Page 1742 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 124: Toxicology in Adults 1211

for a potentially life-threatening condition. However, the risks and Patients unresponsive to atropine, fluids, calcium, and glucagon
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benefits of flumazenil compared to supportive measures alone are not require vasoactive medications. Historically, isoproterenol was used
clear. Flumazenil may cause severe withdrawal or seizures in dependent for its potent β-agonism, but because of frequent clinical failures of
patients. In an animal model of combined cocaine-diazepam poisoning, isoproterenol in β-blocker toxicity, norepinephrine and dopamine are
flumazenil precipitated seizures and increased mortality. Seizures may currently more frequently used.
also occur in combined cyclic antidepressant-benzodiazepine overdose. In the last decade, the use of hyperinsulinemia-euglycemia (HIE) for
In recent years, its role has increasingly become isolated to cases of β-blocker toxicity has become widespread and is generally recommended
reversal of procedural sedation with a benzodiazepine or in known in patients with hemodynamic compromise from β-blocker toxicity.
isolated benzodiazepine overdose without a history of chronic usage. Although the complete mechanism of insulin’s inotropic effects is still
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Flumazenil is not a recommended component of the “coma cocktail.” 6 being determined, clinical improvement of hypotension has been shown
The recommended initial dose of flumazenil is 0.2 mg (2 mL) IV over in multiple animal models and observational clinical studies. 177,178 The
30 seconds. A further 0.3-mg (3 mL) dose can be given over 30 seconds if usual regimen initiated involves insulin bolus of 1 IU/kg followed by infu-
the desired clinical effect is not seen within 30 seconds. Additional 0.5-mg sion at 1 IU/kg/h. In the euglycemic patient, dextrose (as a 25-g bolus) can
doses can be administered over 30 seconds at 1-minute intervals as needed be given with the initial insulin bolus and then as a continuous infusion
to a total dose of 3 mg. Flumazenil dosed beyond 3 mg generally provides of dextrose 0.5 g/kg/h. This should be accompanied by frequent bedside
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little benefit. Patients should be monitored for resedation. Resedation glucose checks and titration of glucose infusion as needed. Patients should
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usually occurs within 0.5 to 3.0 hours after the first flumazenil dose. In be monitored for hypokalemia, although as whole-body potassium is
some cases, repeat doses of flumazenil or a continuous infusion (0.1- likely normal despite low measured serum levels, potassium supplementa-
0.5 mg/h) is necessary. Hepatic dysfunction changes the pharmacoki- tion is generally not recommended unless levels fall below 2.5 mEq/dL.
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netic profile of flumazenil, requiring downward adjustment in dosage. 165 Animal studies and case reports have begun to emerge on the use of
Naloxone may partially reverse the antianxiety effects of benzodiaze- intravenous lipid emulsion (ILE) therapy in multiple severe toxicities,
pines, but it does not significantly alter motor or respiratory effects. 166,167 including those associated with β-blockers. Initially gaining popularity
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■ β-BLOCKERS in anesthesia literature for reversal of cardiopulmonary arrest associ-
ated with local anesthetic toxicity, recent case reports and studies have
In the 2008 Annual Report of the AAPCC, cardiovascular medica- described similar results in multiple other overdoses: atenolol, pro-
tions as a group were the tenth most common exposure reported but pranolol, verapamil, lamotrigine, tricyclic antidepressants, sertraline,
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accounted for the fourth most number of deaths. In a large retrospec- and quetiapine. The mechanism of action of ILE in poisoning
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tive review of 52,156 cases of β-blocker overdose, there were 164 deaths. is thought to be threefold: (1) acting as a “lipid sink” for free drug,
Propranolol was responsible for the greatest number of toxic exposures (2) improving mitochondrial fatty acid transport in anesthetic toxicity,
(44%) and implicated as the primary cause of death in a disproportion- and (3) increasing cardiac myocyte intracellular calcium concentra-
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ately higher percentage of fatalities (71%). 168 tion leading to a direct inotropic effect. Most current human reports
Clinical features of β-blocker overdose depend on the drug type, describe using ILE in either cardiopulmonary arrest or in severe hemo-
amount and timing of overdose, coingestions, and comorbidities. The dynamic instability despite aggressive therapy (with IV fluids, atropine,
diagnosis is usually established on clinical grounds; blood levels are glucagon, calcium, vasopressors, cardiac pacing, and high-dose insulin)
available but do not correlate well with toxicity. Risk factors for cardio- with published case reports describing rapid improvement of hemo-
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vascular morbidity include coingestion of another cardioactive drug and dynamic status. Although not yet specifically studied, the protocol
a β-blocker with myocardial membrane–stabilizing activity (acebutolol, described by the Association of Anaesthetists of Great Britain & Ireland
betaxolol, pindolol, or propranolol). Most patients develop β-blocker is as follows: (1) IV bolus of lipid emulsion 20% 1.5 mL/kg over 1 min-
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toxicity within 4 hours of ingestion. Asymptomatic patients with a ute; (2) IV infusion of lipid emulsion 20% at 15 mL/kg/h; (3) repeat
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normal electrocardiogram after 6 hours generally do not require ICU bolus dose at 5 minute intervals × 2 as needed for pulselessness or other
monitoring. 171 worsening of hemodynamic status; (4) after 5 minutes if hemodynamic
status not improved or worsening, increase infusion to 30 mL/kg/h.
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Cardiovascular complications of β-blockers include hypotension, bra-
edema. Other clinical manifestations of overdose are bronchospasm, ■ CALCIUM-CHANNEL BLOCKERS
dycardia, atrioventricular block, congestive heart failure, and pulmonary
hypoglycemia, hyperkalemia, lethargy, stupor, coma, and seizures. The Calcium-channel blockers (CCBs) selectively inhibit the movement of
risk of seizure is highest with propranolol, particularly when the QRS calcium ions through the membrane of cardiac and vascular smooth
complex is >100 ms. 172 muscle during the slow inward phase of excitation-contraction. These
Initial stabilization of patients with β-blocker toxicity includes fluid agents have varying degrees of cardiovascular effects. Verapamil is a
resuscitation (if there are no clear signs of fluid overload) and atropine significant negative inotrope; nifedipine has significant vasodilatory
to correct hypotension and bradycardia, although these measures may effects. Verapamil and diltiazem both depress the sinus node and slow
be inadequate in significant overdose. Activated charcoal should be con- conduction through the atrioventricular node.
sidered within 1 to 2 hours of ingestion in patients with normal mental The most common cardiovascular effect of CCB overdose is hypo-
status and relative hemodynamic stability. tension, which generally occurs within 6 hours (except with sustained-
Calcium has been used in the management of β-blocker toxicity for release preparations, in which toxicity may not be evident for 12 hours).
its ability to reverse negative inotropy caused by β-blockers, although Conduction abnormalities are worsened with concurrent β-blocker
it does not reliably improve bradycardia or atrioventricular block in ingestion and existing cardiovascular disease. Nausea, vomiting,
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experimental models. 173,174 Glucagon has also been used in β-blocker hyperglycemia, confusion, lethargy, and coma have all been reported.
toxicity because of its positive inotropic and chronotropic effects medi- Gastric lavage may be useful for up to 8 hours after ingestion of a
ated through adenyl cyclase, increasing cAMP and intracellular calcium sustained-release preparation. Whole-bowel irrigation has similarly
influx. Improvements in heart rate and blood pressure occur quickly been used for sustained-release preparations but should only be used
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and may preclude the need for high-dose catecholamine infusion. in patients who are hemodynamically stable with normal mental
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Glucagon is given in boluses of 5 to 10 mg IV over 1 minute until a status. 185,186 Multidose AC and hemodialysis are not indicated.
response is seen, followed by an infusion of the amount required for the Hypotension is treated first with fluids and vasopressors. For refrac-
initial bolus dosed at an hourly rate. For example, if a patient required a tory hypotension, calcium chloride infusions (0.2 mL/kg of 10% solution
10 mg IV initial bolus to affect heart rate, the infusion should be started over 5-10 minutes) are recommended. Additional calcium infusions (by
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at 10 mg/h. 177 bolus or constant infusion) are warranted in patients who demonstrate

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