Page 1746 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 124: Toxicology in Adults 1215

than 30%). Conversion of 25% to 30% of hemoglobin to methemoglo- and mucous membranes, lethargy, delirium, coma, tachycardia, ileus,
bin effectively treats cyanide poisoning, although in usual practice, myoclonus, and urinary retention are manifestations of anticholinergic
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methemoglobin levels generally remain less than 20%. Induction of toxicity. These symptoms are described by the common mnemonic:
methemoglobinemia has several disadvantages, including the reduction “blind as a bat, hot as a hare, dry as a bone, red as a beet, mad as a hatter.”
of oxygen transport by hemoglobin (which may be further aggravated Cardiovascular effects consist of sinus tachycardia with prolongation
by concurrent carboxyhemoglobinemia if there is concurrent carbon of the QRS, QTc, and PR intervals. Occasionally, sinus tachycardia with
monoxide poisoning) and the risk of hemolysis in glucose-6-phosphate QRS prolongation is difficult to distinguish from ventricular tachycar-
dehydrogenase (G6PD)–deficient patients. In one study evaluating dia. Torsades de pointes is rare. Various forms of atrioventricular block
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serial cyanide, methemoglobin, and carbon monoxide levels in seven may accompany cyclic antidepressant overdose. Right bundle-branch
critically ill smoke inhalation patients receiving sodium nitrite, peak block is common.
measured methemoglobin levels did not occur until a mean of 50 minutes A QRS interval longer than 0.10 second reliably predicts serious
following sodium nitrite administration. The total oxygen-carrying intoxication (except in cases of amoxapine overdose) requiring moni-
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capacity reduced by the combination of carboxyhemoglobin and methe- toring until resolution. QRS duration <0.1 second is rarely associated
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moglobin was never more than 21%. Methylene blue should be avoided with arrhythmias or seizures. Patients with QRS >0.10 second are at
to treat methemoglobinemia because it releases free cyanide. risk for seizures and arrhythmias. In another trial, the height of the R
Sodium thiosulfate is safe and effective in cyanide poisoning. It acts as a wave in ECG lead aVR (greater than 3 mm) as well as the ratio of S/R aVR
sulfur donor to rhodanese and other sulfurtransferases, thereby enhanc- (greater than 0.7) were found to be better predictors of seizure and/or
ing conversion of cyanide to thiocyanate to be excreted in the urine. 262,263 arrhythmias than a QRS duration greater than 100 ms. 270
The dose is 12.5 g IV (50 mL of a 25% solution) over 10 minutes. Hypotension is common, although hypertension also occurs. It results
Half this dose may be repeated in 2 hours for persistent toxicity. from α-adrenergic blockade causing venodilation as well as decreased
Coadministration of thiosulfate with nitroprusside (in a ratio of 1:10 myocardial contractility. In severe cases, hypotension may be refractory
thiosulfate to nitroprusside) effectively eliminates the possibility of to fluid administration and vasopressors and associated with pulmonary
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cyanide intoxication without altering the efficacy of nitroprusside. edema.
Treatment with sodium thiosulfate can cause thiocyanate toxicity, par- Seizures are common in cyclic antidepressant overdose. They may
ticularly in the setting of renal insufficiency. Fortunately, thiocyanate is be short-lived and self-limited or prolonged and refractory. Neurologic
readily dialyzable. deterioration may be abrupt and unpredictable. A “downward spiral”
Hydroxycobalamin (vitamin B a; marketed as Cyanokit) is a cyanide occurs when seizures or arrhythmias cause metabolic acidosis, which
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antidote capable of reducing red blood cell and plasma cyanide concen- increases the fraction of free drug and enhances toxicity.
trations by binding to cyanide, which is then excreted in the urine as The diagnosis of cyclic antidepressant overdose depends on a history of
cyanocobalamin. Although occasionally causing transient hypertension, ingestion or a high index of suspicion and compatible clinical features, and
bradycardia, and red discoloration of skin and urine, hydroxycobala- it should be considered in all altered patients with QRS prolongation and/
min has been found to be safe and effective in cyanide toxicity. No or characteristic aVR ECG changes. Urine toxicology for tricyclic antide-
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prospective randomized human trials have been performed to compare pressants is of little benefit. Quantitative serum levels aid in the diagnosis
hydroxycobalamin to traditional cyanide antidote kits (sodium/amyl but are generally not available quickly enough to alter initial management.
nitrite with sodium thiosulfate), although animal studies have sug- Treatment of cyclic antidepressant overdose starts with identifying
gested improved mean arterial pressure in swine treated with hydroxy- and treating life-threatening problems. Sodium bicarbonate (1-2 mEq/kg
cobalamin versus sodium nitrite. Hydroxycobalamin, because of its IV bolus) is indicated if there is widening of the QRS interval. Boluses
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red color, is known to interfere with several chemistry methodologies of sodium bicarbonate are thought to be effective by two mechanisms:
affecting measurement of carbon monoxide oximetry, aspartate ami- sodium load to overcome the effective cardiac sodium channel blockade
notransferase, total bilirubin, creatinine, phosphorus, and glucose. As as well as serum alkalinization. In the case of cyclic antidepressant over-
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with thiosulfate, coadministration of hydroxycobalamin (25 mg/h IV) dose, sodium bicarbonate has not been shown to be effective in enhancing
with nitroprusside may protect against nitroprusside-induced cyanide urinary elimination of the drug. Sodium bicarbonate should be continued
toxicity. The currently recommended dose of hydroxycobalamin in until there is narrowing of the QRS interval, hypernatremia occurs, or
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adult acute cyanide poisoning is 5 g IV, which may be repeated based on serum pH exceeds 7.5 to 7.55. In intubated patients, hyperventilation
clinical response. If hydroxycobalamin is available, it is used in place can assist in achieving alkalemia concurrently with sodium bicarbonate.
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of nitrites and in conjunction with sodium thiosulfate. The electrocardiogram (ECG) should be followed closely in all cases with
Additional treatment strategies include removal and isolation of all abnormal ECGs for 48 to 72 hours. In general, patients should remain
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contaminated clothing. Health care workers should avoid contact with in an ICU for 12 hours after discontinuation of all therapy and they should
cyanide-containing solutions and vapors. Gastric emptying is recom- be asymptomatic with a normal ECG and pH before transfer. 272
mended for acute ingestions, followed by AC. There is no role for hemo- Lidocaine is the drug of choice when ventricular arrhythmias
dialysis or hemoperfusion except to clear high levels of thiocyanate. are refractory to sodium bicarbonate. Class 1a antiarrhythmics
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(eg, procainamide) are contraindicated in cyclic antidepressant overdose
■ CYCLIC ANTIDEPRESSANTS because of added cardiac toxicity. Physostigmine should not be used in
cyclic antidepressant overdose because of possible worsening of cardiac
Tricyclic antidepressants include amitriptyline, desipramine, doxepin, imip- conduction disturbances and its association with death. Flumazenil
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ramine, nortriptyline, protriptyline, and amoxapine. In overdose, these should be avoided because of the risk of precipitating seizures. 274,275
drugs primarily affect the central nervous and cardiovascular systems. Hypotension refractory to sodium bicarbonate should be treated with
Lesser effects are seen in the gastrointestinal tract. Central nervous system vasopressors. A pulmonary artery catheter rarely helps direct therapy
toxicity results from anticholinergic effects and inhibition of neural reuptake and may be arrhythmogenic. Norepinephrine and phenylephrine are
of norepinephrine or serotonin. Cardiovascular manifestations stem from the preferred vasopressors because cyclic antidepressants deplete pre-
anticholinergic effects, inhibition of neural uptake of norepinephrine or synaptic catecholamine stores, limiting the effectiveness of dopamine.
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serotonin, peripheral α-adrenergic blockade, and membrane depressant Dopamine and other vasopressors may cause an exaggerated vasopres-
effects specifically involving the sodium channel. Most patients develop sor response in the presence of cyclic antidepressants because of inhibi-
symptoms within the first 6 hours after ingestion or not at all. tion of catecholamine reuptake. An enhanced hypertensive response to
Clinical presentation is divided into anticholinergic effects, cardio- phenylephrine can also be seen in anticholinergic overdose because anti-
vascular effects, and seizures. Mydriasis, blurred vision, fever, dry skin cholinergics interfere with phenylephrine-induced reflex bradycardia.

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