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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,
CHEST / 140 / 3 / SEPTEMBER, 2011
795
796
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
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
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
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
1. Kaufman DM, Hegyi T, Duberstein JL. Heroin intoxication
in adolescents. Pediatrics. 1972;50(5):746-753.
2. Sporer KA. Acute heroin overdose. Ann Intern Med. 1999;
130(7):584-590.
3. Hoffman JR, Schriger DL, Luo JS. The empiric use of naloxone in patients with altered mental status: a reappraisal.
Ann Emerg Med. 1991;20(3):246-252.
4. Buck ML, Blumer JL. Opioids and other analgesics. Adverse
effects in the intensive care unit. Crit Care Clin. 1991;7(3):
615-637.
5. Wald PH, Weisman RS, Goldfrank L. Opioids. Top Emerg Med.
1985;7(3):9-17.
6. Clark RF, Wei EM, Anderson PO. Meperidine: therapeutic
use and toxicity. J Emerg Med. 1995;13(6):797-802.
7. Kahn LH, Alderfer RJ, Graham DJ. Seizures reported with
tramadol. JAMA. 1997;278(20):1661.
8. Stork CM, Redd JT, Fine K, Hoffman RS. Propoxypheneinduced wide QRS complex dysrhythmia responsive to
sodium bicarbonatea case report. J Toxicol Clin Toxicol.
1995;33(2):179-183.
9. Whitcomb DC, Gilliam FR III, Starmer CF, Grant AO.
Marked QRS complex abnormalities and sodium channel
blockade by propoxyphene reversed with lidocaine. J Clin
Invest. 1989;84(5):1629-1636.
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):
1741-1758.
14. Derlet RW, Rice P, Horowitz BZ, Lord RV. Amphetamine
toxicity: experience with 127 cases. J Emerg Med. 1989;7(2):
157-161.
www.chestpubs.org
15. Gay GR, Inaba DS, Sheppard CW, Newmeyer JA. Cocaine:
history, epidemiology, human pharmacology, and treatment.
A perspective on a new debut for an old girl. Clin Toxicol.
1975;8(2):149-178.
16. Rosenberg J, Pentel P, Pond S, Benowitz N, Olson K.
Hyperthermia associated with drug intoxication. Crit Care
Med. 1986;14(11):964-969.
17. Leshner AI. Molecular mechanisms of cocaine addiction.
N Engl J Med. 1996;335(2):128-129.
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.
1980;16(4):499-508.
22. Derlet RW, Albertson TE, Rice P. Antagonism of cocaine,
amphetamine, and methamphetamine toxicity. Pharmacol
Biochem Behav. 1990;36(4):745-749.
23. Espelin DE, Done AK. Amphetamine poisoning. Effectiveness of chlorpromazine. N Engl J Med. 1968;278(25):
1361-1365.
24. Kierzkowska B, Staczyk J, Kasprzak JD. Myocardial infarction in a 17-year-old body builder using clenbuterol. Circ J.
2005;69(9):1144-1146.
25. Victor M, Brausch C. The role of abstinence in the genesis
of alcoholic epilepsy. Epilepsia. 1967;8(1):1-20.
26. Yost DA. Alcohol withdrawal syndrome. Am Fam Physician.
1996;54(2):657-664., 669.
27. Beaver KM, Gavin TJ. Treatment of acute anticholinergic
poisoning with physostigmine. Am J Emerg Med. 1998;
16(5):505-507.
28. Frascogna N. Physostigmine: is there a role for this antidote
in pediatric poisonings? Curr Opin Pediatr. 2007;19(2):
201-205.
29. Gowdy JM. Stramonium intoxication: review of symptomatology in 212 cases. JAMA. 1972;221(6):585-587.
30. Longo VG. Behavioral and electroencephalographic effects
of atropine and related compounds. Pharmacol Rev. 1966;
18(2):965-996.
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
CHEST / 140 / 3 / SEPTEMBER, 2011
803
Approximate
Detection Period
4d
24 h
3 wk
3d
4 wk
3d
3d
4 wk
4d
8d
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.
www.chestpubs.org
799
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
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
1. Kaufman DM, Hegyi T, Duberstein JL. Heroin intoxication
in adolescents. Pediatrics. 1972;50(5):746-753.
2. Sporer KA. Acute heroin overdose. Ann Intern Med. 1999;
130(7):584-590.
3. Hoffman JR, Schriger DL, Luo JS. The empiric use of naloxone in patients with altered mental status: a reappraisal.
Ann Emerg Med. 1991;20(3):246-252.
4. Buck ML, Blumer JL. Opioids and other analgesics. Adverse
effects in the intensive care unit. Crit Care Clin. 1991;7(3):
615-637.
5. Wald PH, Weisman RS, Goldfrank L. Opioids. Top Emerg Med.
1985;7(3):9-17.
6. Clark RF, Wei EM, Anderson PO. Meperidine: therapeutic
use and toxicity. J Emerg Med. 1995;13(6):797-802.
7. Kahn LH, Alderfer RJ, Graham DJ. Seizures reported with
tramadol. JAMA. 1997;278(20):1661.
8. Stork CM, Redd JT, Fine K, Hoffman RS. Propoxypheneinduced wide QRS complex dysrhythmia responsive to
sodium bicarbonatea case report. J Toxicol Clin Toxicol.
1995;33(2):179-183.
9. Whitcomb DC, Gilliam FR III, Starmer CF, Grant AO.
Marked QRS complex abnormalities and sodium channel
blockade by propoxyphene reversed with lidocaine. J Clin
Invest. 1989;84(5):1629-1636.
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):
1741-1758.
14. Derlet RW, Rice P, Horowitz BZ, Lord RV. Amphetamine
toxicity: experience with 127 cases. J Emerg Med. 1989;7(2):
157-161.
www.chestpubs.org
15. Gay GR, Inaba DS, Sheppard CW, Newmeyer JA. Cocaine:
history, epidemiology, human pharmacology, and treatment.
A perspective on a new debut for an old girl. Clin Toxicol.
1975;8(2):149-178.
16. Rosenberg J, Pentel P, Pond S, Benowitz N, Olson K.
Hyperthermia associated with drug intoxication. Crit Care
Med. 1986;14(11):964-969.
17. Leshner AI. Molecular mechanisms of cocaine addiction.
N Engl J Med. 1996;335(2):128-129.
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.
1980;16(4):499-508.
22. Derlet RW, Albertson TE, Rice P. Antagonism of cocaine,
amphetamine, and methamphetamine toxicity. Pharmacol
Biochem Behav. 1990;36(4):745-749.
23. Espelin DE, Done AK. Amphetamine poisoning. Effectiveness of chlorpromazine. N Engl J Med. 1968;278(25):
1361-1365.
24. Kierzkowska B, Staczyk J, Kasprzak JD. Myocardial infarction in a 17-year-old body builder using clenbuterol. Circ J.
2005;69(9):1144-1146.
25. Victor M, Brausch C. The role of abstinence in the genesis
of alcoholic epilepsy. Epilepsia. 1967;8(1):1-20.
26. Yost DA. Alcohol withdrawal syndrome. Am Fam Physician.
1996;54(2):657-664., 669.
27. Beaver KM, Gavin TJ. Treatment of acute anticholinergic
poisoning with physostigmine. Am J Emerg Med. 1998;
16(5):505-507.
28. Frascogna N. Physostigmine: is there a role for this antidote
in pediatric poisonings? Curr Opin Pediatr. 2007;19(2):
201-205.
29. Gowdy JM. Stramonium intoxication: review of symptomatology in 212 cases. JAMA. 1972;221(6):585-587.
30. Longo VG. Behavioral and electroencephalographic effects
of atropine and related compounds. Pharmacol Rev. 1966;
18(2):965-996.
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
CHEST / 140 / 3 / SEPTEMBER, 2011
803
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