the disturbance occurred rapidly (eg, acute salt ingestion), then speedier correction is appropriate.
         1. Hypovolemia. Administer NS (0.9% sodium chloride) to restore volume, then switch to half NS in dextrose (D₅W 0.45% sodium chloride).
         2. Volume overload. Treat with a combination of sodium-free or low-sodium fluid (eg, 5% dextrose or D₅W 0.25% sodium chloride) and a loop diuretic such as furosemide, 0.5-1 mg/kg IV.
         3. Lithium-induced nephrogenic DI. Administer IV fluids (see Item 2.a above) or offer plain water by mouth. Discontinue lithium therapy. Partial improvement may be seen with oral administration of indomethacin, 50 mg 3 times a day, and hydrochlorothiazide, 50-100 mg/d. Desmopressin and amiloride can also be considered. (Note: diuretics may worsen dehydration and further impair renal function.)
      3. Hyponatremia (serum sodium <130 mEq/L) is a common electrolyte abnormality and may result from a variety of mechanisms. Severe hyponatremia (serum sodium <110-120 mEq/L) can result in seizures and altered mental status.
         1. Pseudohyponatremia may result from a shift of water from the extracellular space (eg, hyperglycemia). Plasma sodium falls by about 1.6 mEq/L for each 100-mg/dL (5.6-mmol/L) rise in glucose. Reduced relative blood water volume (eg, hyperlipidemia or hyperproteinemia) may also produce pseudohyponatremia if older (flame emission) detector devices are used, but this is unlikely with current direct measurement electrodes.
         2. Hyponatremia with hypovolemia may be caused by excessive volume loss (sodium and water) that is partially replaced by free water. To maintain intravascular volume, the body secretes ADH, which causes water retention. A urine sodium level of less than 10 mEq/L suggests that the kidney is appropriately attempting to compensate for volume losses. An elevated urine sodium level (>20 mEq/L) implies renal salt wasting, which can be caused by diuretics, adrenal insufficiency, or nephropathy. A syndrome of salt wasting has been reported in some patients with head trauma (“cerebral salt wasting syndrome”).
         3. Hyponatremia with volume overload occurs in conditions such as congestive heart failure and cirrhosis. Although the total body sodium is increased, baroreceptors sense an inadequate circulating volume and stimulate the release of ADH. The urine sodium level is normally less than 10 mEq/L unless the patient has been on diuretics.
         4. Hyponatremia with normal volume occurs in a variety of situations. Measurement of serum and urine osmolalities may help determine the diagnosis.
            1. Syndrome of inappropriate ADH secretion (SIADH). This disorder results in ADH secretion that is independent of volume or osmolality. Causes include malignancies, pulmonary disease, severe head injury, and some drugs (see Table I-26). The serum osmolality is low, but the urine osmolality is inappropriately increased (>300 mOsm/L). The serum BUN is usually low (<10 mg/dL [3.6 mmol/L]).
            2. Psychogenic polydipsia, or compulsive water drinking (generally >10 L/d), causes reduced serum sodium because of the excessive free water intake and because the kidney excretes sodium to maintain euvolemia. The urine sodium level may be elevated, but urine osmolality is appropriately low because the kidney is attempting to excrete the excess water and ADH secretion is suppressed.
            3. Beer potomania may result from chronic daily excessive beer drinking (>4 L/d) without intake of adequate protein and electrolytes, a process which degrades the normal osmolar gradient needed for urinary diluting capacity. It usually occurs in patients with cirrhosis and poor nutritional status.
            4. Other causes of euvolemic hyponatremia include hypothyroidism, postoperative state, idiosyncratic reactions to diuretics (generally thiazides), and in the context of exertion when free water is used to replete loss of fluids and electrolytes.
      4. Treatment of hyponatremia. Treatment depends on the cause, the patient's volume status, and, most importantly, the patient's clinical condition. Caution: Avoid overly rapid correction of the sodium because brain damage (central pontine myelinolysis) may occur if the sodium is increased by more than 25 mEq/L in the first 24 hours, unless the disorder occurred rapidly (eg, acute water ingestion or exertional hyponatremia), in which case speedier correction is appropriate. Obtain frequent measurements of the serum and urine sodium levels and adjust the rate of infusion as needed to increase the serum sodium by no more than 1-1.5 mEq/h. Arrange consultation with a nephrologist as soon as possible. For patients with profound hyponatremia (serum sodium <110 mEq/L) accompanied by coma or seizures, administer hypertonic (3% sodium chloride) saline, 100-200 mL.
         1. Hyponatremia with hypovolemia. Replace lost volume with NS (0.9% sodium chloride). If adrenal insufficiency is suspected, give hydrocortisone, 100 mg every 6-8 hours. Hypertonic saline (3% sodium chloride) is rarely indicated.
         2. Hyponatremia with volume overload. Restrict water (0.5-1 L/d) and treat the underlying condition (eg, congestive heart failure). If diuretics are given, do not allow excessive free water intake. Hypertonic saline is dangerous in these patients; if it is used, also administer furosemide, 0.5-1 mg/kg IV. Consider hemodialysis to reduce volume and restore the sodium level.
         3. Hyponatremia with normal volume. Asymptomatic patients may be treated conservatively with water restriction (0.5-1 L/d). Psychogenic compulsive water drinkers may have to be restrained or separated from all sources of water, including washbasins and toilets. Demeclocycline (a tetracycline antibiotic that can produce nephrogenic DI), 300-600 mg twice a day, can be used to treat mild chronic SIADH; the onset of action may require a week. For patients with coma or seizures, give hypertonic (3%) saline, 100-200 mL, along with furosemide, 0.5-1 mg/kg.
   6. Hyperkalemia and hypokalemia. A variety of drugs and toxins can cause serious alterations in the serum potassium level (Table I-27). Potassium levels are dependent on potassium intake and release (eg, from muscles), diuretic use, proper functioning of the Na/K-ATPase ion exchange pump, serum pH, and beta-adrenergic activity. Changes in serum potassium levels do not always reflect overall body gain or loss but may be caused by intracellular shifts (eg, acidosis drives potassium out of cells, while beta-adrenergic stimulation drives it into cells).
      1. Hyperkalemia (serum potassium >5 mEq/L) produces muscle weakness and interferes with normal cardiac conduction. Peaked T waves and prolonged PR intervals are the earliest signs of cardiotoxicity. Critical hyperkalemia produces widened QRS intervals, AV block, ventricular fibrillation, and cardiac arrest (see Figure I-4).
         1. Hyperkalemia caused by fluoride intoxication is usually accompanied by hypocalcemia.
         2. Digoxin or other cardiac glycoside intoxication associated with hyperkalemia is an indication for administration of digoxin-specific Fab antibodies.
      2. Treatment of hyperkalemia. A potassium level higher than 6 mEq/L is a medical emergency; a level higher than 7 mEq/L is critical.
         1. Monitor the ECG. QRS prolongation indicates critical cardiac poisoning.
         2. Administer 10% calcium chloride, 5-10 mL, or 10% calcium gluconate, 10-20 mL (Calcium), if there are signs of critical cardiac toxicity such as wide QRS complexes, absent P waves, and bradycardia.
         3. Glucose plus insulin promotes intracellular movement of potassium. Give 50% dextrose, 50 mL (25% dextrose, 2 mL/kg in children), plus regular insulin, 0.1 U/kg IV.
         4. Inhaled beta₂-adrenergic agonists such as albuterol also enhance potassium entry into cells and can provide a rapid supplemental method of lowering serum potassium levels.
         5. Hemodialysis rapidly lowers serum potassium levels.
         6. Hyperkalemia due to cardiac glycoside toxicity (see Digoxin and Other Cardiac Glycosides) usually rapidly improves with administration of digoxin-specific antibodies (see Digoxin-Specific Antibodies).
         7. Sodium bicarbonate, 1-2 mEq/kg IV (Bicarbonate, Sodium), may drive potassium into cells and lower the serum level, but this effect takes up to 60 minutes and clinical studies show equivocal results.
         8. Sodium polystyrene sulfonate (SPS; Kayexalate), 0.3-0.6 g/kg orally in 2 mL of 70% sorbitol per kilogram, is commonly recommended as a potassium-binding resin that can enhance enteric elimination over several hours. However, recent evidence suggests that it is not very effective, and colonic necrosis has been reported in patients with ileus, constipation, gastric ulceration, or other high-risk conditions. Use with caution, if at all. Newer potassium-binding agents including sodium cyclosilicate and patiromer are FDA-approved for treatment of nonemergent hyperkalemia. Their utility in acute hyperkalemia has not been evaluated.
      3. Hypokalemia (serum potassium <3.5 mEq/L) may cause muscle weakness, hyporeflexia, and ileus. Rhabdomyolysis may occur. The ECG shows flattened T waves and prominent U waves. In severe hypokalemia, AV block, ventricular dysrhythmias, and cardiac arrest may occur.
         1. With theophylline, caffeine, or beta₂ agonist intoxication, an intracellular shift of potassium may produce a very low serum potassium level with normal total body stores. Patients usually do not have serious symptoms or ECG signs of hypokalemia, and aggressive potassium therapy is not required.
         2. With barium poisoning, profound hypokalemia may lead to respiratory muscle weakness and cardiac and respiratory arrest; therefore, intensive potassium therapy is necessary. Up to 420 mEq has been given in 24 hours.
         3. Hypokalemia resulting from diuretic therapy may contribute to ventricular dysrhythmias, especially those associated with chronic digitalis glycoside poisoning.
      4. Treatment of hypokalemia. Mild hypokalemia (potassium, 3-3.5 mEq/L) is usually not associated with serious symptoms.
         1. Administer potassium chloride orally or IV. See (Isopropyl Alcohol) for recommended doses and infusion rates.
         2. Monitor serum potassium and the ECG for signs of hyperkalemia from excessive potassium therapy.
         3. If hypokalemia is caused by diuretic therapy, malnutrition, or gastrointestinal fluid losses, measure and replace other ions, including sodium, chloride, and especially magnesium (which protects against renal potassium wasting).
   7. Renal failure.Table I-28 lists examples of drugs and toxins causing renal failure. Acute kidney injury may occur by a direct nephrotoxic action of the poison or acute massive tubular precipitation of myoglobin (rhabdomyolysis), hemoglobin (hemolysis), or calcium oxalate crystals (ethylene glycol). Acute kidney injury may also be secondary to shock caused by blood or fluid loss or cardiovascular collapse.
      1. Assessment. Renal failure is characterized by a progressive rise in the serum creatinine and blood urea nitrogen (BUN) levels, usually accompanied by oliguria or anuria.
         1. The serum creatinine concentration usually rises about 1-1.5 mg/dL per day (88-132 micromol/L/d) after total anuric renal failure.
         2. A more abrupt rise should suggest rapid muscle breakdown (rhabdomyolysis), which increases the creatine load and also results in elevated serum CK levels that may interfere with a determination of the serum creatinine level.
         3. Oliguria may be seen before renal failure occurs, especially with hypovolemia, hypotension, or heart failure. In this case, the BUN level is usually elevated out of proportion to the serum creatinine level.
         4. False elevation of the creatinine level can be caused by nitromethane, isopropyl alcohol, and ketoacidosis owing to interference with the usual colorimetric laboratory (Jaffe) method. The BUN remains normal, which may help to distinguish false from real elevation of the creatinine.
      2. Complications. The earliest complication of acute renal failure is hyperkalemia; this may be more pronounced if the cause of the renal failure is rhabdomyolysis or hemolysis, both of which release large amounts of intracellular potassium into the circulation. Later complications include metabolic acidosis, delirium, and coma.
      3. Treatment
         1. Prevent renal failure, if possible, by administering specific treatment (eg, acetylcysteine for acetaminophen overdose [although of uncertain benefit for this complication], British anti-Lewisite [BAL; dimercaprol] chelation for mercury poisoning, and IV fluids for rhabdomyolysis or shock).
         2. Monitor the serum potassium level frequently and treat hyperkalemia if it occurs.
         3. Do not give supplemental potassium, and avoid cathartics or other medications containing magnesium, phosphate, or sodium, which can build up in uremic patients.
         4. Initiate hemodialysis as needed.
   8. Hepatic failure. A variety of drugs and toxins may cause hepatic injury (Table I-29). Mechanisms of toxicity include direct hepatocellular damage (eg, Amanita phalloides and related mushrooms), formation of hepatotoxic intermediates (eg, acetaminophen or carbon tetrachloride), autoimmune hepatitis (eg, halothane), disruption of hepatocyte metabolic pathways (eg, valproic acid), cholestasis (eg, anabolic steroids), and hepatic veno-occlusive disease (eg, pyrrolizidine alkaloids; see “Plants,”). Ischemic injury (from hypotension, hypoxemia, or carbon monoxide poisoning) can also cause acute liver injury.
      1. Assessment. Laboratory and clinical evidence of hepatitis often does not become apparent until 24-36 hours after exposure to the poison. Subsequently, aminotransferase (AST, ALT) levels rise sharply and may fall to normal over the next 3-5 days. If hepatic damage is severe, measurements of hepatic function (eg, bilirubin and prothrombin time) will continue to worsen after 2-3 days, even as aminotransferase levels are returning to normal. Metabolic acidosis, encephalopathy and hypoglycemia usually indicate a poor prognosis.
      2. Complications
         1. Abnormal hepatic function may result in excessive bleeding owing to insufficient production of vitamin K-dependent coagulation factors.
         2. Fulminant hepatic failure often leads to acute kidney injury, respiratory failure, coma, and death, usually within 5-7 days.
      3. Treatment
         1. Prevent hepatic injury, if possible, by administering specific treatment (eg, acetylcysteine for acetaminophen overdose).
         2. Make a thorough inventory of all medications, including prescription and over-the- counter medications, herbal preparations, homeopathic remedies, and dietary supplements. Identify and immediately discontinue potential culprit hepatotoxic xenobiotics. Livertox®, a regularly updated database maintained by the National Institute of Diabetes and Digestive and Kidney Diseases, is an excellent resource for identifying these agents.
         3. Obtain baseline and daily electrolytes, aminotransferase, bilirubin, glucose levels, and prothrombin time. In addition to direct tests of hepatic function, acidosis and renal dysfunction indicate a poor prognosis.
         4. Provide intensive supportive care for hepatic failure and encephalopathy (eg, glucose for hypoglycemia, fresh-frozen plasma or clotting factor concentrates for coagulopathy, or lactulose for encephalopathy).
         5. Extracorporeal liver assist devices have been used to augment hepatic function (“hepatic dialysis”) in experimental studies and small clinical trials. However, these are not widely available, and routine use is not currently recommended.
         6. Liver transplant may be the only effective treatment once massive hepatic necrosis has resulted in severe encephalopathy and metabolic derangements.
4. Toxicology screening¹. To maximize the utility of the toxicology laboratory, it is necessary to understand what the laboratory can and cannot do and how knowledge of the results will affect the patient. Comprehensive blood and urine screening is of little practical value in the initial care of the poisoned patient, mainly because of the delay in obtaining results. However, specific toxicologic analyses and quantitative levels of certain drugs may be extremely helpful. Before ordering any tests, always ask these two questions: (1) How will the result of the test alter the approach to treatment? and (2) Can the result of the test be returned in time to affect therapy positively? Although the cost of testing should not enter into management decisions, some specialty tests may be expensive and more difficult to justify.
   1. Limitations of toxicology screens. Owing to long turnaround time (1-5 days), lack of availability, reliability factors, and the low risk for serious morbidity with supportive clinical management, toxicology screening is estimated to affect management in fewer than 15% of all cases of poisoning or drug overdose.
      1. Although rapid immunoassays for urine drug testing are widely available and inexpensive, and have fast turnaround times, some assays suffer from poor sensitivity for some members of a drug class (eg, benzodiazepines, synthetic opioids), whereas other assays produce false-positive results to structural analogs and drugs that are themselves not part of a targeted drug class (eg, amphetamine screens). In many other cases, there are no immunoassays available at all. Table I-30 lists substances often included in a hospital-based, rapid urine drug screen.
      2. Comprehensive toxicology screens performed by regional reference laboratories may look specifically for 200-300 drugs among more than 10,000 possible drugs or toxins (or 6 million chemicals). Some drugs and chemicals are not typically included in comprehensive screening panels because of rarity of use, difficult or unreliable assay methods, or other reasons (Table I-31). It is important to communicate with the hospital and/or reference laboratory to determine what drugs are detected in the various screening panels offered and what samples (urine, whole blood, serum) are preferred.
         1. Comprehensive screening panels performed by mass spectrometry (GC-MS or LC-MS/MS) have high specificity and sensitivity but results are usually not available in real time. At best, some academic centers can deliver results within the same day. Some drugs that are present in therapeutic amounts may be detected on the screen even though they are causing no clinical symptoms (clinical false positives).
         2. Because many drugs are neither sought nor detected during toxicology screening, a negative result does not always rule out poisoning; the negative predictive value of the screen is only about 70%. In contrast, a positive result has a predictive value of about 90%.
         3. The specificity of toxicologic tests is dependent on the method and the laboratory. The presence of other drugs, drug metabolites, disease states, or incorrect sampling may cause erroneous results (Table I-32).
   2. Adulteration of urine to evade drug detection may be attempted by persons undergoing enforced drug testing. Methods used include ingestion of water or diuretics to dilute the urine, and addition of substances to the urine (eg, acids, baking soda, bleach, metal salts, nitrite salts, glutaraldehyde, or pyridinium chlorochromate) to inactivate, either chemically or biologically, the initial screening immunoassay to produce a negative test. Adulteration is variably successful depending on the agent used and the type of immunoassay. Laboratories that routinely perform urine testing for drug surveillance programs often have methods to test for some of the adulterants as well as assay indicators that suggest possible adulterations.
   3. Uses for toxicology screens
      1. Comprehensive screening of urine and blood should be carried out whenever the diagnosis of brain death is being considered to rule out the presence of common depressant drugs that might result in a temporary and potentially reversible absence of brain activity (quantitative serum levels of detected drugs may need to be sent to a regional reference laboratory). Toxicology screens may be used to confirm clinical impressions during hospitalization and should be inserted in the permanent medicolegal record. This may be important if homicide, assault, or child abuse is suspected.
      2. Selective screens (eg, for “drugs of abuse”) with rapid turnaround times are often used to confirm clinical impressions and may aid in disposition of the patient. Positive results may need to be verified by confirmatory testing with a second method, depending on the circumstances.
   4. Approach to toxicology testing
      1. Communicate clinical suspicions to the laboratory.
      2. Most clinical laboratories have a specimen retention policy ranging from a few days to a week. If it is anticipated that specialized testing may need to be performed at some later date, ask the hospital laboratory to save blood and urine specimens (at refrigerated or frozen condition) beyond their usual retention protocol.
      3. Urine is usually the best sample for broad qualitative screening. Compared with urine, blood testing has a narrow window of detection, depending on the half-life of the drug. When the drug is present in the blood, quantitation may help evaluate impairment of the subject by the drug.
      4. Decide if a specific quantitative blood level may assist in management decisions (eg, use of an antidote or dialysis; Table I-33). Quantitative levels are helpful only if there is a predictable correlation between the serum level and toxic effects.
      5. A regional poison control center (1-800-222-1222) or toxicology consultant may provide assistance in considering certain drug etiologies and in selecting specific tests.
5. Imaging studies may reveal important aspects of toxic exposures.
   1. Radiographs can detect some foreign bodies (either ingested or retained in subcutaneous tissue), ingested tablets, drug-filled condoms or packets, and some ingested or injected liquids (eg, chloral hydrate, arsenic, mercury).
      1. The radiograph is useful only if positive; studies suggest that few tablets are predictably visible (Table I-34), and radiopacity may vary by manufacturer due to choice of excipients (eg, calcium carbonate) or other factors.
      2. Do not attempt to determine the radiopacity of a tablet by placing it directly on the x-ray plate. This often produces a false-positive result because of an air contrast effect.
   2. Ultrasound of soft tissues can detect the depth and spread of subcutaneous edema following high-pressure hydrocarbon injection injuries or cytotoxic snakebites.
   3. Computerized tomography (CT) scans and magnetic resonance imaging (MRI) are increasingly used.
      1. CT and MRI can identify intracranial complications of poisoning, such as basal ganglia infarcts (carbon monoxide; cyanide) or hemorrhage (methanol), cerebral edema, anoxic/ischemic injury, leukoencephalopathy (toluene or vaporized heroin), or gas emboli (concentrated hydrogen peroxide).
      2. Abdominal imaging with CT/MRI has also been used to detect ingested drug packets, pipes, vials, or other paraphernalia, although the sensitivity is uncertain.
      3. CT scans of the neck, chest, and abdomen can be used to evaluate the extent of injury from corrosive chemicals, as an adjunct to endoscopic assessment.