CHEST

Postgraduate Education Corner

CONTEMPORARY REVIEWS IN CRITICAL CARE MEDICINE

Toxicology in the ICU

Part 1: General Overview and Approach to Treatment
Michael Levine, MD; Daniel E. Brooks, MD; Carrie A. Truitt, MD; Brian J. Wolk, MD;
Edward W. Boyer, MD, PhD; and Anne-Michelle Ruha, MD

Poisonings, adverse drug effects, and envenomations continue to be commonly encountered.

Patients often present critically ill and warrant ICU admission. Many other patients who are initially stable have the potential for rapid deterioration and require continuous cardiopulmonary
and neurologic monitoring. Given the potential for rapid deterioration, and because patients
need continuous monitoring, ICU admission is frequently required. This article is the first of a
three-part series to be published in CHEST; it discusses general management, laboratory tests,
enhanced elimination, and emerging therapies. The second article will address the management
of specific overdoses; the last will cover plants, mushrooms, envenomations, and heavy metals.
CHEST 2011; 140(3):795806
Abbreviations: AC 5 activated charcoal; AG 5 anion gap; AMS 5 altered mental status; CCB 5 calcium channel blocker;
CRRT 5 continuous renal replacement therapy; EET 5 extracorporeal elimination technique; HD 5 hemodialysis;
HIE 5 hyperinsulinemic euglycemia; ILE 5 IV lipid emulsion; NMS 5 neuroleptic malignant syndrome; OG 5 osmol gap;
UDS 5 urine drug screen; Vd 5 volume of distribution; WBI 5 whole bowel irrigation

frequently encounter critically ill patients

Physicians
who were poisoned under a variety of circum-

stances. The wide range of clinical syndromes that

occur as a result of overdose or recreational use of
an ever-increasing array of available prescription and
illicit drugs provides a continuous challenge to the
intensive care physician. This article is the first of a
three-part series to be published in CHEST and discusses general management, laboratory tests, enhanced
elimination, and emerging therapies. The second article
will focus on the management of specific overdoses;
Manuscript received October 4, 2010; revision accepted May 23,
2011.
Affiliations: From the Department of Medical Toxicology
(Drs Levine, Brooks, Truitt, and Ruha), Banner Good Samaritan
Medical Center, Phoenix, AZ; and the Division of Medical
Toxicology (Drs Wolk and Boyer), Department of Emergency
Medicine, University of Massachusetts, Worcester, MA.
Correspondence to: Michael Levine, MD, Department of
Medical Toxicology, Banner Good Samaritan Medical Center,
925 E McDowell Rd, 2nd Floor, Phoenix, AZ 85006; e-mail:
michael.levine@bannerhealth.com
2011 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians (http://www.chestpubs.org/
site/misc/reprints.xhtml).
DOI: 10.1378/chest.10-2548
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the last will cover plants, mushrooms, envenomations,

and heavy metals.

Toxidromes
Specific toxic syndromes (toxidromes) arise from
similarities in the pharmacology of many poisons,
permitting treatment to be started empirically, based
on clinical presentation without definitive knowledge
of the offending agent. The classic toxidromes include
opioid, sedative-hypnotic, anticholinergic, cholinergic,
and sympathomimetic (Table 1).
The classic opioid toxidrome results from the stimulation of opioid receptors by naturally occurring opiates, such as morphine and codeine, or by synthetic
opioids, such as oxycodone, hydrocodone, hydromorphone, and fentanyl. The toxidrome is characterized
by bradypnea, depressed mental status, and miosis.1,2
Miosis and a respiratory rate of 12 breaths/min
are both sensitive (88% and 80%, respectively) and
specific (90% and 95%, respectively) for predicting
a response to naloxone.3 Opioids produce a general depression in autonomic activity; bradycardia,
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5 increased; 5 very increased; 2 5 no change or increased; 2 5 no change or decreased; 5 decreased; 5 increased or decreased; 2 5 no change; NMS 5 neuroleptic malignant syndrome;
SLUDGE 5 salivation, lacrimation, urination, defecation, GI (diarrhea), emesis; Temp 5 temperature.

2
2
2
2

Moist/diaphoretic
Moist/diaphoretic
Moist/diaphoretic
2

Depression

Variable

Sedative-hypnotic
Sedative withdrawal
Serotonin syndrome
Sympathomimetic

2
Anticholinergic (Antimuscarinic)
Cholinergic
NMS
Opioid

Mumbling speech, picking movements

SLUDGE syndrome, miosis, bronchorrhea
Lead-pipe rigidity
Some opioids (eg, meperidine) may not
cause miosis

Agitation common
Clonus and rigidity greater in lower extremities
Agitation common

2
2
Dry
Wet
Moist/diaphoretic

Delirium
Variable
Variable
Depression

Other
Reflexes
Bowel Sounds

2
2

Mucous
Membrane/Skin
Pupils
Mental Status
Respiratory
Rate
Pulse
BP
Temp
Toxidrome

Table 1Common Toxidromes

hypotension, and hypothermia are common. Hypoactive bowel sounds are possible.4,5
This classic toxidrome may be obscured in mixed
overdoses, and several opioids have unique clinical
features of importance. Meperidine, propoxyphene,
and tramadol can cause seizures.6-9 Miosis is not reliably present in the setting of tramadol or meperidine
toxicity,10 or with mixed ingestions. Propoxyphene
produces sodium channel blockade, which is associated with QRS prolongation and cardiovascular
collapse,8,9 whereas potassium efflux blockade and
QT prolongation are commonly observed with methadone toxicity.11 The rapid administration of highdose IV fentanyl can induce chest wall rigidity, which
can complicate ventilation.12
The sedative-hypnotic toxidrome also produces a
generalized decrease in autonomic activity. Agents
that may produce this toxidrome include benzodiazepines, benzodiazepine-like agents (eg, zolpidem), barbiturates, carisoprodol, chloral hydrate, ethanol, and
baclofen. In most cases, CNS depression is enhanced
via binding at postsynaptic g-aminobutyric acid type
A channels, thereby promoting chloride influx and
neuronal hyperpolarization.13 Characteristic clinical
effects are anxiolysis and, as mentioned earlier, CNS
depression. Respiratory depression and hypothermia
may also occur.
The sympathomimetic toxidrome is often caused
by stimulants such as cocaine and methamphetamine.
Several over-the-counter and prescription medications, such as pseudoephedrine, caffeine, and agents
used to treat attention deficit disorders (eg, methylphenidate), can also produce this toxidrome. Signs
may include tachycardia, hypertension, hyperthermia,
tachypnea, CNS excitation, and diaphoresis. Pupils
are characteristically dilated but reactive.14,15 Agitation and muscular hyperactivity are common and
may produce life-threatening hyperthermia.16
Sympathomimetics produce a general increase in
sympathetic tone via several mechanisms, depending on the drug.17-19 These include increased release
of catecholamines, inhibition of reuptake, direct receptor stimulation, and altered neurotransmitter metabolism.18 The differing modes of action may explain
why cocaine intoxication responds well to benzodiazepines, whereas amphetamine-induced toxicity may
be relatively resistant.20-23 Another example of a sympathomimetic, clenbuterol, is a long-acting direct
b-agonist used for its anabolic and lipolytic properties.
Its use may result in tachycardia, hyperglycemia, hypokalemia, and myocardial infarction.19,24
Sedative-hypnotic withdrawal syndrome can appear
similar to the sympathomimetic toxidrome, and occurs
with abrupt discontinuation of a sedative-hypnotic
agent following prolonged use. In patients with alcohol
withdrawal, seizures may result, with . 90% occurring

Postgraduate Education Corner

Conclusions
Severe clinical illness can occur following overdose
or exposure to certain chemicals and illicit substances.
Many agents produce toxidromes, which allows the
physician to identify a probable poisoning syndrome
and empirically determine the most appropriate
management. Knowledge of the various routes of
decontamination, emerging antidotal therapies, and
opportunities for enhanced elimination allow for provision of optimal care in the critical care setting. Many
cases of poisoning present diagnostic and therapeutic
challenges. It is recommended that physicians consult a medical toxicologist or regional poison control
center (800-222-1222) to discuss individual cases to
assist in the management of each patient.
Acknowledgments
Financial/nonfinancial disclosures: The authors have reported
to CHEST that no potential conflicts of interest exist with any
companies/organizations whose products or services may be discussed in this article.

References
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6. Clark RF, Wei EM, Anderson PO. Meperidine: therapeutic
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9. Whitcomb DC, Gilliam FR III, Starmer CF, Grant AO.
Marked QRS complex abnormalities and sodium channel
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10. Ghoneim MM, Dhanaraj J, Choi WW. Comparison of four
opioid analgesics as supplements to nitrous oxide anesthesia.
Anesth Analg. 1984;63(4):405-412.
11. Krantz MJ, Mehler PS. QTc prolongation: methadones
efficacy-safety paradox. Lancet. 2006;368(9535):556-557.
12. Ackerman WE, Phero JC, Theodore GT. Ineffective ventilation during conscious sedation due to chest wall rigidity
after intravenous midazolam and fentanyl. Anesth Prog.
1990;37(1):46-48.
13. Burt DR. Reducing GABA receptors. Life Sci. 2003;73(14):
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14. Derlet RW, Rice P, Horowitz BZ, Lord RV. Amphetamine
toxicity: experience with 127 cases. J Emerg Med. 1989;7(2):
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15. Gay GR, Inaba DS, Sheppard CW, Newmeyer JA. Cocaine:
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16. Rosenberg J, Pentel P, Pond S, Benowitz N, Olson K.
Hyperthermia associated with drug intoxication. Crit Care
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17. Leshner AI. Molecular mechanisms of cocaine addiction.
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18. Sulzer D, Sonders MS, Poulsen NW, Galli A. Mechanisms
of neurotransmitter release by amphetamines: a review.
Prog Neurobiol. 2005;75(6):406-433.
19. Hoffman RS, Kirrane BM, Marcus SM; Clenbuterol Study
Investigators. A descriptive study of an outbreak of
clenbuterol-containing heroin. Ann Emerg Med. 2008;52(5):
548-553.
20. Goldfrank LR, Hoffman RS. The cardiovascular effects of
cocaine. Ann Emerg Med. 1991;20(2):165-175.
21. Guinn MM, Bedford JA, Wilson MC. Antagonism of intravenous cocaine lethality in nonhuman primates. Clin Toxicol.
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22. Derlet RW, Albertson TE, Rice P. Antagonism of cocaine,
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24. Kierzkowska B, Staczyk J, Kasprzak JD. Myocardial infarction in a 17-year-old body builder using clenbuterol. Circ J.
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of alcoholic epilepsy. Epilepsia. 1967;8(1):1-20.
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27. Beaver KM, Gavin TJ. Treatment of acute anticholinergic
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28. Frascogna N. Physostigmine: is there a role for this antidote
in pediatric poisonings? Curr Opin Pediatr. 2007;19(2):
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29. Gowdy JM. Stramonium intoxication: review of symptomatology in 212 cases. JAMA. 1972;221(6):585-587.
30. Longo VG. Behavioral and electroencephalographic effects
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31. OMalley GF, Seifert S, Heard K, Daly F, Dart RC.
Olanzapine overdose mimicking opioid intoxication.
Ann Emerg Med. 1999;34(2):279-281.
32. Watemberg NM, Roth KS, Alehan FK, Epstein CE. Central
anticholinergic syndrome on therapeutic doses of cyproheptadine. Pediatrics. 1999;103(1):158-160.
33. Eddleston M, Dawson A, Karalliedde L, et al. Early management after self-poisoning with an organophosphorus or
carbamate pesticide-a treatment protocol for junior doctors.
Crit Care. 2004;8(6):R391-R397.
34. Bird SB, Gaspari RJ, Dickson EW. Early death due to severe
organophosphate poisoning is a centrally mediated process.
Acad Emerg Med. 2003;10(4):295-298.
35. De Bleecker JL. The intermediate syndrome in organophosphate poisoning: an overview of experimental and clinical
observations. J Toxicol Clin Toxicol. 1995;33(6):683-686.
36. Boyer EW, Shannon M. The serotonin syndrome. N Engl J
Med. 2005;352(11):1112-1120.
37. Sternbach H. The serotonin syndrome. Am J Psychiatry. 1991;
148(6):705-713.
38. Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM.
The Hunter Serotonin Toxicity Criteria: simple and accurate
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For example, because of structural similarities with

the tricyclics, diphenhydramine, cyclobenzaprine,
carbamazepine, and quetiapine may cause a falsepositive tricyclic antidepressant screen.48-53 Because
of the frequent false-positives from a UDS, results
should be considered preliminary until confirmed
by gas chromatography-mass spectrometry. The test
specificity varies, depending on the immunoassay
used. A UDS may also remain positive for a prolonged
period, so in many cases it will only suggest the historical use of an agent (Table 2).51,54 Urinary levels of
most drugs do not correlate with intoxication.
Obtaining serum drug concentrations may also be
useful in some circumstances. As examples, lithium,
digoxin, valproic acid, carbamazepine, phenytoin, salicylate, and acetaminophen concentrations may all
influence management (Table 3). Others, such as tricyclic antidepressants, are of less use because specific concentrations do not correlate well with clinical
findings. However, in some cases they may be useful
in confirming excessive exposure.
Gaps
The anion gap (AG) is the difference between the
measured dominant cations and anions, with a normal AG occurring between 4 and 12 mEq/L. An elevated AG usually results from increased unmeasured
anions and assists in narrowing the differential for
metabolic acidosis (Table 4). A low or negative AG
may occur with lithium, bromide, or iodide.55,56 Hyperlipidemia or hypoalbuminemia may also cause a
decreased AG.56-58
The osmolal gap (OG) is the difference between the
measured osmolality (mOsm/kg water) and the calculated osmolarity (mOsm/L) and is used to detect the
presence of osmotically active substances (Fig 1).59,60
Table 2Detection Period of Commonly Detected
Drugs on a Urine Drug Screen
Drug
Amphetamine, methamphetamine
Barbiturate
Short acting (eg, pentobarbital)
Long acting (eg, phenobarbital)
Benzodiazepines
Short acting (eg, lorazepam)
Long acting (eg, diazepam)
Cocaine metabolite (benzoylecgonine)
Marijuana (cannabinoids)
Single use
Long-term use
Opiates (varies by agent)
Phencyclidine

Approximate
Detection Period
4d
24 h
3 wk
3d
4 wk
3d
3d
4 wk
4d
8d

Modified with permission from Chattergoon et al51 and McQuillen

and Anderson.54
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Table 3Specific Serum Concentrations That May

Affect Management
Acetaminophen
Carbamazepine
Cooximetry (carboxyhemoglobin, methemoglobin, sulfhemoglobin)
Digoxin
Selected metals (iron, lead, mercury; based on history and clinical
findings)
Lithium
Phenytoin
Salicylate
Theophylline, caffeine
Toxic alcohol (ethylene glycol, isopropanol, methanol)
Valproic acid

Concentrations of sodium, BUN, creatinine, glucose,

and measured osmolality, which are used in determining the OG, must be obtained simultaneously
in order to increase validity. The normal OG ranges
from 214 to 10.54,60 Ethanol, ethylene glycol, methanol, isopropanol, excipients (eg, propylene glycol),
ketones, and shock states can raise the OG.61,62 It
is important to remember that the large normal
range for the OG may allow a patient to have a
normal value despite a clinically significant gap for
that patient.
The arterial oxygen saturation gap is the calculated
percentage saturation (based on Po2 and pH) minus
the percentage saturation measured by multiwavelength cooximetry (not simple pulse oximetry). An
arterial oxygen saturation gap of . 5% usually results
from elevated levels of carboxyhemoglobin, methemoglobin, or sulfhemoglobin. Cyanide poisoning does
not result in an increased oxygen saturation gap.63
Coma Cocktail
Historically, the initial treatment of patients with
undifferentiated AMS included use of a coma
cocktail, which refers to IV administration of dextrose, thiamine, and naloxone. Rapid glucose testing
is often available, in which case hypoglycemia can
be confirmed and rapidly corrected. If rapid glucose
analysis is unavailable, dextrose should be administered empirically.64
Thiamine (vitamin B1) is administered routinely
with dextrose, in a dose of 100 mg, to prevent precipitation of Wernicke encephalopathy. This concern
is not evidence based and is attributed to a poorly
described case series.65 However, Wernicke encephalopathy can complicate other medical conditions,
including hyperemesis gravidarum.66 In suspected
hypoglycemia, dextrose should not be withheld if
thiamine is not available immediately.64 Furthermore,
for true cases of suspected Wernicke encephalopathy,
higher doses of thiamine are recommended.67
Postgraduate Education Corner

Table 4MUDPILES Mnemonic for Causes of

Anion-Gap Acidosis
Methanol, metformin
Uremia
Diabetic ketoacidosis
Paraldehyde, propylene glycol, propofol
Iron, isoniazid, ibuprofen
Lactate
Ethanol (alcoholic ketoacidosis), ethylene glycol
Salicylates, starvation ketoacidosis

In the treatment of mixed opioid agonist-antagonists

such as buprenorphine, the reversal with naloxone
follows a bell-shaped curve. IV doses . 4 mg are less
effective than smaller doses, thus reemphasizing the
need for careful titration.78,79 When multiple sedativehypnotic agents contribute to respiratory depression,
naloxone may cause adverse reactions without clinical benefit.80
GI Decontamination

The purpose of administering naloxone, a competitive opioid receptor antagonist, is to reverse opioidinduced respiratory depression. An ideal therapeutic
goal is to prevent intubation without precipitating
withdrawal. As such, a reasonable starting dose is
0.2 to 0.4 mg IV. This can be increased rapidly to a
dose of 2 to 10 mg if no effect is achieved. The typical
half-life is 30 to 80 min, so additional doses may be
required for reversal of resedation.68,69 If multiple
doses are administered, a continuous infusion of twothirds the minimal effective dose may be administered per hour.70 Repeated doses of naloxone are
often needed for agents with long half-lives, such as
methadone or extended-release oxycodone. In addition to precipitation of opioid withdrawal, adverse
reactions to naloxone include development of noncardiogenic pulmonary edema or seizures (with tramadol or meperidine).64,71-77

GI decontamination refers to any measures undertaken to minimize absorption of the toxin from the
GI tract. These measures have traditionally included
activated charcoal (AC), syrup of ipecac, gastric lavage,
and whole-bowel irrigation (WBI). Because of a lack
of proven benefit and undesirable side effects, however, the use of ipecac and gastric lavage are no longer
recommended routinely.80-82
AC is most likely to be of benefit if given within 1 h
of ingestion, although patients with certain ingestions, such as salicylate, may benefit from delayed
administration.83,84 The recommended dose is 0.5
to 1 g/kg in children or 25 to 100 g in adults. Importantly, AC does not bind well to hydrocarbons, alcohols, or most metals (except thallium).85 Aspiration is
a potential complication and may result in prolonged
hospitalization, lung injury, or death.83,86-89 Therefore, AC administration is contraindicated unless the

Figure 1. Osmolal gap calculations. CF 5 correction factor; EtOH 5 ethanol; Glu 5 glucose; Na 5 sodium;
OG 5 osmol gap.
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patient is able to protect his or her airway or has

been intubated. Common side effects include vomiting, abdominal bloating, constipation, or diarrhea.83
Relative contraindications include anticipated endoscopy or abdominal surgery. Cathartics (eg, sorbitol)
should not be used.90 Importantly, the routine use of
AC has not been demonstrated convincingly to reduce
morbidity or mortality.
Unlike single-dose charcoal, which is used for gastric decontamination, the administration of repeated,
scheduled doses of charcoal is a form of enhanced
elimination and is referred to as multiple-dose AC.
Although multiple-dose AC has been recommended
and shown to decrease serum levels for various
agents (theophylline, dapsone, phenobarbital, carbamazepine, and quinine),91 its use has not been
demonstrated to improve patient-oriented outcomes
(eg, mortality). Its routine use is not recommended.
WBI involves administering large volumes (1.5-2 L/h)
of a polyethylene glycol-based solution to facilitate
rapid transit of a toxin through the GI tract. In volunteer studies, WBI was effective in decreasing absorption of enteric-coated aspirin and sustained-release
lithium tablets.92,93 Although it is not recommended
routinely, WBI should be considered following ingestion of highly toxic, extended-release preparations
such as verapamil, metals such as iron (especially those
preparations with high concentrations of elemental
iron), or asymptomatic drug packers.94-98 Contraindications include compromised airway, ileus, and bowel
obstruction.94 As in the case of charcoal, data demonstrating improved clinical outcomes are lacking.
Endoscopy has been used to remove button batteries or drug bezoars, whereas laparotomy has been
used to remove illicit drug packets (body packers or
stuffers).98 Button batteries lodged in the esophagus
or trachea mandate endoscopic removal.99 Symptomatic leakage of sympathomimetic drug packets generally mandates immediate laparotomy, whereas leakage
of packets of heroin can be managed more conservatively. Bowel obstruction due to drug packet ingestion also requires operative management.98
Enhanced Elimination
All xenobiotics, or exogenous chemicals, achieve
effectiveness and toxicity based on the ability to reach
target tissues. Pharmacokinetic variables include
absorption, distribution, metabolism, clearance, and
elimination. Extracorporeal elimination techniques
(EETs) seek to reduce or prevent toxic concentrations in target tissue. The ability of EETs to remove
a xenobiotic depends on the xenobiotics molecular
weight, protein binding, and apparent volume of distribution (Vd). Substances with a small Vd (, 1 L/kg)
have limited penetration into tissue and maintain
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a relatively high intravascular concentration. Low

molecular weight, low Vd, high water solubility,
and low protein binding allow the xenobiotic to
be removed more effectively by hemodialysis (HD)
because the xenobiotic can cross the filtration membrane easier and dissolve into the dialysate.
The main EET used in the management of poisoning is HD, which can both reduce drug/metabolite
concentrations and correct fluid and electrolyte abnormalities. A list of xenobiotics that undergo significant
clearance by HD is given in Table 5. Hemoperfusion
has advantages over HD for the treatment of some
poisonings because of its ability to remove substances
with high protein binding, such as carbamazepine,100
but is no longer available in most US centers.
The advantages of HD are technical ease and availability. Because HD removes xenobiotics only from
circulating blood, intercompartmental transfer or
prolonged absorption may require prolonged or recurrent treatments. This scenario commonly occurs with
the treatment of lithium toxicity, where levels can rise
again because of redistribution many hours after HD
is completed. In cases where rebound is a concern, a
precartridge level should be obtained before terminating HD. Because HD may also remove therapeutic medications, the dosing interval of some drugs
may need to be decreased.
Newer EET techniques include molecular adsorbent recirculating system, sustained low-efficiency
dialysis, extended daily dialysis, and continuous renal
replacement therapy (CRRT).101-103 These techniques
may aid in the treatment of poisoned patients but
in general should be considered adjunctive therapy.
Additionally, several studies have failed to show that
CRRT is safer in hypotensive patients.104,105
Specific Xenobiotics Removed by HD
Salicylates have a low molecular weight, a relatively
small Vd, and significant protein binding, but after
overdose, the fraction of unbound drug increases,
Table 5Xenobiotics Removed by Hemodialysis
Salicylates
Phenobarbital
Theophylline
Methanol
Ethylene glycol
Lithium
Diethylene glycol
Propylene glycol
Isopropyl alcohol
Valproic acid
Carbamazepine
This list contains some of the more common substances for which
hemodialysis is effective, but not all cases will require hemodialysis.
Postgraduate Education Corner

allowing for effective HD.106 There are no specific

evidence-based guidelines for when to initiate HD in
the treatment of salicylate toxicity. Generally, AMS,
pulmonary edema, seizures, and elevated and rising
salicylate concentrations despite aggressive supportive
care, or serum levels nearing 100 mg/dL following
an acute overdose, typically require emergent use of
HD.107
Li1 has a low molecular weight, minimal protein
binding, and a small Vd. As with salicylate toxicity,
clear, evidence-based guidelines for when to initiate
HD do not exist. Furthermore, because HD has
not been demonstrated to improve clinical outcomes with Li1 toxicity, there is some variability in
clinical practice and controversy surrounding the best
treatment. Many medical toxicologists believe the
decision as to whether to remove Li1 via HD should
be based more on clinical findings, such as the presence of encephalopathy or neurotoxicity, then on
levels alone.108 Acute Li1 ingestion may result in
predistribution levels well above 4 mEq/L within
the first few hours of ingestion, but may produce
only minimal clinical effects. Alternatively, some
propose that Li1 should be removed by HD before
it reaches the CNS.106 Newer forms of extracorporeal
therapy such as CRRT have been proposed for use
in Li1 toxicity based on the ability to slowly remove
lithium and eliminate rebound. However, because of
limited evidence supporting CRRT, HD is still the
recommended modality for extracorporeal removal
of Li1.106
Ethylene glycol and methanol have low molecular
weights, limited protein binding, and a small Vd.109
HD effectively removes both the parent compounds
and their toxic metabolites while correcting pH, fluid
status, and electrolytes.110 Fomepizole, a safe and
effective inhibitor of alcohol dehydrogenase, has
changed the indications of HD following methanol
or ethylene glycol ingestions. Before fomepizole, the
threshold for initiating HD was a plasma concentration of 50 mg/dL.111 Currently, if a patient is treated
with fomepizole, elevated concentrations of toxic
alcohols alone should not prompt use of HD.112 However, significant metabolic acidosis or renal dysfunction associated with any specific toxic alcohol level is
likely to require HD.111 Although isopropanol may
also be removed by HD, it is metabolized to acetone
and causes much less toxicity, making HD unnecessary in the vast majority of cases.
Urinary Alkalinization: Some drugs become ionized
and undergo ion trapping in urine at elevated urine
pH, limiting reabsorption and enhancing elimination. Table 6 includes xenobiotics in which urinary
alkalinization is recommended.113 A general goal of urinary alkalinization is to maintain a urine pH 7.5,114
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Table 6Xenobiotics For Which Urinary Alkalinization

Increases Clearance
Salicylatesa
Chlorpropamide
2,4-dichlorophenoxyacetic acid
Diflunisal
Fluoride
Mecoprop (MCPP, a chlorphenoxy herbicide)
Methotrexate
Phenobarbitalb
a The most recent recommendations of the American Academy of
Clinical Toxicology and the European Association of Poison Control Centres and the Clinical Toxicologists Position Statement is that
based on volunteer and clinical studies, urine alkalinization should be
considered as first line treatment for patients with moderately severe
salicylate poisoning who do not meet the criteria for hemodialysis.113
b Phenobarbital is the only barbiturate shown to benefit from urinary
alkalinization.

although in the case of salicylate, increased renal salicylate clearance occurs up to about pH 8.5. There
is no standard method of producing alkaluria. Many
physicians infuse 150 mEq NaHCO3 in 1 L of 5%
dextrose in water (D5W) solution. Potassium supplementation is usually needed in the absence of
hyperkalemia to prevent paradoxical urinary aciduria
from distal tubular reabsorption of Na1 in exchange
for protons rather than K1.
Emerging Therapies
Several therapies have emerged in recent years for
the treatment of poisonings. These include hyperinsulinemic euglycemia (HIE) therapy for the treatment
of severe calcium channel blocker (CCB) toxicity, IV
lipid emulsion (ILE) therapy for shock due to lipophilic drugs, and hydroxocobalamin for the treatment
of cyanide toxicity.
Hyperinsulinemia Euglycemia
Toxicity from CCB poisoning is characterized
by hypotension, hypokalemia, cardiac dysrhythmias,
metabolic acidosis, and hyperglycemia. The hyperglycemia is multifactorial in origin. First, CCB impair
calcium influx through the l-type calcium channels
in the pancreatic b cells, resulting in impaired insulin release. In addition, CCB poisoning results in
impaired intracellular signaling and insulin resistance.115 During CCB toxicity, the myocardial cells
change their preferred energy substrate from free
fatty acids to glucose.116 High-dose insulin therapy
has been shown to promote cellular uptake of glucose
into adipose and muscle tissue, reduce cytosolic calcium concentration, and promote intracellular potassium movement.116,117 The use of HIE may increase
CHEST / 140 / 3 / SEPTEMBER, 2011

801

myocardial contractility and mean arterial pressure,

but typically does not reverse bradycardia or conduction defects.116-118 Clinical improvement often begins
approximately 30 min after therapy is commenced.117
Although there is moderate human experience with
HIE, its use in CCB toxicity has not been validated
prospectively and may be associated with potential
adverse effects including hypoglycemia and hypokalemia.117,119 However, it is unlikely that a prospective randomized controlled trial on HIE will ever be
conducted.118
Although various guidelines for the use of HIE
exist, one approach involves giving an IV bolus of
1 unit/kg of insulin, followed by a maintenance insulin infusion of 0.5 to 1 unit/kg/h.120 Glucose should
be monitored frequently. Unless the patient is significantly hyperglycemic, an initial bolus of 1.0 g/kg
of glucose should be given followed by a continuous
glucose infusion of 0.5 g/kg/h. This infusion should
be titrated based on the patients blood sugar level.
Hyperinsulinemic euglycemic therapy is most likely
to be of benefit in patients who are hyperglycemic
and in those with decreased cardiac contractility.
The exact timing as to when to start HIE is somewhat controversial. Given the lack of controlled trials,
its use certainly cannot be recommended as first-line
therapy.117 However, because its use as a last ditch
effort seems to be associated with failure,116,118 it
seems reasonable to start HIE shortly after a patient
fails to improve with standard therapies including
vasopressors. Hyperinsulinemic euglycemic therapy
is most likely to be of benefit in patients who are
hyperglycemic and in those with decreased cardiac
contractility.
IV Lipid Emulsion
Based on limited data, the use of ILE has been
cited as standard of care for treating neurotoxicity or
cardiotoxicity due to local anesthetics.121 In 2006, the
first cases of ILE use in humans were reported and
involved successful resuscitation after cardiac arrest
following local anesthetic toxicity.122,123 Animal models
have demonstrated benefit in the management of bupivacaine,124 clomipramine,125 verapamil,126,127 and possibly propranolol.128 There is also a case of prolonged
cardiac arrest due to lamotrigine and bupropion whose
successful resuscitation involved ILE.113
The exact mechanism of ILE is unknown, but likely
involves decreasing the toxins Vd by shifting lipophilic drugs into the vascular compartment and limiting target tissue concentration. Other theories
include inhibition of mitochondrial metabolism of
lipids, impairment of fatty acid delivery to mitochondria, and activation of potassium and calcium channels involved with local anesthetic toxicity.129
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Use of ILE should be considered for patients with

severe toxicity due to a lipophilic drug who do not
respond to standard measures. ILE is available in
10%, 20%, and 30% solutions, and several dosing regiments have been suggested. No prospective human
studies have been performed. Based on human experience and animal research, one regimen involves
administering 1.5 mL/kg of a 20% ILE over 1 min,
followed by a continuous infusion of 0.25 mL/kg/min
for 60 min.130 If there is no response to the initial
bolus, it can be repeated twice in 5-min increments.
If hypotension persists, the maintenance infusion can
be increased to 0.5 mL/kg/min.129 Pyrogenic reactions, hyperlipidemia, pulmonary injury, hepatosplenomegaly, thrombocytopenia, and fat embolism
are theoretic concerns.131 When administered as a
resuscitative drug, however, few adverse events have
been described. Because of the lipemia, laboratory
studies may be difficult to analyze transiently or may
produce spurious results.132 It is important to recognize that propofol is not a substitute for ILE, because
of myocardial depressant effects and different lipid
content.133
Hydroxocobalamin
Traditional therapy for cyanide toxicity involves the
administration of nitrites (to produce methemoglobinemia) and sodium thiosulfate (to convert cyanide into
thiocyanate).134 These therapies may not be ideal for
patients who have high carboxyhemoglobin levels.135
Hydroxocobalamin (Cyanokit) is an alternative cyanide antidote now approved by the US Food and Drug
Administration. Hydroxocobalamin is vitamin B12a,
the precursor for cyanocobalamin (vitamin B12). It
combines with cyanide to form cyanocobalamin, which
is then excreted renally.136 The typical treatment dose
is 5 g IV, which can be repeated once if needed. In a
swine model, the administration of hydroxocobalamin and sodium thiosulfate appeared to be as effective as sodium nitrite and sodium thiosulfate in the
treatment of cyanide toxicity.134 When using both
antidotes, they cannot be administered in the same
IV because of incompatability.137 Hydroxocobalamin has some side effects. Although not necessarily
undesired, it can augment mean arterial pressure
because of the nitric oxide scavenging effects of
cobalamin.134,138 Use of hydroxocobalamin transiently
produces a pink discoloration of tissue and blood,
abnormal cooximetry measurements, and altered
serum values for aspartate aminotransferase, bilirubin,
creatinine, magnesium, and iron.139-141 Because of the
blood discoloration, HD machines may interpret a
blood leak incorrectly and delay or prevent the use
of HD.142 An acneiform rash and erythema are commonly encountered.
Postgraduate Education Corner

Conclusions
Severe clinical illness can occur following overdose
or exposure to certain chemicals and illicit substances.
Many agents produce toxidromes, which allows the
physician to identify a probable poisoning syndrome
and empirically determine the most appropriate
management. Knowledge of the various routes of
decontamination, emerging antidotal therapies, and
opportunities for enhanced elimination allow for provision of optimal care in the critical care setting. Many
cases of poisoning present diagnostic and therapeutic
challenges. It is recommended that physicians consult a medical toxicologist or regional poison control
center (800-222-1222) to discuss individual cases to
assist in the management of each patient.
Acknowledgments
Financial/nonfinancial disclosures: The authors have reported
to CHEST that no potential conflicts of interest exist with any
companies/organizations whose products or services may be discussed in this article.

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