Antidote Use in the Critically Ill Poisoned Patient - Fasterweb.es

23 Pages·2006·0.15 MB·English

ANALYTIC REVIEWS
Antidote Use in the Critically Ill
Poisoned Patient
David P. Betten, MD*
Rais B. Vohra, MD†
Matthew D. Cook, DO†
Michael J. Matteucci, MD†‡
Richard F. Clark, MD†
of these treatments have long since fallen out of
The proper use of antidotes in the intensive care setting
favor because they were found to offer little or no
when combined with appropriate general supportive care
benefit and in many cases produce significant detri-
may reduce the morbidity and mortality associated with
severe poisonings. The more commonly used antidotes mental effects. Strychnine, cocaine, and other stim-
that may be encountered in the intensive care unit ulants, for example, were commonly used in the
(N-acetylcysteine, ethanol, fomepizole, physostigmine, 1920s and 1930s for barbiturate overdoses. Their
naloxone, flumazenil, sodium bicarbonate, octreotide,
inherent toxicity and the low mortality rate associ-
pyridoxine, cyanide antidote kit, pralidoxime, atropine,
ated with barbiturate poisonings treated with sup-
digoxin immune Fab, glucagon, calcium gluconate and
chloride, deferoxamine, phytonadione, botulism anti- portive care alone led to their eventual dismissal [1].
toxin, methylene blue, and Crotaline snake antivenom) Antidotes commonly used today, when adminis-
are reviewed. Proper indications for their use and knowl- tered in conjunction with aggressive supportive
edge of the possible adverse effects accompanying antido-
care, are often able to decrease the severity and
tal therapy will allow the physician to appropriately
duration of symptoms while possessing safety pro-
manage the severely poisoned patient.
files more benign than their predecessors. In certain
Key words: antidote, poisoning, overdose circumstances, when used promptly and appropri-
ately, their use may be life saving.
The infrequent presentation of individuals
The use of antidotes for poisonings has been requiring particular antidotes and the relatively high
explored for thousands of years. The vast majority cost of antidotes has resulted in many hospitals car-
rying inadequate quantities of some of the more
From *Department of Emergency Medicine, Sparrow Health commonly used antidotes [2,3]. Antidote stocking
System, Michigan State University College of Human Medicine, guidelines were recently established by a multidis-
Lansing, Michigan, †University of California, San Diego, California
Poison Control System, San Diego, California, and ‡Department of ciplinary panel of 12 health care professionals.
Sixteen antidotes were unanimously identified by
Emergency Medicine, Naval Medical Center, San Diego, California.
the consensus panel for stocking (Table 1) [4].
Received Sep 30, 2005, and in revised form Feb 24, 2006.
Hospitals not possessing these antidotes should at
Accepted for publication Mar 1, 2006.
the minimum have pre-identified neighboring
Address correspondence to David P. Betten, MD, Department health care centers that will readily be able to trans-
of Emergency Medicine, Sparrow Health System, Michigan State
port these antidotes on an emergency basis.
University College of Human Medicine, 1215 E. Michigan Ave,
The following is a brief review of some of the
Lansing, MI 48912-1811, or e-mail: [email protected].
more commonly used antidotes that may be used in
Betten DP, Vohra RB, Cook MD, Matteucci MJ, Clark RF. Antidote
the intensive care setting. Given the complexity of
use in the critically ill poisoned patient. J Intensive Care Med.
management of severely poisoned patients and
2006;21:255-277.
subtleties in the use of many antidotes, further con-
This review was co-written by LCDR Michael J. Matteucci, MC,
sultation with a medical toxicologist or poison cen-
USN, while a Fellow at UCSD Medical Center training in Medical
ter (national poison center hot line: 1-800-222-1222)
Toxicology. The views expressed in the article are those of the
authors and do not reflect the official policy or position of the should be considered. The management of acute
Department of the Navy, Department of Defense, nor the US and chronic heavy metal poisonings (arsenic, lead,
Government. mercury, etc) is not addressed, and the reader is
DOI: 10.1177/0885066606290386 referred to several excellent reviews pertaining to
Copyright © 2006 Sage Publications 255
Betten et al
Table 1. Consensus Stocking Guidelines of 20 Commonly Encountered Antidotes for Hospitals That Accept
Emergency Admissions as Determined by an Expert Multidisciplinary Panel [4]
Consensus Not Reached Not Recommended
Recommended for Stocking for Routine Stocking for Routine Stocking
N-acetylcysteine Flumazenil Black widow antivenin
Crotalid snake antivenin Physostigmine Ethylenediamine tetraacetic acid
Calcium gluconate/chloride
Sodium bicarbonate
Cyanide antidote kit
Deferoxamine
Digoxin immune Fab
Dimercaprol
Atropine
Ethanol
Fomepizole
Glucagon
Methylene blue
Naloxone
Pralidoxime
Pyridoxine
appropriate indications for treatment and methods sulfate that promotes acetaminophen metabolism
of administration of common chelation agents [5-9]. through the nontoxic sulfation pathway. (2) NAC
directly converts NAPQI to nontoxic cysteine and
mercaptate conjugates. (3) NAC reduces NAPQI back
to acetaminophen, where it may be further elimi-
Acetaminophen Poisoning
nated by other nontoxic routes. In the setting of pro-
gressive hepatic failure, NAC may offer further
Acetaminophen misuse is responsible for more hos-
benefit as a result of its nonspecific antioxidant
pitalizations following overdose than any other
effects and free radical scavenging properties in addi-
common pharmaceutical agent. Although aceta-
tion to NAC-mediated improvement in microvascular
minophen possesses an outstanding safety profile at
perfusion [12,13].
therapeutic doses, a rapid course of progressive
When administered early (<8 hours) after acute
hepatic failure leading to death may occur following
ingestion, NAC is almost completely effective in
large overdoses when treatment is delayed. It has
preventing significant hepatotoxicity. The benefit of
been estimated that 450 deaths annually and nearly
this antidote is lessened beyond 8 hours following
40% of all cases of acute liver failure in the United
overdose as glutathione stores become further
States are secondary to the inappropriate use of
depleted [14]. Treatment should be initiated imme-
acetaminophen [10,11]. Toxicity occurs as a result of
diately for any suspected toxic acetaminophen inges-
acetaminophen’s metabolism via cytochrome p450
tion beyond 8 hours. Current US Food and Drug
to N-acetyl-p-benzoquinoneimine (NAPQI). At thera-
Administration (FDA)–approved treatment options
peutic doses of acetaminophen, NAPQI is detoxified
include either oral or intravenous NAC. Oral NAC is
by glutathione to nontoxic conjugates; however,
administered as a 140 mg/kg loading dose followed
with excess dosing and exhaustion of glutathione
by 70 mg/kg every 4 hours for an additional 17
reserves, NAPQI accumulates, initiating a cascade of
doses for any patient with a toxic ingestion as plot-
events capable of producing hepatocyte damage and
ted on the Rumack-Matthew nomogram. Should
fulminant hepatic failure.
signs of progressive hepatic damage be present
after this 72-hour period, treatment with NAC may
N-acetylcysteine still be of some benefit and should be continued
until a definitive clinical and laboratory improve-
N-acetylcysteine (NAC) prevents NAPQI-induced ment is noted. Success has been demonstrated with
hepatoxicity through several mechanisms: (1) NAC a shortened treatment duration of oral NAC in
functions as a glutathione (GSH) precursor that may several studies when administered to appropriate
increase GSH availability as well as provide inorganic candidates [15-17]. Early NAC discontinuation
256 Journal of Intensive Care Medicine 21(5); 2006
Antidote Use
should be considered only after a minimum of at N-acetylcysteine given orally is often poorly tol-
least 20 hours of oral NAC administration when no erated due to its “rotten egg” sulfur smell. High-dose
further acetaminophen is detectable in the serum antiemetics may be needed to prevent emesis. Any
and hepatic transaminases and prothrombin times NAC dose vomited within 1 hour from ingestion
are normal. should be readministered. If vomiting is present and
Intravenous NAC has been used throughout persistent beyond 8 hours following acetaminophen
Europe, Canada, Australia, and portions of the United ingestion, intravenous NAC should be strongly con-
States for more than 2 decades with success demon- sidered. Intravenous NAC has been used effectively
strated in treatment durations of 20 to 48 hours [18- and relatively safely throughout the world for more
20]. Intravenous NAC recently gained FDA approval than 20 years [19]. Anaphylactoid reactions with
in the United States for patients treated within 8 to 10 intravenous NAC may occur as a dose- and rate-
hours following an acute toxic acetaminophen inges- related effect; however, these reactions are generally
tion. It is administered as a 140-mg/kg loading dose minor (pruritis, vomiting) and usually respond to
over 15 minutes followed by a 50-mg/kg infusion antihistamines and a slowing of the NAC infusion
over 4 hours, concluding with a 16-hour infusion of rate [20,24]. Major adverse effects and death follow-
100 mg/kg. When intravenous NAC is initiated ing intravenous NAC administration are exceedingly
beyond 8 to 10 hours postingestion, it should be con- rare and are most commonly related to rapid intra-
tinued beyond the 20-hour infusion if needed until venous loading in patients with underlying airway
acetaminophen is no longer measurable and transam- disease or in the case of NAC dosing errors [25,26].
inases are normal or returning to normal.
The indication and duration of NAC therapy in
chronic acetaminophen poisoning are less clearly Toxic Alcohol Poisoning
defined. Healthy adults can likely tolerate at least 7
g of acetaminophen over 24 hours without risk of Ingestions of methanol and ethylene glycol are ine-
hepatotoxicity. Individuals with underlying liver dis- briating to the central nervous system but are oth-
ease, HIV, or malnutrition may be at increased risk erwise nontoxic prior to their enzymatic conversion
with smaller ingestions. Treatment should be consid- by alcohol dehydrogenase (ADH) and aldehyde
ered with greater than 4 g per day in this population dehydrogenase (ALD) to their acidic metabolites.
if there is any laboratory evidence of hepatotoxicity ADH and ALD convert methanol to formate, a reti-
or if serum acetaminophen concentrations are ele- nal toxin causing visual defects and papilledema
vated (>10 mg/L). Treatment of individuals meeting [27-29]. Ethylene glycol is metabolized by ADH and
these criteria is reasonable given the uncertainty of ALD to glycolic acid and later to oxalic acid, which
the ingestion, the difficulty in predicting who will precipitates with calcium in renal tubules and other
develop subsequent hepatic damage, and the lack of tissues [30]. Each of these metabolites is acidic, and
clinical studies that address chronic overdose man- their accumulation results in a “wide anion gap”
agement [21]. Treatment with NAC, either orally or acidosis. This acidosis may be delayed for several
intravenously, should continue until acetaminophen hours after initial ingestion because of delayed
is not detected and transaminases and prothrombin metabolism, especially in the presence of ethanol.
time are normal or normalizing. Poisoning with other alcohols such as propylene
Death following single acute acetaminophen glycol and isopropanol is intoxicating but does not
ingestions in children less than age 5 has not been require antidotal therapy, because their metabolites
reported despite extremely elevated acetaminophen generally do not lead to irreversible organ toxicity.
levels and delays in treatment onset. A predomi-
nance of the sulfation pathway (which produces
nontoxic metabolites), increased glutathione Fomepizole/Ethanol
reserves, and improved regenerative capabilities of
young livers are theorized to account for this pro- The goal of antidotal therapy in toxic alcohol poi-
tective effect [22]. Misdosed infants and children soning is to prevent metabolism of the parent com-
with acute febrile illnesses who experience chronic pounds to their toxic metabolites. Competitive
acetaminophen poisoning are not afforded a similar inhibition of ADH can be achieved by administra-
protection and appear to be an at-risk group [23]. tion of either ethanol or 4-methylpyrrazole (fomepi-
Those receiving greater than 75 mg/kg/day should zole) (Fig 1). When given early following methanol
have laboratory evaluation performed and treatment or ethylene glycol ingestion, these antidotes are
with NAC initiated if transaminase abnormalities are completely protective against metabolic conversion;
present or acetaminophen levels are elevated. however, once metabolism has occurred, supportive
Journal of Intensive Care Medicine 21(5); 2006 257
Betten et al
Fomepizole/
Ethanol
Methanol Ethylene Glycol
Alcohol dehydrogenase Alcohol dehydrogenase
Formaldehyde Glycoaldehyde
Aldehyde dehydrogenase Aldehyde dehydrogenase
Formic Acid Glycolic Acid
Folic acid
Glycoxylic Acid
H2O + CO2 Thiamine Mg2+, Pyryidoxine
α-hydroxy- β Oxalic acid Hipurric acid
-ketoadipic aicd
Fig 1. Competitive enzymatic inhibition of alcohol dehydrogenase by fomepizole and ethanol prevents metabolism of
methanol and ethylene glycol to toxic metabolites (bold type). Enzymatic cofactor supplementation (boxes) may offer
greater rate of metabolism to nontoxic metabolites.
care, treatment of acidosis with sodium bicarbonate, levels greater than 50 mg/dL. Further indications for
and enhancement of elimination of the toxic dialysis include deteriorating vital signs despite
metabolites with hemodialysis are required to atten- intensive supportive care, metabolic acidosis (pH
uate injury [29,31,32]. <7.25) refractory to sodium bicarbonate administra-
Because serum levels of methanol and ethylene tion and supportive care, renal failure, and severe
glycol are often unavailable immediately, antidotal electrolyte derangements. All patients should
therapy for toxic alcohol poisoning is often indi- receive supplemental cofactors (discussed below).
cated in the presence of surrogate markers of toxic- Ethanol is administered as a 10% solution in D5W
ity. The presence of an unexplained serum osmolar and should be infused to maintain a serum concen-
gap or a high anion gap metabolic acidosis should tration of 100 to 150 mg/dL. The loading dose is 600
prompt the consideration of toxic alcohol poison- to 700 mg/kg over 30 minutes, followed by a main-
ing. Significant toxic alcohol poisoning may occur tenance infusion of 66 mg/kg/h (for nondrinkers) to
even with a “normal” osmolar gap given the 154 mg/kg/h (for chronic drinkers) [33]. Hourly
interindividual variability of baseline osmolar gaps. serum ethanol concentrations are required to titrate
This is particularly true with ethylene glycol poison- the infusion rate for the desired level. During dialy-
ing. The presence of urinary crystals and urine fluo- sis, the maintenance dose of ethanol should be
rescence (occasionally seen because of fluorescene increased to 169 to 257 mg/kg/h (higher rates for
present in many antifreeze products) following eth- chronic ethanol abusers) because ethanol will also
ylene glycol ingestion can aid in the diagnosis when be removed. Oral dosing with ethanol can be initi-
present but is unreliable and may be absent even ated in the rare circumstance that neither intra-
with high-level exposures. venous ethanol nor fomepizole is available; the
Treatment with ethanol or fomepizole should be suggested initial oral loading dose is 4 ounces of 80-
administered to all patients with a history concern- proof whiskey (40% ethanol by volume) [28,30].
ing for methanol or ethylene glycol ingestion and Fomepizole is a potent ADH inhibitor, displaying
those with documented levels of 20 mg/dL or an affinity that is 500 times that of ethanol and 5000
greater of either agent. Treatment should also be to 10000 times that of methanol and ethylene gly-
considered in the setting of large anion gap meta- col [32]. Fomepizole is more expensive than ethanol
bolic acidosis or significant osmolar gaps of uncer- but offers a more desirable side effect profile [34]. It
tain etiology. Antidotal treatment of toxic alcohol does not cause inebriation, hypoglycemia, hyperos-
poisoning should be continued until the levels of molarity, or vasodilation. It is not metabolized and
methanol or ethylene glycol are below 20 mg/dL therefore will not further deplete reduced nicoti-
and clinical symptoms of toxicity are resolving namide adenine dinucleotides (NADH) or generate
[28,30]. Given the long half lives of methanol (43-54 more acid as the metabolism of ethanol would. No
hours) and ethylene glycol (14-18 hours) during serum levels of fomepizole are necessary to guide
ethanol and fomepizole administration, hemodialy- dosing [31]. The loading dose is 15 mg/kg, followed
sis should be considered for plasma toxic alcohol by 4 maintenance doses at 10 mg/kg. Thereafter, the
258 Journal of Intensive Care Medicine 21(5); 2006
Antidote Use
maintenance dose should be increased to 15 mg/kg both central and peripheral sites [39,40,42,43]. In
to offset an increased rate of degradation of fomepi- recent decades, enthusiasm for this agent has
zole [35,36]. Hemodialysis removes a significant pro- waned because of concerns of precipitating
portion of circulating fomepizole, necessitating a seizures and reported cardiotoxicity in the setting of
decrease in the maintenance-dosing interval to 4 TCA overdose [44-48].
hours during the procedure [27,33]. Alternatively, a Diagnostic use of physostigmine can be consid-
continuous infusion of 1.5 mg/kg/h has been ered in patients with altered mental status and signs
reported to achieve a therapeutic level of fomepi- of antimuscarinic toxicity. Complete reversal of signs
zole during hemodialysis [28,30]. and symptoms (particularly altered mental status)
Following toxic alcohol poisoning, certain vita- after physostigmine administration suggests the pres-
mins can function as cofactors, potentially maxi- ence of antimuscarinic toxicity. The therapeutic use
mizing degradation of the alcohol to nontoxic of physostigmine is recommended by some authors
metabolites (Fig 1). For methanol toxicity, folic acid to reverse life-threatening tachycardia, hyperthermia,
or folinic acid (leucovorin) at a daily dose of 1 or severe agitation resulting from antimuscarinic tox-
mg/kg intravenously (IV) should be given to all icity; however, this agent should be used only as a
patients [36]. For patients with suspected ethylene therapeutic adjunct to conventional treatments for
glycol toxicity, administration of pyridoxine (50 mg these conditions [41].
IV every 6 hours), thiamine (100 mg daily by oral Although in past decades physostigmine had
or IV routes), and magnesium (usually 2 g daily by been administered safely to thousands of TCA-
oral or IV routes) is recommended.36 The mecha- poisoned patients, convulsions and dysrhythmias
nism by which these cofactors reduce the toxic following physostigmine have been described in
effects caused by methanol and ethylene glycol is multiple case reports of TCA overdose [45,46,47,49].
not well understood; thus, their use should be con- These reports are difficult to interpret because TCAs
sidered an adjunctive measure with fomepizole, are proconvulsants by themselves in overdose.
ethanol, and, if needed, hemodialysis. Sodium Pentel [44] reported 2 individuals who developed
bicarbonate can correct severe acidosis and slow seizures before, and asystole following, physostig-
central nervous system (CNS) penetration of the mine administration. Both individuals were relatively
injurious metabolites but does not stop their gener- bradycardic before administration of physostigmine,
ation or enhance elimination. and 1 had a first-degree atrioventricular block.
Another case series reported a single convulsion
among 39 patients given diagnostic physostigmine
Antimuscarinic Poisoning for varying antimuscarinic substance ingestions; this
patient had also convulsed prior to physostigmine
Anticholinergic drugs competitively block mus- administration [50]. These and other similar reported
carinic acetylcholine receptors in the CNS, in termi- cases suggest that physostigmine-related complica-
nal parasympathetic synapses, and on the salivary tions can be avoided through careful selection of
and sweat glands. These agents typically produce patients without high-risk characteristics, such as
the “antimuscarinic toxidrome” characterized by electrocardiographic (ECG) evidence of TCA over-
tachycardia, mydriasis, dry, flushed skin, urinary dose. We suggest that contraindications to the use of
retention, dry mucosae, ileus, and confused delir- physostigmine include QRS or QTc prolongation,
ium with mumbling speech, seizures, hallucinations, relative bradycardia or intraventricular conduction
and agitation [37,38]. Many compounds can induce block, a cardiotoxic TCA ingestion (generally at least
the antimuscarinic syndrome, including antihista- 1 g), or underlying seizure disorder.
mines, tricyclic antidepressants (TCAs), antiparkin- In adults, the standard dose of physostigmine is
sonian agents, typical and atypical antidepressants, 1 to 2 mg IV given by slow push (1 mg over 1-2
and atropine-like alkaloids in Datura stramonium minutes) in a monitored setting. The use of benzo-
and Atropa belladonna plant species.39,40,41 diazepines prior to physostigmine administration is
recommended by some clinicians to reduce the risk
of adverse drug reactions. Lack of complete rever-
Physostigmine sal after 4 mg makes antimuscarinic toxidrome an
unlikely cause of altered mental status. The onset of
Reversal of antimuscarinic symptoms is achieved effect occurs within 5 to 20 minutes, and duration
with the use of physostigmine. Physostigmine is a is 45 minutes to 1 hour. Antimuscarinic toxicity
tertiary carbamate that reversibly disables acetyl- returns often with milder severity once the anti-
cholinesterase, increasing levels of acetylcholine in dote’s effects wane [42].
Journal of Intensive Care Medicine 21(5); 2006 259
Betten et al
The clinician must be prepared to recognize and respiratory depression for at least 2 hours after the
treat cholinergic effects that may occur following last dose of naloxone prior to medical clearance
physostigmine administration, such as emesis, [51,55,58].
hypersalivation, bradycardia, diaphoresis, diarrhea, Serious adverse events after even high doses of
bronchorrhea, and bronchospasm. Less commonly, naloxone are extremely rare. However, naloxone
nicotinic effects of fasciculations, weakness, and should be cautiously used in a patient with normal
paralysis may be present as well. Severe bradycar- respirations, even when opioid overdose is sus-
dia or bronchorrhea should be treated with pected. Opioid-dependent patients may experi-
atropine (one-half the physostigmine dose), which ence withdrawal after naloxone administration and
should be readily available. Seizures are generally become only more agitated and dysphoric [59]. Use
brief and self-limited and should be treated with of naloxone may also “unmask” the toxicity of
standard doses of benzodiazepines. coingestants, such as TCAs, and concurrently
abused substances (a popular drug combination is
heroin with cocaine, also termed a “speedball”)
Opioid Poisoning [51]. Naloxone has been rarely reported to induce
noncardiogenic pulmonary edema following infu-
The term opioids encompasses the naturally occur- sion, but these reports also suggest the possibility
ring opiate compounds from the poppy plant of pre-existing acute lung injury prior to naloxone
(Papaver somniferum) as well as synthetic and administration [51,60].
semisynthetic compounds that have similar clinical Long-acting opioid antagonists (nalmefene, nal-
effects [49]. Opioids are potent agonists of the µ, κ, trexone) have similar effects but longer durations of
and δ receptors in the CNS [51]. Sedation and action (nalmefene 4-6 hours; naltrexone 10-24
hypoventilation are among the most common symp- hours) than naloxone [51,61]. Long-acting opioid
toms of overdose. Complications of opioid overdose reversal agents are not appropriate first-line anti-
include hypoxic injury to virtually any organ system, dotes because undesirable withdrawal symptoms
rhabdomyolysis, intestinal ileus, nerve compression can persist for several hours. Furthermore, a pro-
injury, intravenous injection-related infectious dis- longed observation period after the last dose may
eases, and a poorly understood phenomenon of be necessary because life-threatening effects of opi-
noncardiogenic pulmonary edema [52-54]. oid toxicity may recur after naltrexone or nalme-
fene have been metabolized [61].
Naloxone
Benzodiazepine Poisoning
Naloxone is a synthetic antagonist of opioid receptors
and reverses apnea in opioid overdose. The onset of Poisoning with benzodiazepine compounds is gen-
action is almost immediate after intravenous, intra- erally marked by mild to moderate sedation but
muscular, intranasal, or endotracheal dosing, and the most often follows a benign course. However,
duration of effect is 1 to 4 hours [55,56]. when these agents are combined in overdose with
Suspected or known opioid toxicity with demon- other sedating compounds such as ethanol, they
strable respiratory depression (rate <8/min) is the can cause respiratory arrest and severe morbidity
primary indication for naloxone. The smallest dose [62]. Symptoms of benzodiazepine poisoning
that effectively restores respiratory drive should be include decreased responsiveness, hyporeflexia,
administered. The required intravenous dose is hypothermia, hypotension, and respiratory depres-
typically 0.04 to 0.4 mg, although administration by sion. Significant derangements in vital signs are not
other routes or following overdose of high-potency consistent with benzodiazepine overdose. A para-
synthetic compounds such as fentanyl or pro- doxical excitatory reaction may rarely accompany
poxyphene may require higher doses [51].If there the therapeutic use of benzodiazepines for proce-
is no increase in respiratory drive after administra- dural sedation [63]. Benzodiazepines have a specific
tion of 10 mg of naloxone, a search should con- binding site on the γ-aminobutyric acid (GABA)
tinue for alternative etiologies of CNS depression. type A receptor complex in the CNS, a chloride
Recurrent or prolonged sedation, such as can be channel that causes neuronal hyperpolarization
the case in methadone intoxication, may require [64]. Binding of benzodiazepines increases the fre-
treatment with continuous intravenous infusion of quency of channel opening when GABA (the major
two thirds of the initial effective dose per hour [57]. inhibitory neurotransmitter in the CNS) binds at a
Patients must be monitored for recurrence of separate site on the complex [65].
260 Journal of Intensive Care Medicine 21(5); 2006
Antidote Use
Table 2. Medications Commonly Associated With QRS or barbiturates may be needed to stop further seizure
Prolongation Due to Impaired Sodium Channel Influx [4] activity. The diagnostic use of flumazenil for coma of
unknown cause must be weighed against the possi-
Tricyclic antidepressants
bility of precipitating seizures or withdrawal symp-
Carbamezapine
toms in high-risk patients.
Diphenhydramine Quinidine
Propoxyphene Procainamide
Cocaine Flecainide
Thioridazine Encainide Cardiac Sodium Channel Poisoning
Mesoridazine Amantadine
Fluoxetine Quinine Tricyclic antidepressants are the classic example of
agents causing toxicity by inhibiting rapid sodium
channel influx in the cardiac conduction system.
Flumazenil Cardiac toxicity results from a slowing of cardiac
action potentials by slowing sodium channel influx
Flumazenil is a competitive antagonist at the benzo- in phase 0. This leads to a delay in depolarization
diazepine site on the GABA-A receptor complex resulting in electrocardiogram QRS and QT prolon-
[66]. By preventing the binding of benzodiazepines, gation and an increased risk of ventricular dys-
flumazenil decreases the inward chloride current; rhythmias. Similar sodium channel blocking effects
the subsequent neuronal depolarization reverses on the heart can be seen in overdose with numer-
CNS and respiratory depression [64,66]. It is effective ous other substances that should be evaluated and
in reversing sedation of benzodiazepine and non- treated in a similar fashion (Table 2) [76].
benzodiazepines that share activity at the benzodi-
azepine receptor, such as zolpidem [64,67-69]. It is
also effective in the treatment of paradoxical excita- Sodium Bicarbonate
tory reactions to benzodiazepines [63].63Intravenous
flumazenil induces reversal in 5 to 10 minutes and Sodium bicarbonate should be considered for the
has a duration of action of 15 to 245 minutes in management of toxic ingestion of all substances
healthy adults. Patients with hepatic failure may with sodium channel effects and evidence of car-
have a prolonged response to flumazenil [70,71]. diac toxicity. The effectiveness of this agent is a
Repeat doses may be required to treat ingestions of result of both the increased sodium concentration
compounds with prolonged effects. produced and increased serum alkalinization.
In adults, the starting dose of flumazenil to Tricyclic antidepressants are weak bases. As a
reverse benzodiazepine-induced sedation is 0.2 mg result, serum alkalinization will increase the pro-
IV. If the initial dose of flumazenil is ineffective, it portion of non-ionized drug. The non-ionized TCA
can be followed by 0.3- to 0.5-mg doses every form may have a greater distribution throughout tis-
minute as needed up to a maximum of 3 mg [72]. sue, causing a greater proportion of drug to move
Lack of any response after this dose makes coma away from the cardiac conductive system, resulting
attributable to benzodiazepines highly unlikely. A in less sodium channel blockade. Alkalinization
continuous flumazenil infusion of 0.1 to 0.5 mg/h also accelerates recovery of sodium channels by
may be needed to prevent resedation in some cases neutralizing the protonation of the drug-receptor
[73].Following flumazenil discontinuation, patients complex [77,78]. This results in a more rapid move-
should be observed for several hours to ensure that ment of the neutral form of the drug away from the
resedation from longer acting benzodiazepines sodium channel receptor. A similar benefit of serum
does not occur. alkalinization can be duplicated with controlled
Flumazenil is well tolerated and effective in hyperventilation [79].
sedated patients with isolated benzodiazepine over- Increased extracellular sodium concentrations pro-
dose. In chronic users and those with physical duced by sodium bicarbonate may produce a more
dependence on benzodiazepines, flumazenil can rapid sodium channel influx by way of an increased
precipitate withdrawal symptoms and seizures [74]. sodium concentration gradient [80]. Experimental
Flumazenil has caused convulsions in patients with models testing alkalinization with sodium free buffers
head injury, those with underlying seizure disorders, for TCA toxicity were not as effective as sodium
and those who have coingested proconvulsant bicarbonate in reducing cardiotoxicity. A role for
drugs, such as TCAs, and should be avoided in these hypertonic saline administration has been proposed
populations [74,75]. Should seizures occur following in the setting of persistent cardiotoxicity and QRS
flumazenil administration, high-dose benzodiazepines prolongation when alkalinization has been optimized
Journal of Intensive Care Medicine 21(5); 2006 261
Betten et al
(pH 7.45-7.55), although controlled trials supporting act similarly by depolarizing pancreatic β-islet cells,
this in humans are lacking [81]. triggering exocytosis of preformed insulin and
Administration of sodium bicarbonate should be resulting in facilitated end-organ glucose uptake [85-
considered in individuals with cardiac conduction 87]. In overdose, or in the absence of adequate
delays, ventricular dysrhythmias, or hypotension food intake, sulfonylureas can cause prolonged,
when the ingestion of a sodium channel-blocking life-threatening hypoglycemia [88]. Onset of
drug is suspected. QRS durations of greater than 160 sulfonylurea-induced hypoglycemia is typically
milliseconds are typically implicated in cases that within 8 hours of ingestion, with hypoglycemic
progress into ventricular dysrhythmias and in which effects lasting 6 to 72 hours depending on the agent
seizure activity is most likely to develop [82]. ingested [89-91]. The shorter acting meglitinides typi-
Treatment with sodium bicarbonate should be con- cally take effect in less than 1 hour, with hypo-
sidered with QRS duration greater than 100 to 120 glycemic effects lasting 1 to 4 hours [91,92]. Case
milliseconds, because this affords an ample margin of reports and animal studies, however, have found pro-
safety should an individual quickly decompensate. longed hypoglycemic effects of 6 to 24 hours follow-
An R wave in lead aVR greater than or equal to 3 mm ing meglitinide ingestion [93,94]. Although there are
has been found to be equally predictive of individu- few data on meglitinide overdose, treatment options
als who may develop ventricular dysrhythmias [83]. are expected to be similar to sulfonylureas.
In addition, sodium bicarbonate appears to be of
some benefit in improving blood pressure and car-
Dextrose
diac output in hypotensive patients with narrow com-
plex rhythms following tricyclic antidepressant
Any patient who overdoses with an oral hypo-
ingestions [84]. Although capable of reversing cardiac
glycemic agent should be observed for a minimum
conduction sodium channel effects, sodium bicar-
of 8 hours, during which glucose levels should be
bonate is unable to affect other TCA properties such
monitored every 1 to 2 hours [90]. Patients should
as seizures, anticholinergic toxicity, and α-adrenergic
be allowed to eat and drink freely during this obser-
receptor antagonism and thus should be considered
vation period. If hypoglycemia occurs, patients
as only part of TCA overdose management.
should receive IV dextrose as a bolus (D50W or
Sodium bicarbonate is most typically adminis-
D25W) or infusion (D10W or D5W) in order to
tered as a 50-mL ampule of 8.4% solution. The
maintain euglycemia. Overly aggressive dextrose
amount of sodium bicarbonate necessary for rever-
administration leading to hyperglycemia may result
sal of cardiotoxicity in these cases may vary. In the
in further pancreatic insulin release and rebound
setting of QRS widening or hypotension, 2 ampules
hypoglycemia [85,86]. Prolonged hypertonic dex-
administered over 1 to 2 minutes is an appropriate
trose (>10%) infusion through a peripheral IV site is
starting dose. The serum pH of the patient should
not recommended because phlebitis may occur. Any
be closely monitored, with a goal of 7.45 to 7.55.
patient with hypoglycemia requiring IV dextrose fol-
Serial blood gas analyses may be needed to guide
lowing sulfonylurea or meglitinide overdose should
further treatment. If QRS widening remains or
be admitted and observed for a minimum of 24
recurs, additional sodium bicarbonate ampules
hours [90,92]. Patients should be monitored for sev-
should be infused if the goal pH has not been
eral hours after discontinuation of IV dextrose to
exceeded. Death from TCA toxicity occurs gener-
ensure no recurrence of hypoglycemia.
ally within the first 1 to 2 hours, making continuous
infusions of sodium bicarbonate unnecessary in
most situations. In addition, bolus infusions of Octreotide
sodium bicarbonate may be more appropriate to
rapidly raise extracellular sodium concentrations. Octreotide is a long-acting, synthetic somatostatin
Alkalinization can be discontinued with hemody- anologue [95]. In the setting of oral hypoglycemic
namic stability and resolution of ECG abnormalities. agent overdose, octreotide potently and selectively
binds to somatostatin receptors on pancreatic β-
islet cells, decreasing insulin secretion to near basal
Oral Hypoglycemic Poisoning rates and inhibiting rebound hypoglycemia [96-99].
Octreotide is well absorbed via subcutaneous or IV
Sulfonylureas and meglitinides are widely used for routes and has a duration of action of approxi-
treatment of non-insulin-dependent diabetes melli- mately 6 to 12 hours. Diazoxide, previously used
tus, and together they account for the majority of with regularity for sulfonylurea-induced hypo-
cases of drug-induced hypoglycemia. These drugs glycemia, is less efficacious and is associated with
262 Journal of Intensive Care Medicine 21(5); 2006
Antidote Use
more frequent adverse side effects (hypotension, INH-depleted pyridoxine and pyridoxal-5-phosphate
tachycardia, nausea, and vomiting) than octreotide, stores and stop further seizures. Paradoxically, reple-
and it is now rarely used [95,100]. tion of pyridoxine stores reverses both the CNS
Octreotide is indicated for cases of oral hypo- excitatory (seizure) and inhibitory (coma) effects of
glycemic agent–induced hypoglycemia after initial INH [112,113].
control of hypoglycemia with IV dextrose or when Intravenous pyridoxine is indicated for the treat-
hypoglycemia is refractory to dextrose therapy [91]. ment of INH-induced seizures and coma. When the
Adults may receive 50 µg and children 1 µg/kg IV or amount of INH ingested is known, 1 g of pyridox-
subcutaneously every 6 to 12 hours as needed ine per gram of INH ingested should be adminis-
[90,101]. Octreotide has been found to be superior to tered immediately. If the amount of INH ingested is
IV dextrose and diazoxide in maintaining euglycemia unknown, an empiric dose of 5 g of pyridoxine is
and has decreased or eliminated the need for IV dex- suggested in adults, or 70 mg/kg (maximum 5 g) in
trose in simulated human sulfonylurea overdoses [95]. children. Should seizures persist, the initial dose
Patients should be monitored for recurrence of hypo- should be repeated every 20 minutes until the
glycemia for 24 hours or more after the last octreotide desired effect is achieved [114]. Pyridoxine should
dose in cases of long- acting sulfonylurea overdose be mixed in 50 to 100 mL of 5% dextrose in water
[98,102]. Adverse effects following administration and may be administered at a rate of 0.5 g/min
include nausea, vomiting, diarrhea, crampy abdomi- [114,115]. With appropriate pyridoxine dosage
nal pain, injection site pain, dizziness, fatigue, flush- administration, desired effects should be evident
ing, headache, and hyperglycemia [103]. within minutes [112,113,116]. A prophylactic IV
dose of 5 g of pyridoxine has been suggested for
asymptomatic patients who present within 2 hours
Isoniazid Poisoning of a significant INH ingestion, but the efficacy of
this therapy has not been studied [107].
Isoniazid (isonicotinic hydrazide, INH) has been Pyridoxine hydrochloride for IV administration is
used for the treatment and prophylaxis of tubercu- supplied in 1-mL vials containing 100 mg/mL [115].
losis since 1952 [104]. It is rapidly absorbed after Given the high doses that may be needed and the
oral ingestion with peak blood concentrations and manufacturer’s packaging of just 100 mg/vial, 50 to
toxic effects occurring within 1 to 6 hours [105]. 150 or more vials may be required to adequately
INH toxicity is a result of its ability to produce a treat INH-poisoned patients. Many hospitals lack
deficiency of pyridoxal-5-phosphate, the active adequate IV pyridoxine to treat even 1 severely
form of pyridoxine and a required cofactor for glu- intoxicated individual [117]. In the event IV pyri-
tamic acid decarboxylase (GAD). In the absence of doxine is unavailable, the oral form may be
functional GAD, glutamic acid is unable to be con- crushed and administered orally as a slurry at a sim-
verted to GABA, the primary CNS inhibitory neuro- ilar dosage to the IV form [114]. Pyridoxine should
transmitter. Following INH overdose, decreased be administered concomitantly with benzodi-
production and activity of GABA on postsynaptic azepines because a synergistic anticonvulsive effect
receptors result in seizures and metabolic acidosis has been demonstrated in animal studies [118].
secondary to seizure-induced lactic acidosis [106]. Pyridoxine may also have an antidotal role in
INH-induced seizures may be prolonged and poisonings by monomethylhydrazine, a structurally
refractory to GABA agonists such as benzodi- similar substance to INH found in the Gyromitra
azepines [104,107]. Coma is another prominent fea- mushrooms and rocket fuel that is capable of pro-
ture of INH overdose, the exact mechanism of ducing toxicity similar to INH [104]. Large acute (IV)
which is yet to be defined [108,109]. and chronic (oral) pyridoxine overdoses have been
associated with isolated sensory neuropathies in a
stocking-glove pattern; however, this should not be
Pyridoxine of concern in the acute management of the above
poisonings [110,119].
Pyridoxine is a water-soluble essential vitamin that
has no known metabolic effects by itself [110,111].
Pyridoxine must be converted to the active Cyanide Poisoning
pyridoxal-5-phosphate before it can act as a coen-
zyme for the decarboxylation of glutamic acid to Exposure to cyanide occurs through various routes
GABA [110,111]. When administered at appropriate including inhalation (hydrogen cyanide), ingestion
doses, exogenous pyridoxine is able to replenish (sodium and potassium cyanide salts, laetrile,
Journal of Intensive Care Medicine 21(5); 2006 263
Betten et al
plant-derived cyanogenic glycosides), and intra- sodium thiosulfate (10 mg of thiosulfate per 1 mg of
venous administration of cyanide-containing medica- nitroprusside) is recommended during rapid and pro-
tions (nitroprusside). Cyanide rapidly diffuses into longed nitroprusside infusions (>3 µg/kg/min).132
tissues and binds to the cytochrome oxidase complex, Amyl nitrite pearls may be crushed into gauze
disrupting the mitochondrial electron transport and held near the patient’s mouth and nose or
chain. The result is inhibition of oxidative phosphory- under the lip of an oxygen mask for inhalation (30
lation and cellular hypoxia leading to anaerobic seconds of each minute) while IV access is
metabolism, metabolic acidosis, seizures, coma, car- obtained. Once IV access is established, sodium
diovascular collapse, and death. Clinical effects fre- nitrite may be administered as 10 mL of 3% solution
quently occur rapidly following cyanide exposure; (300 mg) for adults, or 0.2 to 0.33 mL/kg (maximum
however, compounds such as acetonitrile and propi- 10 mL) for children at 2.5 mL/min [123,124]. A lower
onitrile may result in delayed toxicity as parent com- dose may be necessary in anemic patients to avoid
pounds are hepatically converted to cyanide [120-122]. severe methemoglobin effects [124]. Co-oximetry
should be used to monitor and maintain methemo-
globin levels below 30% [124]. Pulse oximetry read-
Cyanide Antidote Kit ings are inaccurate in methemoglobin-poisoned
patients and will plummet even further following
The current FDA-approved antidote kit for cyanide methylene blue administration. After sodium nitrite
poisoning consists of amyl nitrite, sodium nitrite, infusion, sodium thiosulfate may be administered IV
and sodium thiosulfate (Taylor Pharmaceutical/ as 50 mL of 25% solution (12.5 g) for adults or 1.65
Akorn Inc, Decatur, IL).123 Amyl nitrite and sodium mL/kg (maximum 50 mL) for children [124]. If initial
nitrite induce methemoglobinemia by oxidizing patient response is inadequate, repeat doses of
iron in hemoglobin from the ferrous (Fe2+) to sodium nitrite and thiosulfate (half of the initial
the ferric (Fe3+) form. This ferric iron rapidly doses) may be given 30 minutes later [124].
removes cyanide from cytochrome oxidase forming
cyanomethemoglobin and restoring cellular respira-
tion. Cyanomethemoglobin reacts with thiosulfate Hydroxocobalamin, Hyperbaric
to form thiocyanate, a reaction catalyzed by the Oxygen, and Normobaric Oxygen
enzyme rhodenase. Thiocyanate is renally excreted
leaving methemoglobin free to bind more cyanide Hydroxocobalamin, a cobalt-containing cyanide
[124,125]. Whereas both nitrites and thiosulfate are chelator, has been used safely and effectively in
individually protective in cyanide poisoning, when combination with thiosulfate outside the United
used together they appear to have synergistic effects States since 1970 and is reviewed in detail elsewhere
[124,126]. Nitrite-induced vasodilation may improve [133]. Hyperbaric oxygen therapy for isolated
end-organ perfusion and has been suggested as an cyanide toxicity remains an unproven and contro-
alternative mechanism contributing to the apparent versial modality [134]. Its use is reserved for cases of
effectiveness of the cyanide antidote kit [127]. concomitant carbon monoxide and cyanide expo-
Immediate empiric use of the cyanide antidote kit sure. Normobaric oxygen administration, however,
should be strongly considered for patients with sus- enhances the antidotal effects of nitrites and thiosul-
pected exposure to cyanide, especially those who are fate in animal studies of cyanide poisoning [134,135].
unresponsive or with significant acidosis. Nitrites
should be used cautiously in smoke inhalation
victims because concomitant methemoglobinemia Cholinergic Poisoning
and carboxyhemoglobinemia may severely worsen
oxygen-carrying capacity [128]. In such cases, sodium Cholinergic agents include acetylcholinesterase
thiosulfate may be safely given without prior nitrite (AChE) inhibitors such as carbamate and organophos-
therapy [129]. It has been suggested that the danger phorus (OP) insecticides, and organophosphorus
of sodium nitrite treatment following smoke inhala- nerve agents used in chemical warfare (sarin,
tion is overestimated because carboxyhemoglobin soman, tabun, VX). These agents are well absorbed
may clear more rapidly than methemoglobinemia by ingestion, dermal contact, and inhalation [136].
develops. Potential benefits and risks of treatment Organophosphorus insecticides and nerve agents
should be considered prior to treatment initiation deposit a phosphoryl group at the active site of
[130]. Rapid (or even recommended) infusion rates of AChE, binding and disabling this enzyme. The result-
sodium nitrite may cause hypotension, and vasopres- ing accumulation of acetylcholine (ACh) causes
sor support may be required [128,131]. Prophylactic parasympathetic muscarinic (salivation, lacrimation,
264 Journal of Intensive Care Medicine 21(5); 2006