Overdose, Poisoning, and Withdrawal

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Chapter 58: Overdose, Poisoning, and Withdrawal
KEY POINTS
KEY POINTS
1. Supportive care is most important. “Treat the patient not the poison.”
2. Always check for the common and treatable coingestants: alcohol, acetaminophen, and salicylates.
3. Consider decontamination and the use of antidotes.
4. Empiric treatment with glucose, naloxone and thiamine is generally safe in the comatose patient.
5. Always seek help from your regional poison control center.
GENERAL PRINCIPLES OF OVERDOSE AND POISONING

Introduction
Exposures to toxic substances, whether accidental or intentional, remain a significant contributor to morbidity and mortality in the U.S. Approximately
10,830 calls are placed to the Poison Control hotline daily, while The American Association of Poison Control Centers (AAPCC) reported over 2.3 million
human exposure calls in 2011, most commonly due to analgesics (12.9%), sedatives and antipsychotics (11%), and antidepressants (6.4%).
The American Academy of Clinical Toxicology (AACT) and the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) provide
detailed guidance regarding overdose, poisoning and withdrawal. In addition assistance should always be obtained from regional poison control
centers.
The American Association of Poison Control Centers (AAPCC) can be contacted by the following means: www.aapcc.org or 1-800-222-1222.
History and Physical
Clinicians must follow a systematic and consistent approach throughout evaluation and management. A basic history and physical exam, followed by a
more focused poison-specific exam, is vital, from which point management is directed toward the provision of acute stabilization, supportive care,
prevention of absorption and, when applicable, the use of antidotes and enhanced elimination techniques.
Due to depressed mentation or reluctance to cooperate useful information may be obtainable from a patient's associates (family, friends, and
coworkers), or from first responders and bystanders. Environmental clues such as suicide notes, drug paraphernalia and empty pill bottles can
provide valuable information. Once the patient is identified, reviewing prior hospital records may reveal a history of recent prescriptions, previous
overdoses and any psychiatric history.
Specificity regarding the type of drug or toxin (including; prescription, illicit, over the counter and herbal medications), the dosage, route of exposure,
time of exposure or ingestion and intent requires close attention. Unknown pills or chemicals require identification by consultation with a regional
poison control center, computerized drug database, or product manufacturers.
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Toxidromes are specific symptoms and physical signs that correlate with the manifestations of a drug class on a particular set of neuroreceptors.
Chapter 58: Overdose, Poisoning, and Withdrawal, Edward Mossop; Fred DiBlasio Page 1 / 42
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Performed quickly while resuscitative measures are being instituted, a toxidrome-oriented exam should include vital signs, a focused neurological
exam centered on level of consciousness, pupillary and motor reaction, broad examination of the skin noting moisture, cyanosis, rashes, and puncture
marks, focused evaluation of the respiratory system, and assessment of bowel sounds. See Table 58–1 Toxidromes-oriented physical exam and Table
overdoses and any psychiatric history.
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Specificity regarding the type of drug or toxin (including; prescription, illicit, over the counter and herbal medications), the dosage, route of exposure,
time of exposure or ingestion and intent requires close attention. Unknown pills or chemicals require identification by consultation with a regional
poison control center, computerized drug database, or product manufacturers.
Toxidromes are specific symptoms and physical signs that correlate with the manifestations of a drug class on a particular set of neuroreceptors.
Performed quickly while resuscitative measures are being instituted, a toxidrome-oriented exam should include vital signs, a focused neurological
exam centered on level of consciousness, pupillary and motor reaction, broad examination of the skin noting moisture, cyanosis, rashes, and puncture
marks, focused evaluation of the respiratory system, and assessment of bowel sounds. See Table 58–1 Toxidromes-oriented physical exam and Table
58–2: Toxidrome clinical findings.
Table 58–1
Toxidrome oriented physical exam.
Toxidrome-Oriented Examination
Vital signs
Focused neurologic exam centered on level of consciousness (alert, responsive to voice, responsive to pain, unresponsive)
Pupillary and motor reaction
Skin examination (moisture, cyanosis, rashes)
Respiratory examination
Assessement of bowel sounds
Reproduced with permission from Rumack BH, Matthew H: Acetaminophen poisoning and toxicity, Pediatrics. 1975 Jun;55(6):871-876
Table 58–2
Common toxidromes.
Category Vital Signs Mental Status Physical Signs Agent/Drug
Sympathomimetic hypertension, tachycardia Hyperalert, Mydriasis, tremor, increased peristalsis seizures Cocaine, MDMA
hyperthermia, tachypnea euphoric Mephedrone,
agitated, Methamphetamine
delirium
Opioid Hypotension, bradycardia, Stupor, Miosis, hyporeflexia Morphine,

apnea, shallow breathing, lethargy, coma oxycodone,
hypothermia fentanyl
Sedative-Hypnotic Hypotension, bradycardia, Stupor, coma, Hyporeflexia, ataxia, Benzodiazepines,

apnea slurred speech zolpidem,
barbiturates
Anticholingeric Hypertension, tachycardia, Agitated, Mydriasis, dry flushed skin, urinary retention, decreased Atropine,
hyperthermia delirium, bowel sounds, dry mucus membranes, seizures antidepressants,
hallucinations antihistamines
Cholinergic Bradycardia, apnea, Confusion, Miosis, salivation, lacrimation, diaphoresis, nausea, Organophosphates
shallow breathing agitation, coma vomiting, urination, defecation, muscle fasciculations,
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Hallucinogenic Hyperthermia, Agitated but Mydriasis, synesthesia, nystagmus PCP, LSD,
hypertension, tachycardia oriented, mushrooms, MDMA
Assessement of bowel sounds Access Provided by:
Reproduced with permission from Rumack BH, Matthew H: Acetaminophen poisoning and toxicity, Pediatrics. 1975 Jun;55(6):871-876
Table 58–2
Common toxidromes.
Category Vital Signs Mental Status Physical Signs Agent/Drug
Sympathomimetic hypertension, tachycardia Hyperalert, Mydriasis, tremor, increased peristalsis seizures Cocaine, MDMA
hyperthermia, tachypnea euphoric Mephedrone,
agitated, Methamphetamine
delirium
Opioid Hypotension, bradycardia, Stupor, Miosis, hyporeflexia Morphine,

apnea, shallow breathing, lethargy, coma oxycodone,
hypothermia fentanyl
Sedative-Hypnotic Hypotension, bradycardia, Stupor, coma, Hyporeflexia, ataxia, Benzodiazepines,

apnea slurred speech zolpidem,
barbiturates
Anticholingeric Hypertension, tachycardia, Agitated, Mydriasis, dry flushed skin, urinary retention, decreased Atropine,
hyperthermia delirium, bowel sounds, dry mucus membranes, seizures antidepressants,
hallucinations antihistamines
Cholinergic Bradycardia, apnea, Confusion, Miosis, salivation, lacrimation, diaphoresis, nausea, Organophosphates
shallow breathing agitation, coma vomiting, urination, defecation, muscle fasciculations,
weakness, seizures, arrhythmia
Hallucinogenic Hyperthermia, Agitated but Mydriasis, synesthesia, nystagmus PCP, LSD,

hypertension, tachycardia oriented, mushrooms, MDMA
psychosis,
anxiety
Serotonin Hyperthermia, tachycardia, Agitation, Increased muscle tone, hyperreflexia, clonus SSRIs,
hypertension, tachypnea confusion dextromethorphan,
TCAs,
amphetamines
SSRI: selective serotonin reuptake inhibitor;
TCA: tricyclic antidepressants;
PCP: phencyclidine;
LSD: Lysergic acid diethylamide;
MDMA: Methylenedioxymethamphetamine
Investigations
Labs
Bedside serum glucose testing is a requirement for any patient with altered mentation, after which immediate empiric dextrose administration is
recommended in cases where measurement result is low, or not available. Thiamine should also be replaced in patients suspected to be deficient, to
prevent precipitation of Wernicke encephalopathy (chronic alcoholics). However, it is not recommended to delay glucose administration while
thiamine is administered.
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Investigations
Labs
Bedside serum glucose testing is a requirement for any patient with altered mentation, after which immediate empiric dextrose administration is
recommended in cases where measurement result is low, or not available. Thiamine should also be replaced in patients suspected to be deficient, to
prevent precipitation of Wernicke encephalopathy (chronic alcoholics). However, it is not recommended to delay glucose administration while
thiamine is administered.
Salicylates, acetaminophen, and alcohol are all easily available and commonly used agents, therefore may be co-ingested in addition to other
medications in deliberate overdose attempts. Acetaminophen and salicylates are also found in numerous combination preparations of prescription
drugs and over-the-counter medications. These agents therefore may worsen outcomes or complicate presenting symptoms and signs in an overdose.
Because these agents are so commonly used and potentially treatable, it is recommended to routinely check these blood levels in all overdose patients.
Additional basic investigations should include, complete blood count (CBC), serum electrolytes, blood urea nitrogen, serum creatinine, coagulation
profile, liver function tests (LFTs), creatine kinase (CK), arterial blood gas (ABG), serum osmolality, calculated osmolar gap, and a urine analysis
(crystals, myo- or hemoglobinuria).
Specific scenarios may necessitate additional testing including specific drug levels, or testing for methemoglobin and carboxyhemoglobin. Serum
concentrations may be of utility in the management of salicylate, acetaminophen, barbiturates, digoxin, ethanol, iron, lithium, and theophylline
overdose as these serum assays provide rapid result and are widely available.
Urine toxicology screen does not necessarily reflect current intoxication, and may serve in some cases as a distracter rather than a diagnostic aid in
patients with change in mental status.
EKG
An electrocardiogram may assist in the evaluation for the presence and severity of specific ingestions, or may demonstrate drug-related cardiotoxicity.
Serially, the electrocardiogram (EKG) can facilitate the monitoring of progression of specified toxicities. Performed in all subjects with suspected drug
ingestion, the key features to note include heart rate, dysrhythmia, axes, and intervals (QRS and QTc).
Imaging
In some cases, a plain abdominal film may demonstrate radiopaque medications such as iron tablets, and enteric-coated preparations, while indirect
visualization of drug packets (body packers and stuffers) may be demonstrated by the alteration of bowel gas patterns. Additionally, visualized
radiographic evidence of non-cardiogenic pulmonary edema and/or Adult Respiratory Distress Syndrome on an anterior posterior (AP) chest film, can
suggest the exposure to specific toxic agents.
A non-contrast head Computerized Tomography (CT) should be considered in anyone with a change in mental status to exclude non-toxicological
causes. In addition significant hypertension and change in mental status, in the setting of overdose with agents with stimulant properties, may be
secondary to intracranial complications such as hemorrhage, stroke or encephalopathy.
Initial Hospital Care
“Treat the patient, not the poison” is the adage summating the guiding principle of medical toxicology, and the treatment of this certain population of
patients. Still, the methods are generally similar to those utilized frequently in the care of critically ill patients.
In the majority of cases, general supportive care is paramount and frequently sufficient to affect complete recovery, yet initial therapeutic measures
will depend on the toxin ingested, severity of illness, and time elapsed between exposure and presentation. Assistance should always be obtained from
regional poison control centers.
Airway
Acute respiratory failure and severe acid-base disturbances demand endotracheal intubation and mechanical ventilation. Intubation for the purpose
of airway protection should be undertaken early in the poisoned patient with depressed mental status unless a rapidly reversible cause is known given
high risk of aspiration, which is increased at times when gastric decontamination must be performed.
Hemodynamic Support
Abnormal hemodynamics such as blood pressure, heart rate, and temperature should be treated in the standard way as per hospital guidelines. An
appropriate volume of isotonic intravenous crystalloids should be used to treat hypotension. Refractory hypotension and shock should be treated
with direct-acting vasopressors (norepinephrine, epinephrine, or vasopressin) however this may be ineffective in cases of calcium channel overdose
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Acute respiratory failure and severe acid-base disturbances demand endotracheal intubation and mechanical ventilation. Intubation for the purpose
of airway protection should be undertaken early in the poisoned patient with depressed mental status unless a rapidly reversible cause is known given
high risk of aspiration, which is increased at times when gastric decontamination must be performed.
Hemodynamic Support
Abnormal hemodynamics such as blood pressure, heart rate, and temperature should be treated in the standard way as per hospital guidelines. An
appropriate volume of isotonic intravenous crystalloids should be used to treat hypotension. Refractory hypotension and shock should be treated
with direct-acting vasopressors (norepinephrine, epinephrine, or vasopressin) however this may be ineffective in cases of calcium channel overdose
(see calcium channel overdose).
Hypertension as sequelae of agitation, or arising directly from ingestion of agents with stimulant properties, can be treated initially with sedatives such
as benzodiazepines. Should hypertension require specific therapy due to associated end-organ dysfunction (hypertensive emergency),
dihydropyridine subclass calcium-channel blockers are preferable given a profile of potent vasodilatation and few negative effects on cardiac
conduction and contractility.
Hyperthermia should be very closely monitored. When the temperature exceeds 39 degrees Celsius urgent cooling is required. Numerous techniques
exist and initially should include the use of fans, antipyretic medications (unless contra-indicated), cold IV fluids and ice baths. More specialized
methods include the use of intravenous cooling catheters and cooling pads applied to the skin. Those with excessive agitation, recurrent seizures or
increased muscular tone may require sedation and paralysis to prevent excessive heat production.
Control of Seizures
Seizures resulting from poisoning or withdrawal are best initially treated with benzodiazepines from which escalation to antiepileptic drugs may be
necessitated by persistence of seizures, noting that phenytoin is not recommended in the poisoned patient. In case of refractory seizure, general
anesthesia and paralytic agents may be required, and treatment should be monitored with serial or continuous electroencephalography (EEG).
Altered Mental State-Agitation or Coma
Drug associated agitated behavior is best treated with benzodiazepine administration, complimented by high-potency antipsychotics as indicated.
Antipsychotics should however be used with caution as they can lower seizure threshold and worsen hyperthermia and arrhythmias (prolong QT) in
certain cases of poisoning. Coma or depressed mental state management should focus on protection of the airway. In those patients with a depressed
mental status with no compromise in airway, empiric treatments with naloxone, glucose and thiamine can be administered. The routine use of
flumazenil, in the obtunded patient, for potential benzodiazepine overdose is not recommended due to the numerous adverse reactions associated.
Rhabdomyolysis
Rhabdomyolysis is a clinical condition characterized by myocyte injury and leakage of intracellular contents into the extracellular space. The most
serious complication is renal failure and it is estimated that 8%-15% of all cases of acute renal failure (ARF) are caused by rhabdomyolysis. There are
numerous triggers of rhabdomyolysis, however the final common pathway is depletion of muscle ATP stores causing loss of myocte integrity causing
dysfunction and release of intracellular contents.
Myocyte injury leads to release and increased levels of creatine kinase (CK), myoglobin, potassium, phosphorous, and uric acid. Calcium levels may be
low. Myoglobin is excreted in the urine, which becomes a red/brown color. Heme pigment casts cause renal tubular injury and renal failure, which may
worsen electrolyte abnormalities and produce an anion gap metabolic acidosis. Other serious complications include cardiac arrhythmias and arrest,
compartment syndrome and disseminated intra-vascular coagulation (DIC). Patients usually report muscle pain, weakness and dark urine. Diagnosis is
made by detecting markedly elevated levels of CK (usually greater than 5000 IU/L) with evidence of myoglobinuria on urine dipstick and microscopy.
Drug overdose or poisoning is a common cause of rhabdomyolysis and falls into 3 groups. 1. Trauma: Overdose victims may suffer muscle trauma from
accidents or impulsive behavior leading to direct muscle injury. 2. Non-traumatic exertional: Overdose patients may develop extensive muscle activity
from agitation or seizures, which can also cause extreme hyperthermia leading to myocyte injury. 3. Non-traumatic non-exertional: Certain drugs or
toxins can lead to direct myocyte damage. Other drugs may induce coma leading to ischemic compression. Drug induced hyperthermia, without
muscle activity, can lead to increased muscle energy demands and subsequent injury. See Table 58–3: Common drugs associated with rhabdomyolysis.
Table 58–3
Common drugs associated with rhabdomyolysis.
Chapter 58: Overdose, Poisoning, and Withdrawal, Edward Mossop; Fred DiBlasio
Common drugs associated with rhabdomyolysis Page 5 / 42
Lysergic acid diethylamide (LSD) HIV medications
accidents or impulsive behavior leading to direct muscle injury. 2. Non-traumatic exertional: Overdose patients may develop extensive muscle activity
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from agitation or seizures, which can also cause extreme hyperthermia leading to myocyte injury. 3. Non-traumatic non-exertional: Certain drugs or
toxins can lead to direct myocyte damage. Other drugs may induce coma leading to ischemic compression. Drug induced hyperthermia, without
muscle activity, can lead to increased muscle energy demands and subsequent injury. See Table 58–3: Common drugs associated with rhabdomyolysis.
Table 58–3
Common drugs associated with rhabdomyolysis.
Common drugs associated with rhabdomyolysis
Lysergic acid diethylamide (LSD) HIV medications
Alcohol Statins
Heroin Macrolides
Cocaine Colchicine
Amphetamines Carbon monoxide
Methadone Cyclosporine
Mushrooms Antipsychotics
Antihistamines selective serotonin reuptek inhibitor (SSRIs)
Management of rhabdomyolysis from a poison, drug or toxin initially involves discontinuing the offending agent and using decontamination or
enhanced elimination techniques to remove any drug or toxin. Aggressively control any hyperthermia, hyperactivity or agitation. Early and aggressive
fluid resuscitation is the mainstay of treatment to prevent renal injury. Fluids should be started if CK levels are > 5000 IU/L. The optimal fluid and rate of
repletion are unclear. Fluid repletion should be continued until plasma CK levels decrease to < 5000 IU/L and urine is dipstick negative for hematuria. A
forced alkaline diuresis, raising urine pH is raised to above 6.5 with sodium bicarbonate, may diminish the renal toxicity of heme however there is no
strong evidence to support this.
Decontamination and Enhanced Elimination
Decontamination involves removal of the toxin/poison from patient surfaces and gastrointestinal (GI) tract. In addition enhanced elimination
techniques including ion tapping, chelation therapy, hemodialysis, hemoperfusion, and lipid emulsion can be used to remove poisons/toxins already
absorbed.
Decontamination
Surface Decontamination
Surface decontamination involves the removal of dermal and ocular toxins by irrigation. The eye should be irrigated with an isotonic crystalloid until a
physiological pH is restored.
Gastrointestinal Decontamination
The practice known as GI decontamination refers to the functional removal of ingested toxins from the GI tract in order to decrease absorption. No
controlled clinical studies have demonstrated that the “routine” use of GI decontamination reduces morbidity and mortality in poisoned patients.
However, evidence from human volunteer trials and clinical studies suggest that decontamination may reduce the absorption of toxins in the GI tract
and may be helpful in select circumstances
Many methods have faded from clinical practice due to evidence based delineation of poor efficacy, and high risks, as well as position papers compiled
by AACT and EAPCCT.
1. Ipecac—The only emetic suitable for use in humans is syrup of ipecac, and despite its unique niche, use has significantly declined due to lack of
proven efficacy and risk of adverse events and therefore is not recommended.
2. Orogastric lavage—Gastric lavage involves the insertion of a large-bore 36- to 40-French orogastric tube and the subsequent positioning of the
patient in the left lateral decubitus position with the head of the bed in Trendelenburg position. The instillation of approximately 250mL of water or
However, evidence from human volunteer trials and clinical studies suggest that decontamination may reduce the absorption of toxins in the GI tract
and may be helpful in select circumstances Access Provided by:
Many methods have faded from clinical practice due to evidence based delineation of poor efficacy, and high risks, as well as position papers compiled
by AACT and EAPCCT.
1. Ipecac—The only emetic suitable for use in humans is syrup of ipecac, and despite its unique niche, use has significantly declined due to lack of
proven efficacy and risk of adverse events and therefore is not recommended.
2. Orogastric lavage—Gastric lavage involves the insertion of a large-bore 36- to 40-French orogastric tube and the subsequent positioning of the
patient in the left lateral decubitus position with the head of the bed in Trendelenburg position. The instillation of approximately 250mL of water or
saline follows, with the immediate evacuation via suction applied to the distal end of the tube. This cycle is completed until the evacuated solution is
free of pill fragments or particulate matter. This method is only considered to be useful in the first hour post ingestion and has been used for agents
that do not bind well to activated charcoal as well as for specific life threatening poisons such as tricyclic's, theophylline and cyanide.
Recent papers however, suggest that gastric lavage may be associated with serious complications, namely aspiration, esophageal perforation,
hypothermia and death. The American Association of Poison Centers (AAPC) and the European Association of Poisons Centres and Clinical
Toxicologists (EAPCCT) have issued a joint statement that gastric lavage should not be employed routinely, if ever, in the management of poisoned
patients.
3. Activated charcoal—Activated charcoal (AC) is an organic material, which adsorbs chemicals with a molecular weight range of 100-1000 Daltons,
preventing gastrointestinal absorption and subsequent toxicity. The agent can be administered orally or via a nasogastric tube, in single- and multi-
dose regimens depending on the toxin ingested, and is administered in a slurry in water containing 25 to 100 g initially (or for single dosing) followed
by 25 to 50 g every 2 to 4 hours in adults, unless the toxin dose is known, in which case the dosing of charcoal to toxin is a 10:1 ratio.
Many chemicals adsorb avidly to AC in a dose dependent fashion but certain substances particularly highly ionic compounds with low molecular
weight, mineral acids, and strong bases do not bind well. AC has not been shown to adsorb ethanol, even when administered prior to ethanol
ingestion. See Table 58–4: Poisons not well bound to activated charcoal.
Table 58–4
Poisons not well bound to activated charcoal.
A C not recommended
Lead
Mercury
Iron
Zinc
Acid/Alkalis
Hydrocarbons
Alcohols
Lithium
Calcium
Magnesium
Potassium
Those most likely to benefit from single dose activated charcoal (SDAC) must present within one hour of poison ingestion, but despite lack of evidence,
potential for benefit later in the course cannot be excluded.
Contraindications include a depressed mental status without airway protection (risk of aspiration), increased risk of severity of aspiration based on
ingested toxin (eg, hydrocarbon ingestion), a need for endoscopy, ingestion of a poorly adsorbed toxin (metals including iron, lithium, alkali, mineral
acids, alcohols), presence of intestinal obstruction, or concern for decreased peristalsis.
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Potassium
Those most likely to benefit from single dose activated charcoal (SDAC) must present within one hour of poison ingestion, but despite lack of evidence,
potential for benefit later in the course cannot be excluded.
Contraindications include a depressed mental status without airway protection (risk of aspiration), increased risk of severity of aspiration based on
ingested toxin (eg, hydrocarbon ingestion), a need for endoscopy, ingestion of a poorly adsorbed toxin (metals including iron, lithium, alkali, mineral
acids, alcohols), presence of intestinal obstruction, or concern for decreased peristalsis.
The AACT/EAPCCT recommends multiple-dose activated charcoal (MDAC) be considered only for patients having ingested life threatening amounts of
carbamazepine, dapsone, phenobarbital, quinine or theophylline. See Table 58–5: AACT/EAPCCT recommended drugs amenable to repeat dosing of
activated charcoal.
Table 58–5
AACT/EAPCCT recommended drugs amenable to repeat dosing of activated charcoal.
Drugs amenable to repeat dosing of activated charcoal
Carbamazepine
Dapsone
Phenobarbital
Quinine
Theophylline
4. Bowel irrigation—Whole bowel irrigation refers to the rapid elimination of unabsorbed toxin from the GI tract through the use of iso-osmotic
polyethylene glycol solution at 25 to 40 mL/kg/hr until the rectal effluent is clear. Enteric-coated and extended-release preparations, certain metals, as
well as drug packets could be expelled expeditiously in this manner.
Despite an absence of specific evidence to support improved outcomes, sizeable iron overdoses, carrying high morbidity, may benefit from this
therapy noting the lack of an alternative.
Enhanced Elimination Techniques
Ion Trapping and Forced Diuresis
The urinary excretion of some drugs can be enhanced by alkalization of the urine with the administration of intravenous sodium bicarbonate to
produce urine with a pH >/= 7.5, exploiting the fact that the ionization of a weak acid is increased in an alkaline environment thereby making it lipid in-
soluble, reducing reabsorption and enhancing elimination by trapping the toxin in the urine.
Urine alkalization should be considered first line treatment in patients with moderate to severe salicylate poisoning that do not meet criteria for
hemodialysis. See Table 58–6: Drugs with enhanced elimination by alkaline diuresis.
Table 58–6
Drugs with enhanced elimination by alkaline diuresis.
Alkaline diuresis
Salicylates
Methotrexate
Barbiturates Page 8 / 42
Fluoride
produce urine with a pH >/= 7.5, exploiting the fact that the ionization of a weak acid is increased in an alkaline environment thereby making it lipid in-
soluble, reducing reabsorption and enhancing elimination by trapping the toxin in the urine. Access Provided by:
Urine alkalization should be considered first line treatment in patients with moderate to severe salicylate poisoning that do not meet criteria for
hemodialysis. See Table 58–6: Drugs with enhanced elimination by alkaline diuresis.
Table 58–6
Drugs with enhanced elimination by alkaline diuresis.
Alkaline diuresis
Salicylates
Methotrexate
Barbiturates
Fluoride
Sulfonamides
Ethylene glycol
Methanol
Chelation Therapy
Chelation therapy involves intravenous, intramuscular or oral administration of chelation agents to bind heavy metals in the blood stream promoting
enhanced renal excretion. See Table 58–7: Different chelation therapies.
Table 58–7
Different chelation therapies.
Agent Route of Administration Metals Bound
Dimercaprol IM with urine alkalizing agent Arsenic, gold, lead, mercury
Penicillamine Oral Copper, arsenic, lead
Deferoxamine IV, IM, or SC Iron
Extracorporeal Techniques
Hemodialysis (HD) can be used to remove certain toxins and correct electrolyte and acid-base disturbances induced by toxins. For HD to be effective,
the toxin must reside primarily in the extracellular fluid.
Hemoperfusion (HP) refers to the circulation of blood through an extracorporeal circuit containing an adsorbent such as activated charcoal or
polystyrene resin. Drugs that are adsorbed by activated charcoal are the same drugs that are amenable to HP.
Hemofiltration, peritoneal dialysis, plasmapheresis, and exchange transfusion can also help eliminate certain toxins. See Table 58–8: Poisons
amenable to hemodialysis.
Table 58–8
Poisons amenable to hemodialysis.
Hemodialysis enhanced
Elimination
Hemoperfusion (HP) refers to the circulation of blood through an extracorporeal circuit containing an adsorbent such as activated charcoal or
polystyrene resin. Drugs that are adsorbed by activated charcoal are the same drugs that are amenable to HP. Access Provided by:
Hemofiltration, peritoneal dialysis, plasmapheresis, and exchange transfusion can also help eliminate certain toxins. See Table 58–8: Poisons
amenable to hemodialysis.
Table 58–8
Poisons amenable to hemodialysis.
Hemodialysis enhanced
Elimination
Alcohols
Lithium
Salicylates
Atenolol
Sot3alol
Theophylline
Procainamide
Barbiturates
Lipid Emulsion
Intravenous lipid emulsions (ILE) are the fats used in total parenteral nutrition, and ILE has been used to treat toxicity due to lipophilic medication
including verapamil, beta blockers, some tricyclic antidepressants, bupivacaine and chlorpromazine.
The proposed mechanism of action is that the ILE acts as a “lipid sink” surrounding a lipophilic drug molecule and rendering it ineffective. A second
mechanism proposed is that fatty acids within the ILE provide the myocardium with a ready energy source thus improving cardiac function.
Antidotes
While in the majority of poisoning cases supportive care is the key element to improving the survival, a small number of toxins are amenable to a “silver
bullet” in the form of an antidote.
By varied means, antidotes reduce or reverse the effects of a poison, but half-life of both the toxin and the antidote must be taken into account during
treatment, especially regarding instances of antidotes that antagonize end-organ effects or inhibit conversion to toxic metabolites. See Table 58–9:
Common antidotes/treatments.
Table 58–9
Common antidotes/treatments.
Common Antidotes/Treatments
Poison/Condition Antidote/Treatment Dose
Acetaminophen N-Acetylcysteine 140 mg/kg po load, then 70 mg/kg every 4 hr for 17 doses
OR
150 mg/kg IV load over 60 min then 50 mg/kg over 4 hr, then 100 mg/kg over
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Anticholinergic Physostigmine 0.5-2 mg IV over 5 min
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Poison/Condition Antidote/Treatment Dose
Acetaminophen N-Acetylcysteine 140 mg/kg po load, then 70 mg/kg every 4 hr for 17 doses
OR
150 mg/kg IV load over 60 min then 50 mg/kg over 4 hr, then 100 mg/kg over
16 hr
Anticholinergic Physostigmine 0.5-2 mg IV over 5 min
Benzodiazepines Flumazenil 0.2 mg/kg IV
Beta blockers Glucagon 0.05 mg/kg IV bolus may repeat every 10 min
Bupivucaine/local anesthetic Lipid emulsion 20% IV 100 ml IV over 1 min, then 400 ml IV over 20 min
Calcium channel antagonists Calcium chloride 10% 0.2-0.25 ml/kg IV

Insulin 1 unit/kg bolus with 50 ml 50% dextrose followed by 1 unit/kg/hr with D10 W
Glucagon 200 ml/hr
Lipid emulsion 20% IV 0.05 mg/kg IV bolus may repeat every 10 min
100 ml IV over 1 min, then 400 ml IV over 20 min
Cholinergic agents Pralidoxime (2-PAM) 1-2 g IV over 5-10 min, then 500 mg/hr infusion
Chronic alcohol/Wernicke Thiamine 100 mg IV

syndrome
Cyanide and nitroprusside Hydroxocobalamin Sodium thiosulfate 70 mg/kg IV (max 5 g in 30 min) Can repeat up to 3 times 50 ml IV
(25%)
Digoxin Digoxin Fab 5-10 vials IV
Ethylene glycol and methanol Ethanol 10% IV Fomepizole 10 ml/kg IV over 30 min then 1.2 ml/kg/hr 15 mg/kg IV, then 10 mg/kg every
12 hr
Heparin Protamine 25-50 mg IV
Iron Deferoxamine 2 g IM, or 15 mg/kg/hr IV (max dose, 6-8 g/day)
Methemoglobin/oxidizing Methylene blue 1-2 mg/kg IV

chemicals
Methotrexate Folic acid 1-2 mg/kg IV every 4-6 hr
Neuroleptic malignant Dantrolene 1-2.5 mg/kg IV

syndrome Bromocriptine 2.5 mg po every 6 hr
Opioids Naloxone 0.1-2 mg IV Titrate to response
Serotonin syndrome Cyproheptadine 4-12 mg po Repeat every 2 hr
Tricyclic antidepressants Sodium bicarbonate 1-2 mEq/kg IV bolus Repeat as needed
Disposition
After the initial evaluation, treatment and observation period, patients who suffer from severe toxicity or who are at risk for complications should be
admitted to the ICU. Advanced age, abnormal body temperature, and suicidal intent are associated with an increased risk of death.
Sustained-release products, and agents with delayed onset or prolonged action may require up to 24 hrs. of observation to ensure safety.
Tricyclic antidepressants Sodium bicarbonate 1-2 mEq/kg IV bolus Repeat as needed
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Disposition
After the initial evaluation, treatment and observation period, patients who suffer from severe toxicity or who are at risk for complications should be
admitted to the ICU. Advanced age, abnormal body temperature, and suicidal intent are associated with an increased risk of death.
Sustained-release products, and agents with delayed onset or prolonged action may require up to 24 hrs. of observation to ensure safety.
SEDATIVE-HYPNOTIC OVERDOSE
Sedatives and hypnotics are very commonly abused agents and include; benzodiazepines, barbiturates, and nonbenzodiazepines (zolpidem,
zopicline, buspirone, GHB gamma-hydroxybutyric acid). Their use is frequently combined with alcohol and other drugs such as opiates. Typically
patients have depressed neurological signs and can develop cardiac, respiratory, renal and gastrointestinal dysfunction. Withdrawal from sedative-
hypnotics is often associated with seizures, which can be fatal.
Benzodiazepines
Benzodiazepines (alprazolam, diazepam, lorazepam) are sedative-hypnotic agents used to treat anxiety, seizures, withdrawal states, insomnia and
drug associated agitation. Benzodiazepines enhance the inhibitory effect of the neurotransmitter gamma-aminobutyric acid (GABA), which manifests
in central nervous system depression.
Clinical Features
Benzodiazepine overdose produces a specific sedative-hypnotic toxidrome. Mild to moderate overdose resembles that of ethanol. The majority of
symptoms and signs are neurological and include somnolence, emotional lability, confusion, incoordination, impaired cognition, ataxia, and slurred
speech, and may induce horizontal and vertical nystagmus, midriasis and hyporeflexia. Cardiovascular signs include hypotension and bradycardia.
Short-term amnesia is a common and often desirable effect especially when used for procedural sedation or general anesthesia. Ingested alone these
agents rarely cause significant toxicity, however coma and respiratory and cardiac arrest can be seen in the setting of co-ingestion with other
depressants. Rarely patients can exhibit paradoxical excitement, agitation and disinhibition. Predisposition appears to be for younger and older age
groups, as well as underlying psychiatric disorders though the mechanism remains unknown.
Differential Diagnosis
Barbiturates, nonbenzodiazepine sedatives (zolpidem, gamma hydroxybutyrate, etc), alcohol and opiates can all cause similar features. Serum and
urine toxicological testing is of limited value, as levels do not correlate with clinical findings.
Treatment
Supportive care is the mainstay of treatment including stabilization of the airway, breathing and circulation followed by routine lab tests, control of
agitation and seizures and management of any subsequent complications (see general principles of overdose and poisoning). Decontamination with
activated charcoal should be considered if ingestion is within 1 hour of presentation. Due to the sedating effects of benzodiazepines and risk of
aspiration, the airway should be secured prior to administration. Gastric lavage, forced diuresis and enhanced elimination techniques are not
effective.
Specific Therapy—Administration of flumazenil, a competitive antagonist of the benzodiazepine receptor, remains controversial due to the low
morbidity and mortality associated with overdose, and the potential for inducing withdrawal seizures in patients who chronically take or abuse
benzodiazepines, or in cases of pro-convulsant co-ingestion. Therefore flumazenil should not be used empirically for the sedative-hypnotic
toxidrome. Its use is reserved for iatrogenic respiratory depression, in a benzodiazepine naïve patient, undergoing procedural sedation with
benzodiazepines. The dose is 0.2mg IV over 30 seconds. Onset of action may take 6 to 10 minutes, with repeat dosing sometimes necessary. A
maximum of 3 mg should not be exceeded in a one hour period.
Withdrawal
Withdrawal from benzodiazepines may be fatal. Abrupt abstinence is marked by tremor, anxiety, perceptual disturbances, dysphoria, insomnia,
sweating, psychosis, and seizures. Onset is usually within 8 to 48 hours dependent on the half-life of the benzodiazepine and the chronicity of use.
Treatment usually involves reintroduction of a benzodiazepine. Tapering of a long-acting benzodiazepine, such as diazepam, over a few months may
circumvent withdrawal, and should initially be started at a dose that abates symptoms.
Barbiturates
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Withdrawal
Withdrawal from benzodiazepines may be fatal. Abrupt abstinence is marked by tremor, anxiety, perceptual disturbances, dysphoria, insomnia,
sweating, psychosis, and seizures. Onset is usually within 8 to 48 hours dependent on the half-life of the benzodiazepine and the chronicity of use.
Treatment usually involves reintroduction of a benzodiazepine. Tapering of a long-acting benzodiazepine, such as diazepam, over a few months may
circumvent withdrawal, and should initially be started at a dose that abates symptoms.
Barbiturates
Barbiturate use is much less common than benzodiazepine use however is associated with greater mortality and morbidity. Barbiturates cause a dose
dependent neuronal depression with symptoms and signs similar to benzodiazepines. Blood levels of barbiturates are useful and may help guide
therapy. Treatment is supportive. Myocardial depression is more common with barbiturates over other sedatives and may require vasopressor therapy
to maintain blood pressure. Decontamination with activated charcoal within 1 hour of ingestion helps reduce absorption. The AACT/EAPCCT
recommends multiple-dose activated charcoal should be considered for cases of phenobarbital toxicity. Alkalization of the urine with sodium
bicarbonate may enhance renal elimination. Hemodialysis can be used in severe cases of phenobarbital toxicity.
Nonbenzodiazepine Sedative-Hypnotics
This includes medications such as buspirone, carisoprodol, chloral hydrate, melatonin, and zolpidem. In general treatment is supportive. Activated
charcoal is recommended within 1 hour of ingestion. Of note flumazenil is ineffective. Gamma hydroxybutyrate (GHB) is a nonbenzodiazepine sedative
that is potentially fatal and becoming more popular in Europe and the United States and is discussed in detail below.
Gamma Hydroxybutyrate (GHB)
Gamma hydroxybutyrate or gamma hydroxybutyric acid (GHB) is a naturally occurring 4-carbon central nervous system (CNS) depressant with a
structure similar to gamma aminobutyric acid (GABA) capable of crossing the blood brain barrier. GHB is lipid-soluble with no significant protein
binding and exerts its effects via a novel GHB receptor as well as GABA B receptors.
Initially it was synthesized in Europe and used as a general anesthetic however, its use was discontinued due to numerous adverse effects. GHB has
also been used legitimately as treatment for insomnia, narcolepsy, depression and to help wean people from alcohol. It is currently FDA approved in
the USA for treatment of narcolepsy and cataplexy as sodium oxybate. GHB causes numerous different clinical effects and was marketed in the 1980s as
a bodybuilding and weight loss supplement due to its effects on increasing growth hormone levels. The drug more recently has become abused in
nightclubs for its euphoric, relaxation and sexual stimulation effects. GHB is currently illegal in most countries and is produced illicitly and is easily
available on the internet or can be produced at home. The drug is also available as GBL (gamma butyrolactone) and BD (1,4 butanediol) both precursor
drugs that are not as tightly controlled, however are rapidly metabolized to GHB in the bloodstream. GBL and BD are found in many industrial organic
solvents such as acetone-free nail polish removers, paint strippers, cleaning products, and glue debonders and are often marketed as such to avoid
detection. The prevalence of GHB use is not known, partly because the drug is not included in drug surveys or on hospital drug screens. Assays are
available but are not easily accessible. However due to the low cost, ease of availability and questionable legal status its use is becoming more popular.
Users develop dependence and experience significant withdrawal on discontinuation.
GHB is sold as a sodium salt, in a powder or granular form and dissolves in water to form a clear, colorless, odorless liquid. GBL is sold directly as a
colorless, odorless liquid. GHB has a salty taste and is frequently added to various drinks to mask the flavor. GHB is rapidly absorbed and eliminated
with a half-life of approximately 30 minutes. It exhibits zero order kinetics at low doses and has a very narrow therapeutic index. Users find it difficult to
titrate doses and only need to consume slightly more than their usual dose to develop significant toxicity. GHB manifests a steep dose-effect curve with
rapid onset of effect followed by abrupt clearing. Typically the effects last up to 2 hours however, dependent users may dose the drug every 30 minutes
to 1 hour.
Clinical Features
Illicit users of GHB and GBL generally fall into two groups. The first group uses the drugs for possible therapeutic health benefits, such as bodybuilders
and people attempting self-treatment of insomnia, depression and anxiety. GHB has been shown to increase growth hormone levels and lean body
mass. A second group is recreational users, who take the drug at clubs, and bars. At low therapeutic doses GHB has stimulant properties with users
experiencing euphoria, disinhibition and enhanced sensuality and empathic states. This can lead to unsafe sexual practices and increased rates of
sexually transmitted diseases. Also the drug is often abused concurrently with other illicit drugs such as MDMA, methamphetamine, cocaine, and
alcohol.
Due to the narrow therapeutic index acute toxicity is common and users may accidently overdose. Toxicity manifests as a dose dependent CNS
depressant. Hypotension, bradycardia, hypothermia, and respiratory depression are common. At lower doses patients can be agitated and show self-
destructive behavior. At higher doses rapid sedation and coma is common and patients can be completely unresponsive to painful stimuli. However
due to the steep dose-effect curve, abrupt recovery is common, and users can awake suddenly 1-2 hours after intoxication. Miosis may be evident as
and people attempting self-treatment of insomnia, depression and anxiety. GHB has been shown to increase growth hormone levels and lean body
mass. A second group is recreational users, who take the drug at clubs, and bars. At low therapeutic doses GHB has stimulant properties with users
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experiencing euphoria, disinhibition and enhanced sensuality and empathic states. This can lead to unsafe sexual practices and increased rates of
sexually transmitted diseases. Also the drug is often abused concurrently with other illicit drugs such as MDMA, methamphetamine, cocaine, and
alcohol.
Due to the narrow therapeutic index acute toxicity is common and users may accidently overdose. Toxicity manifests as a dose dependent CNS
depressant. Hypotension, bradycardia, hypothermia, and respiratory depression are common. At lower doses patients can be agitated and show self-
destructive behavior. At higher doses rapid sedation and coma is common and patients can be completely unresponsive to painful stimuli. However
due to the steep dose-effect curve, abrupt recovery is common, and users can awake suddenly 1-2 hours after intoxication. Miosis may be evident as
well as nystagmus. Respiratory arrest is the most common cause of death. Amnesia after use is common and this combined with its sedating effects
makes GHB a choice for drug-facilitated sexual assault.
GHB toxicity is a clinical diagnosis and assays are not easily available. Agitation followed by obtundation, bradycardia, and hypothermia followed by
abrupt recovery points towards GHB. Barbiturates, benzodiazepines, alcohol and opiates can all cause similar features. Urine toxicology screen may
not necessarily reflect current intoxication, and may serve as a distracter rather than a diagnostic aid.
Treatment/Work Up
activated charcoal should be considered if ingestion is within 1 hour of presentation as long as the airway is stable. Other elimination techniques are
ineffective.
Specific Therapy—In general the treatment is supportive with no effective antidote. Vasopressors may be required for low blood pressure.
Bradycardia should be treated with atropine or temporary pacing if severe. Typically once patients wake up they should be observed for several hours
however, patients rarely comply and often leave against medical advice.
Withdrawal and Dependence
Due to the short half-life and dependent nature of the drug users may have to dose every 1 to 6 hours. As a result withdrawal symptoms can develop as
early as 1 hour after the last dose and usually last between 4 and 14 days. Patients who use the drug for bodybuilding or to relieve insomnia or other
medical conditions are more likely to develop dependence and withdrawal when compared to recreational users that use the drug only when
socializing. Users admitted to the ICU for acute intoxication, or other unrelated conditions, may develop withdrawal while an inpatient.
Neuropsychiatric symptoms are the most common symptoms experienced during withdrawal. Initially users may have some autonomic symptoms
including tachycardia, hypertension, and diaphoresis however vitals signs can remain normal, unlike in alcohol withdrawal. After 24 hours patients
develop extreme agitation, combativeness and anxiety and often will need to be physically restrained. Psychiatric symptoms can develop including
paranoia, hallucinations and delirium. On physical exam patients often have a tremor, increased muscle tone, myoclonic jerks and nystagmus. Unlike
with alcohol and benzodiazepines seizures are less common. Hyperthermia and rhabdomyolysis can develop from the extreme agitation leading to
electrolyte abnormalities and renal failure. Death can occur due to cardiac arrest from electrolyte abnormalities. Supportive care is the mainstay of
treatment. Long acting benzodiazepines such as diazepam are titrated to control agitation and anxiety. Extremely large doses may be required which
may cause significant respiratory depression and require endotracheal intubation and mechanical ventilation. Baclofen (GABA agonist) can be given in
combination with benzodiazepines. Patients resistant to benzodiazepines may require barbiturates or propofol and a secure airway. Creatine kinase
(CK) levels should be followed due to the risk of rhabdomyolysis, which should be treated with fluids. The role of urine alkalization with bicarbonate to
treat rhabdomylosis in poisoned patients is unclear.
DRUGS OF ABUSE
“Drug of abuse” is a very broad term and is defined as any drug (illicit or prescription), chemical, or plant product that is known to be misused for
recreational purposes. The term narcotic generically refers to any psychoactive drug that causes sedation. However, in legal terms it refers to any drug
that is prohibited or regulated by the government. Many classes of drugs have potential for abuse, however in this section we will discuss opioids,
sympathomimetics and hallucinogens. Sedatives are covered in the sedative-hypnotic section. See Table 58–10: Common drugs of abuse.
Table 58–10
Common drugs of abuse.
Class Drug
Opioids Morphine, oxycodone, codeine, fentanyl, heroin

“Drug of abuse” is a very broad term and is defined as any drug (illicit or prescription), chemical, or plant product that is known to be misused for
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recreational purposes. The term narcotic generically refers to any psychoactive drug that causes sedation. However, in legal terms it refers to any drug
that is prohibited or regulated by the government. Many classes of drugs have potential for abuse, however in this section we will discuss opioids,
sympathomimetics and hallucinogens. Sedatives are covered in the sedative-hypnotic section. See Table 58–10: Common drugs of abuse.
Table 58–10
Common drugs of abuse.
Class Drug
Opioids Morphine, oxycodone, codeine, fentanyl, heroin
Sympathomimetics Cocaine, methamphetamine, mephedrone, MDMA
Hallucinogens MDMA, mushrooms, PCP, LSD, cannabis
Sedatives Benzodiazepines, barbiturates, GHB
Opioids
Opioid refers to any drug, natural or synthetic, that is active upon opioid receptors. Opiate refers to naturally occurring drugs extracted from the
opium poppy plant (morphine and codeine). Opioid receptors are found throughout the central and peripheral nervous system and modulate the
release of neurotransmitters with a wide diversity of clinical effects including analgesia, euphoria and anxiolysis. The potency, duration of action and
half-life vary widely between different opioids and significant tolerance can develop.
Clinical Features
Opioid overdose produces a specific toxidrome of reduced level of consciousness, respiratory depression, and pinpoint pupils. Other common
findings include vomiting, ileus, urinary retention, loss of deep tendon reflexes, bradycardia, and histamine release causing hypotension, urticarial
and bronchospasm. Respiratory depression is usually the most serious sequelae. Non-cardiogenic pulmonary edema and ARDS has been associated
with heroin (diacetylmorphine) overdose. Opioids may be administered by almost any route, however most are abused intravenously, which can often
be associated with cutaneous findings as well as systemic illnesses such as hepatitis, HIV, and endocarditis.
Opioids are commonly used with other intoxicants such as alcohol or cocaine. The diagnosis of intoxication is largely clinical and is supported by the
brisk response to naloxone. Blood and urine toxicology screening can identify coingestants however levels are not helpful. Clonidine can produce a
similar clinical picture as opioid intoxication however the response to naloxone is not as pronounced. Sedatives such as benzodiazepines and
barbiturates can look very similar to opioids and there coingestion can make diagnosis challenging.
Treatment/Work Up
Supportive care is the mainstay of treatment including stabilization of the airway, breathing, and circulation followed by routine lab tests, control of
agitation and seizures and management of any subsequent complications (see general principles of overdose and poisoning). Abdominal imaging may
display evidence of body packing or stuffing. Decontamination with activated charcoal is advisable in suspected oral ingestion especially if co-
ingestants are suspected and presentation is within 1 hour. It is reasonable to assume that administration of activated charcoal later than 1 hour post
ingestion may be beneficial for sustained release oral preparations but there is no clinical trial evidence to support this. Whole bowel irrigation with
polyethylene glycol can be used in asymptomatic body packers to help expel packets.
Specific Therapy
1. Transdermal opioids patches should be looked for and removed.
2. An EKG may reveal a prolonged QT interval (in cases of methadone use) with increased risk of developing torsades de pointes, which may require
intravenous magnesium sulfate.
3. Naloxone is the primary treatment for respiratory depression. Aim for reversal of respiratory depression, not full reversal of consciousness. For
apnea administer 0.4 mg IV, SC or IM, if no response after 60 seconds give additional 0.8 mg every 60 seconds up to 2 mg. If still no response give
additional 2 mg. For opioid dependent patients with respiratory depression administer 0.05-0.1 mg doses, to prevent acute withdrawal, until the
desired response is achieved. The preferred route of administration of naloxone is intravenous. For large overdoses consider a naloxone infusion
Specific Therapy
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1. Transdermal opioids patches should be looked for and removed.
2. An EKG may reveal a prolonged QT interval (in cases of methadone use) with increased risk of developing torsades de pointes, which may require
intravenous magnesium sulfate.
3. Naloxone is the primary treatment for respiratory depression. Aim for reversal of respiratory depression, not full reversal of consciousness. For
apnea administer 0.4 mg IV, SC or IM, if no response after 60 seconds give additional 0.8 mg every 60 seconds up to 2 mg. If still no response give
additional 2 mg. For opioid dependent patients with respiratory depression administer 0.05-0.1 mg doses, to prevent acute withdrawal, until the
desired response is achieved. The preferred route of administration of naloxone is intravenous. For large overdoses consider a naloxone infusion
at an hourly rate of 2/3 s of the dose required to wake up the patient per hour.
Withdrawal
Withdrawal from opioids produces a surge in catecholamines producing autonomic instability as well as agitation and personality changes. Onset will
depend on the individual opiate and can by up to 48 hours when associated with long acting drugs such as methadone or extended release
preparations. Symptoms include dysphoria, diaphoresis, rhinorrhea, sneezing, muscle aches and cramps and abdominal pain and diarrhea.
Methadone is a long acting opiate and is the mainstay of treatment for withdrawal and dependence. Clonidine has been used to blunt some of the
autonomic symptoms. Withdrawal seizures will require high doses of long acting benzodiazepines.
Sympathomimetics
Sympathomimetics drugs are a stimulant class of drug that have similar clinical effects as neurotransmitters of the central nervous system such as
catecholamines (norepinephrine, epinephrine, and dopamine). These drugs can act through several mechanisms, such as directly activating alpha and
beta adrengeric postsynaptic receptors, blocking breakdown and reuptake of certain neurotransmitters, or stimulating production and release of
catecholamines. Sympathomimetic drugs are used routinely in hospitals to help support blood pressure and are available with a prescription to treat
common medical conditions such as asthma, narcolepsy or hypotension. Sympathomimetics are also available without a prescription in over the
counter cold and flu preparations. Illicit street preparations are commonly abused and include, cocaine and designer drugs such as MDMA (3,4-
methylenedioxy-methamphetamine), methamphetamine and more recently mephedrone (see Table 58–11).
Table 58–11
Common sympathomimetic drugs.
Drug Use
Norepinephrine, epinephrine, dopamine, midodrine Blood pressure support
Albuterol, levalbuterol Bronchodilation
Modafinil Narcolepsy
Phenylephrine, pseudoephedrine Over the counter cold and flu preparations
Cocaine, MDMA, methamphetamine, mephedrone Most commonly used illicitly
Poisoning from sympathomimetic agents can occur secondary to the use of prescription and nonprescription agents. In 2011, approximately 66,540
cases of sympathomimetic and street drug exposures were reported to the American Association of Poison Control Centers.
Cocaine
Other than alcohol, cocaine is the most common cause of acute drug-related emergency department visits in the United States. Extracted from the
leaves of the coca plant (Erythroxylum coca) the drug originally found utility as a local anesthetic in eye, nose, and throat surgery in its ability to limit
bleeding via blood vessel constriction. Cocaine's effects are primarily medicated by blocking re-uptake of presynaptic dopamine, serotonin and
norepinephrine. Cocaine has a short half-life and the effects typically last no more than 30 minutes.
Designer Drugs
Designer sympathomimetic drugs are substances commonly used in nightclubs to enhance social intimacy and sensory stimulation. They Page
Chapter 58: Overdose, Poisoning, and Withdrawal, Edward Mossop; Fred DiBlasio 16 / 42
are synthetic
derivatives of federally controlled substances created by slightly altering the molecular structure illegally in clandestine laboratories for illicit use.
Many are amphetamine or cathinone analogs, such as mephedrone, methamphetamine and MDMA, with psychoactive properties causing visual
disturbances, but are not true hallucinogens.
Other than alcohol, cocaine is the most common cause of acute drug-related emergency department visits in the United States. Extracted from the
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leaves of the coca plant (Erythroxylum coca) the drug originally found utility as a local anesthetic in eye, nose, and throat surgery in its ability to limit
bleeding via blood vessel constriction. Cocaine's effects are primarily medicated by blocking re-uptake of presynaptic dopamine, serotonin and
norepinephrine. Cocaine has a short half-life and the effects typically last no more than 30 minutes.
Designer Drugs
Designer sympathomimetic drugs are substances commonly used in nightclubs to enhance social intimacy and sensory stimulation. They are synthetic
derivatives of federally controlled substances created by slightly altering the molecular structure illegally in clandestine laboratories for illicit use.
Many are amphetamine or cathinone analogs, such as mephedrone, methamphetamine and MDMA, with psychoactive properties causing visual
disturbances, but are not true hallucinogens.
Mephedrone is a synthetic cathinone derivative of an amphetamine like stimulant, found naturally in the khat plant, which has become extremely
popular and is marketed and sold, on the internet and in stores throughout Europe and the USA, as “bath salts.” The name derives from instances in
which the drugs have been sold disguised as true bath salts. Mephedrone is known to raise both dopamine and norepinephrine, however its exact
mechanism of action is unclear.
Methamphetamine is a strong, highly addictive, neurotoxic, amphetamine derived CNS stimulant that has become cheaper and more popular than
cocaine in some parts of the USA. Its effects are medicated by both increasing the release and by blocking re-uptake of dopamine, norepinephrine and
serotonin. It is more potent and much longer acting than cocaine, with a half-life of approximately 12 hours, and can be produced from over the
counter cold and flu medications. Its use, and associated behaviors, has been associated with increased risk of contracting HIV and hepatitis.
MDMA, more commonly known as “ecstasy” or “molly,” is a synthetic amphetamine derived drug with both stimulant and hallucinogenic properties
that's effects last typically between 4-6 hours. It causes presynaptic release of dopamine, and norepinephrine but also significantly increases the
neurotransmitter serotonin which may precipitate serotonin syndrome. One of its more serious complications is alteration of thermoregulation
causing significant increases in body temperature. See Table 58–11: Common sympathomimetic drugs.
Clinical Features
Sympathomimetic toxicity, regardless of the specific drug, produces a specific toxidrome of hypertension, tachycardia, hyperthermia with mydriasis
and diaphoresis. Hyperthermia is multifactorial and can be caused by extreme agitation in the setting of a hot club environment as well as due to direct
toxicity to thermoregulation. CNS toxicity is manifested as psychomotor agitation, teeth grinding, euphoria, anxiety, psychosis, increased sexual
stimulation, hallucinations and can progress to seizures. Cardiovascular complications include tachy and bradyarrhythmias and extreme hypertension
leading to myocardial ischemia, aortic and coronary artery dissection, intracranial hemorrhage, encephalopathy and ischemic strokes. Other
complications include rhabdomyolysis and renal failure. Death is most commonly secondary to seizures, cardiac arrest or hyperthermia.
Sympathomimetic drugs are commonly associated with body packers and stuffers, which if associated with rupture of a bag, can lead to extreme
systemic symptoms as well as local bowel ischemia and bleeding. Serotonin syndrome (change in mental status, autonomic stimulation and
neuromuscular activity) can occur with MDMA, cocaine and amphetamines. In addition to the above symptoms specific drugs can produce unique
features:
Cocaine—Cocaine is frequently associated with chest pain and EKG changes. Cocaine use in pregnancy has been associated with spontaneous
abortion, placental abruption, and intrauterine growth retardation. Crack cocaine can cause pulmonary complications such as pulmonary edema and
bronchospasm. Due to the very short acting nature of cocaine it is typically abused in a binge pattern.
Mephedrone—Patients intoxicated with mephedrone can present with “excited delirium.” Although not specific, this may be more common in
mephedrone users over other sympathomimetics.
Methamphetamine—Methamphetamine is highly addictive and can be associated with frequent emergency department visits and long-term health
problems such as weight loss, dental problems, and skin sores. Its neurotoxic effects can lead to a loss of fine motor skills and impaired verbal
learning. Methamphetamine is also associated with increased risk of HIV and hepatitis due to needle sharing and increased sexual stimulation.
MDMA—MDMA use can be associated with more hallucinogenic symptoms and distortions in sensory and time perception. Users can be very
emotionally labile and can show extreme empathy towards others. MDMA is often combined with multiple other drugs such as GHB, Viagra and other
stimulants. Further more MDMA is commonly associated with serotonin syndrome, extreme hyperthermia and death.
Diagnosis of sympathomimetic overdose is usually based on clinical signs. Urine drug screens can detect cocaine but are less reliable at detecting
amphetamine derivatives. Withdrawal from opiates, sedatives and alcohol can produce a surge in catecholamines that may present like
sympathomimetic overdose. Psychopharmacological medication overdose, such as tricyclic's and SSRIs can also raise levels of serotonin Page
Chapter 58: Overdose, Poisoning, and Withdrawal, Edward Mossop; Fred DiBlasio and 17 / 42
norepinephrine. Any drug causing serotonin syndrome may mimic sympathomimetic overdose. Disease states such as psychosis and thyrotoxicosis
can present in a similar way. The use of co-ingestants can complicate the diagnosis.
emotionally labile and can show extreme empathy towards others. MDMA is often combined with multiple other drugs such as GHB, ViagraAccess Provided by:
and other
stimulants. Further more MDMA is commonly associated with serotonin syndrome, extreme hyperthermia and death.
Diagnosis of sympathomimetic overdose is usually based on clinical signs. Urine drug screens can detect cocaine but are less reliable at detecting
amphetamine derivatives. Withdrawal from opiates, sedatives and alcohol can produce a surge in catecholamines that may present like
sympathomimetic overdose. Psychopharmacological medication overdose, such as tricyclic's and SSRIs can also raise levels of serotonin and
norepinephrine. Any drug causing serotonin syndrome may mimic sympathomimetic overdose. Disease states such as psychosis and thyrotoxicosis
can present in a similar way. The use of co-ingestants can complicate the diagnosis.
Treatment/Work Up—Supportive care is the mainstay of treatment including stabilization of the airway, breathing and circulation followed by
routine lab tests, control of agitation and seizures and management of any subsequent complications (see general principles of overdose and
poisoning). Troponin levels should be trended to assess for cardiac ischemia. CT imaging of the head may be required to exclude intracranial
complications. Close attention should be given to suspected body packers or stuffers as a sudden release of large amounts of sympathomimetics can
be rapidly fatal. Abdominal imaging may be helpful. Decontamination with activated charcoal is advisable in suspected oral ingestion if presentation is
within 1 hour. Whole bowel irrigation with polyethylene glycol can be used in asymptomatic body packers to help expel packets.
Specific Therapy
1. Benzodiazepines are the mainstay of treatment in sympathomimetic overdose for both cardiovascular (hypertension and tachycardia) and
neurological effects (agitation and seizures). Lorazepam should be administered IV in 2 mg doses and titrated to response. Alternatively diazepam
in 5-10 mg increments can be used. Extremely high doses may be required. Avoid using antipsychotics as they may lower seizure threshold and can
worsen arrhythmias and hyperthermia. Status epilepticus may develop and require phenobarbital or phenytoin if unable to be controlled with
benzodiazepines. Continuous EEG is recommended in this situation.
2. Hypertension not controlled adequately with benzodiazepines should be treated with intravenous titratable medications such as nitroprusside,
phentolamine or calcium channel blockers. Beta-blockers have been used, however they are generally best avoided due to the risk of causing
unopposed alpha stimulation and worsening hypertension.
3. Cardiac ischemia should be treated with aspirin, nitrates, morphine, and oxygen with appropriate specialist referral.
4. Arrhythmias are very common and usually respond to benzodiazepines and intravenous fluids. Persistent narrow complex tachyarrhythmia's can
be treated with verapamil 5-10 mg IV over 5-10 minutes. Wide complex tachyarrhythmia's should be treated with sodium bicarbonate 1-2 mEq/kg IV
titrated to a serum pH of 7.45-7.5.
5. Hyperthermia should be closely monitored. When temperature exceeds 39 degrees Celsius urgent cooling is required. Numerous techniques exist
and initially should include the use of fans, anti-pyretic medications, cold IV fluids, and ice baths. More specialized methods include the use of
intravenous cooling catheters and cooling pads applied to the skin. Those with excessive agitation or recurrent seizures may require paralysis to
prevent excessive heat production. Renal function and CK levels should be followed closely.
6. Rhabdomyolysis should be treated with intravenous fluids. Urine alkalization has not been shown to be beneficial in rhabdomyolysis secondary to
poisoning. See Table 58–12: treatment summary.
Table 58–12
Treatment summary.
Treatment summary of sympathomimetic overdose
Continuous vital signs and serial EKGs
Trend troponin, CK and electrolytes
Consider head CT
Benzodiazepines titrated to response
Nitroprusside or phentolamine for uncontrolled HTN

Sodium bicarbonate for wide complex tachyarrhythmia
Aggressive cooling methods

intravenous cooling catheters and cooling pads applied to the skin. Those with excessive agitation or recurrent seizures may require paralysis to
prevent excessive heat production. Renal function and CK levels should be followed closely. Access Provided by:
poisoning. See Table 58–12: treatment summary.
Table 58–12
Treatment summary.
Treatment summary of sympathomimetic overdose
Continuous vital signs and serial EKGs
Trend troponin, CK and electrolytes
Consider head CT
Benzodiazepines titrated to response
Nitroprusside or phentolamine for uncontrolled HTN
Sodium bicarbonate for wide complex tachyarrhythmia
Aggressive cooling methods
Consider endotracheal intubation for airway protection
Hallucinogens
A hallucinogen is a psychoactive agent that can cause hallucinations, distortions in a person's perception of reality and changes in thought and
emotion. Broadly they are divided into 2 categories: classic hallucinogens and dissociative drugs (see Table 58–13). Hallucinogens are found naturally
in plants and mushrooms but can also be manmade. Almost all hallucinogens contain nitrogen and are classified as alkaloids. The exact mechanism
underlying hallucinogens is unclear but is thought to involve the interaction of numerous neurotransmitters, including serotonin (5-HT), dopamine
and glutamate (NMDA). Due to increases in serotonin associated with hallucinogens they increase the risk of developing serotonin syndrome. See
Table 58–13: Hallucinogens.
Table 58–13
Common hallucinogens.
Classic Hallucinogens Dissociative Hallucinogens
LSD (d-lysergic acid diethylamide) PCP (Phencyclidine)
Mushrooms/Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) Ketamine
Peyote (Mescaline) DXM (Dextromethorphan)
DMT (Dimethyltryptamine)
The most commonly abused hallucinogens are LSD (d-lysergic acid diethylamide), PCP (phencyclidine) Ketamine and mushrooms (Psilocybin).
LSD
LSD is an alkaloid similar to ergotamine and synthesized from lysergic acid, which is found to occur naturally in several species of plant. LSD is one of
the most potent mood-changing chemicals. The most common form is LSD-soaked paper punched into small individual squares, known as “blotters”
which are taken orally. The effects can last up to 12 hours.
PCP
The most commonly abused hallucinogens are LSD (d-lysergic acid diethylamide), PCP (phencyclidine) Ketamine and mushrooms (Psilocybin).
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LSD
LSD is an alkaloid similar to ergotamine and synthesized from lysergic acid, which is found to occur naturally in several species of plant. LSD is one of
the most potent mood-changing chemicals. The most common form is LSD-soaked paper punched into small individual squares, known as “blotters”
which are taken orally. The effects can last up to 12 hours.
PCP
PCP is synthetic arylcycloamine developed as a non-narcotic anesthetic to exert a calming effect at low dose and cataplexy at higher dose without
suppression of blood pressure or respiration. Use was discontinued due to postoperative dysphoria and hallucination. It is used recreationally,
available in powder, crystal, liquid, and tablet forms. PCP is normally snorted, smoked, or orally ingested and the effects typically last for 4-6 hours.
Mushrooms
Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is a naturally occurring tryptamine compound structurally similar to serotonin and is found in
dozens of species of mushrooms. These are commonly known as “magic mushrooms” or “shrooms” and may be orally consumed fresh or dried and
are usually added to other foods to mask their bitter flavor. Effects typically last up to 6 hours.
Ketamine
Ketamine is a dissociative NMDA receptor antagonist, structurally similar to PCP, which has many uses in medicine. It has anesthetic, analgesic, local
anesthetic, amnestic, and bronchodilating properties. It is frequently used by medical professionals for induction and maintenance of anesthesia,
procedural sedation and acute and chronic pain relief. Ketamine is usually abused orally and has a short half-life of approximately 2 hours.
Clinical Features
Hallucinogens produce a specific toxidrome dominated by numerous neuropsychiatric symptoms including a heightened perception of sensory input,
a distorted sense of time, euphoria, and an enhanced sense of well-being. Users typically report spiritual and out of body experiences and feelings but
remain oriented and maintain insight. Negative neuropsychiatric effects include fear, anxiety, dysphoria and an overwhelming sense of dread.
Psychosis may occur and may persist for days. Synesthesia is a unique sensation and occurs when a certain sense or part of a sense is activated leading
to another unrelated sense or part of a sense to be activated concurrently. For example patients may report “hearing” colors. Vital signs can be normal
but usually show tachycardia and hypertension. Hyperthermia can occur with significant overdose. Other physical exam findings include increased
muscle tone, dystonic reactions and mydriasis. Serotonin syndrome (change in mental status, autonomic stimulation and neuromuscular activity) can
occur directly with LSD. Other hallucinogens raise serotonin, which, in the setting of concurrent use of SSRIs or other serotoninergic agents, can
increase the risk of developing serotonin syndrome. Rarely rhabdomyolysis due to hyperthermia and increased muscle activity can occur and lead to
renal failure.
Certain clinical signs can point towards specific hallucinogens:
PCP
PCP can be associated with violent destructive behavior and a perception of super human strength, which may lead users to suffer trauma as a result.
Physical signs include hypersalivation and horizontal and vertical nystagmus. In high doses patients can be catatonic or in a coma. Users typically
experience amnesia, reduced perception of pain, flushing, profuse sweating, and generalized numbness. Elevations in CK are seen more commonly in
PCP intoxication.
Mushrooms
Mushroom intoxication is frequently associated with gastrointestinal symptoms such as diarrhea, colicky abdominal pain, nausea, and vomiting. Users
also may exhibit muscle weakness and ataxia. Certain mushrooms can also cause hepatotoxicity with elevation of liver enzymes.
L S D —LSD users are more likely to experience synesthesia and extremes of emotion with severe anxiety. As with PCP, users can be very impulsive and
suffer serious injuries as a result of poor judgment. Vasospasm leading to strokes and peripheral ischemia has been reported.
Ketamine—Ketamine typically causes tachycardia, hypertension, increased muscle tone, hypersalivation and is associated with amnesia. Rarely users
can develop laryngospasm. Once the effects of ketamine begin to dissipate patients may develop an emergence phenomenon characterized by
delirium and agitation. Long-term users can develop a chronic cystitis leading to decreased bladder compliance and volume.
The diagnosis of hallucinogen toxicity is usually based on clinical signs. Drug urine screens can detect PCP but are unreliable. The main differential
L S D —LSD users are more likely to experience synesthesia and extremes of emotion with severe anxiety. As with PCP, users can be very impulsive and
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suffer serious injuries as a result of poor judgment. Vasospasm leading to strokes and peripheral ischemia has been reported.
Ketamine—Ketamine typically causes tachycardia, hypertension, increased muscle tone, hypersalivation and is associated with amnesia. Rarely users
can develop laryngospasm. Once the effects of ketamine begin to dissipate patients may develop an emergence phenomenon characterized by
delirium and agitation. Long-term users can develop a chronic cystitis leading to decreased bladder compliance and volume.
The diagnosis of hallucinogen toxicity is usually based on clinical signs. Drug urine screens can detect PCP but are unreliable. The main differential
diagnosis would include sympathomimetic toxicity and acute withdrawal from opiates, benzodiazepines or alcohol. Other causes of altered mental
status should be considered such as metabolic derangements, CNS infections and psychiatric conditions.
Treatment/Work Up
activated charcoal is advisable in suspected oral ingestion, if presentation is within 1 hour.
Specific Therapy
1. Patients should be placed in a quiet darkened room with minimal stimulation.
2. Benzodiazepines should be used to treat agitation, hypertension and tachycardia. Lorazepam 1-2 mg IV or diazepam 5-10 mg IV or PO as needed is
recommended.
3. Seizures will require higher doses of lorazepam or diazepam. Avoid using antipsychotics as they may lower seizure threshold and worsen
hyperthermia.
4. Hyperthermia should be closely monitored. Persist hyperthermia should be treated with the use of fans, antipyretics, cold IV fluids and ice baths.
When temperature exceeds 39 degrees Celsius more urgent cooling is required. More specialized methods including the use of intravenous cooling
catheters and cooling pads applied to the skin are rarely needed.
poisoning.
PSYCHIATRIC MEDICATION OVERDOSE

Psychiatric medications are used to treat a wide variety of mental disorders. Mental health medications were first introduced in the mid-20th century.
Prior to this psychiatric patients were treated with morphine and sedatives or confined to hospital. Chlorpromazine was developed in Paris in 1951 and
was the first drug developed specifically with psychopharmacologic actions. It was the first antipsychotic and worked by indiscriminately blocking
central nervous system receptors producing potent anticholinergic, antidopamingeric, antihistaminic and antiadrenergic effects giving rise to the
proprietary name of Largactil, that is, large in action.
Antidepressants frequently feature in the top 10 most prescribed medications in the United States. Abilify (antipsychotic) has the highest sales of any
drug in the United States generating $6.9 billion in 2013. Due to the widespread use of psychiatric medications accidental and intentional overdose is
common. In this section we will focus on tricyclic antidepressants and antipsychotics. Management of stimulants and hypnotics is covered elsewhere.
Tricyclic Antidepressants
Though largely displaced by selective serotonin reuptake inhibitors (SSRIs) and other agents as first line therapy, tricyclic antidepressants (TCAs) are
still used to treat depression and poisoning remains a significant clinical issue. Examples include amitriptyline, doxepin, and imipramine.
TCAs work therapeutically by blocking reuptake of norepinephrine and serotonin, however in toxic amounts they have anticholinergic, antiadrengeric,
and antihistaminic properties as well as blocking GABA receptors and cardiac sodium channels. In overdose blood levels can become extremely high
due to slow GI transit from the anticholingeric effects.
Clinical Features
Ingestion of 15-20 mg/kg would be expected to result in serious, potentially life-threatening symptoms. Patients can present with relatively few
symptoms but can deteriorate rapidly and require urgent assessment on presentation. The effects of poisoning are a combination of central and
peripheral nervous system toxicity and cardiovascular dysfunction. Central and peripheral nervous system effects are due to anticholingeric and
antihistaminic properties. Cardiac toxicity is due to sodium channel blockage and anticholingeric (antimuscarinic, atropine-like) effects. In addition
TCAs work therapeutically by blocking reuptake of norepinephrine and serotonin, however in toxic amounts they have anticholinergic, antiadrengeric,
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and antihistaminic properties as well as blocking GABA receptors and cardiac sodium channels. In overdose blood levels can become extremely high
due to slow GI transit from the anticholingeric effects.
Clinical Features
Ingestion of 15-20 mg/kg would be expected to result in serious, potentially life-threatening symptoms. Patients can present with relatively few
symptoms but can deteriorate rapidly and require urgent assessment on presentation. The effects of poisoning are a combination of central and
peripheral nervous system toxicity and cardiovascular dysfunction. Central and peripheral nervous system effects are due to anticholingeric and
antihistaminic properties. Cardiac toxicity is due to sodium channel blockage and anticholingeric (antimuscarinic, atropine-like) effects. In addition
blockage of alpha 1 adrenergic receptors causes peripheral vasodilatation.
Anticholingeric effects produce a combination of peripheral and central nervous system effects including hyperthermia, tachycardia, mydriasis, dry
flushed skin, urinary retention, dry mucus membranes, ileus, delirium, agitation, coma and seizures. Other findings include nystagmus, divergent
squint, increased muscle tone and respiratory depression. Cardiovascular effects can be fatal and include tachyarrhythmias, heart block, negative
inotropy, and vasodilatation causing hypotension. Coma signals a high risk for severe toxic complications (seizures and arrhythmias) more reliably
than EKG changes. Common EKG findings include right axis deviation, right bundle branch block (RBBB), sinus tachycardia, QT, PR and QRS
prolongation, which can precipitate VF and VT.
Laboratory tests may reveal metabolic acidosis. Death is most commonly due to cardiac arrhythmias.
Suspect TCA overdose if patients present with the anticholingeric toxidrome but also have cardiovascular abnormalities. Antihistamine and
antipsychotic overdose can produce a similar picture. Always consider non-toxicological causes.
Treatment/Work Up
agitation and seizures and management of any subsequent complications (see general principles of overdose and poisoning). A urinary catheter is
useful to monitor urine pH. Decontamination with activated charcoal should be initiated, if presentation is within 1 hour of ingestion. Gastric lavage
should be considered if the patient presents within 1 hour and has ingested a large amount. This will help prevent further absorption from the
decreased GI motility. Dialysis is ineffective due to high protein binding.
Specific Therapy
1. TCA overdose is one of the few conditions where bicarbonate has been shown to be beneficial. Alkalization of the blood with sodium bicarbonate
IV bolus of 1-2 mEq/kg should be given and repeated until blood pH is 7.5-7.55. This will improve hypotension and cardiac arrhythmias. If intubated
transient hyperventilation may be used until bicarbonate is effective. Sodium bicarbonate's effects are mediated by increasing extra-cellular
sodium to increase the electrochemical gradient, and by alkalization of the blood, which decreases the amount of ionized drug.
2. Refractory hypotension that does not respond to fluids or bicarbonate may require a vasopressor and inotrope such as norepinephrine. If this fails
then hypertonic 3% sodium chloride could be given cautiously, 100 mls over 10 minutes through a central line with close monitoring of sodium
levels. This may be repeated no more than 3 times.
3. Arrhythmia's refractory to bicarbonate should be treated with magnesium sulfate 1-2 g IV over 15 minutes. Lidocaine can also be used. If
cardiotoxicity is still unresponsive then intravenous lipid emulsion (ILE) may be given at 1.5 mL/kg of 20% as an IV bolus followed by 0.25-0.5
mL/kg/min for 30-60 minutes to an initial maximum of 500 mL. Any unstable tachyarrhythmia should be treated with synchronized DC
cardioversion.
4. Patients with life threatening instability that fail to respond to the above measures should be considered for veno-arterial extracorporeal
membrane oxygenation (VA-ECMO) to support cardiac output and oxygen delivery as a bridge to recovery.
Serotonin Agents and Serotonin Syndrome
Newer antidepressants including SSRIs, SNRIs, and SDRIs are much more commonly used than TCAs. SNRIs and SDRIs are more toxic than SSRIs but in
general these drugs are much safer than TCAs in overdose.
Serotonin syndrome is a potentially life threatening complication of any medications or illicit substance known to increase serotonin levels (see Table
58–14). Serotonin syndrome can occur from any combination of drugs that increase serotonin levels and does not have to in the setting of a deliberate
overdose. The syndrome is classically associated with the simultaneous administration of two serotonergic agents. However, it can occur Page
Chapter 58: Overdose, Poisoning, and Withdrawal, Edward Mossop; Fred DiBlasio after 22 / 42
initiation of a single serotonergic drug or after increasing the dose of a previous drug. Serotonin syndrome is usually more pronounced from
monoamine oxidase inhibitor use. See Table 58–14: Common drugs known to cause serotonin syndrome.
Serotonin Agents and Serotonin Syndrome
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Newer antidepressants including SSRIs, SNRIs, and SDRIs are much more commonly used than TCAs. SNRIs and SDRIs are more toxic than SSRIs but in
general these drugs are much safer than TCAs in overdose.
Serotonin syndrome is a potentially life threatening complication of any medications or illicit substance known to increase serotonin levels (see Table
58–14). Serotonin syndrome can occur from any combination of drugs that increase serotonin levels and does not have to in the setting of a deliberate
overdose. The syndrome is classically associated with the simultaneous administration of two serotonergic agents. However, it can occur after
initiation of a single serotonergic drug or after increasing the dose of a previous drug. Serotonin syndrome is usually more pronounced from
monoamine oxidase inhibitor use. See Table 58–14: Common drugs known to cause serotonin syndrome.
Table 58–14
Common drugs known to cause serotonin syndrome.
Drugs of Abuse Prescription Drugs
MDMA SSRIs
Amphetamines SNRIs
Cocaine SDRIs
LSD MAOIs
TCAs
Linezolid
Fentanyl
Clinical Features
Classically serotonin syndrome produces a triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. Mental status
changes can be anxiety, delirium, restlessness, and disorientation. Autonomic hyperactivity manifests as diaphoresis, mydriasis, tachycardia,
hyperthermia, hypertension, vomiting, and diarrhea. Neuromuscular abnormalities include, tremor, muscle rigidity, myoclonus, hyperreflexia, ocular
clonus, and akathesia. Neuromuscular findings are generally more pronounced in the lower extremities.
Serotonin syndrome is a clinical diagnosis and requires a through history and physical exam. The main differentials include, neuroleptic malignant
syndrome (NMS), malignant hyperthermia anticholinergic toxicity, sympathomimetic toxicity, or withdrawal from opioids, sedatives or alcohol. Other
non-toxicological causes such as meningitis, hypoglycemia etc should also be considered. To assist with diagnosis you can use the Hunter toxicity
criteria. See Table 58–15: Hunter toxicity criteria.
Table 58–15
Hunter toxicity criteria for serotonin syndrome.
Hunter Toxicity Criteria
To fulfill the criteria, the patient must have ingested a serotonergic agent and meet one of the stipulated conditions:
spontaneous clonus inducible clonus plus agitation

of diaphoresis
ocular clonus plus agitation or diaphoresis tremor plus hyperreflexia

°
hypertonia plus temperature abobe 38 C plus ocular clonus or inducible clonus
Serotonin syndrome is a clinical diagnosis and requires a through history and physical exam. The main differentials include, neuroleptic malignant
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syndrome (NMS), malignant hyperthermia anticholinergic toxicity, sympathomimetic toxicity, or withdrawal from opioids, sedatives or alcohol. Other
non-toxicological causes such as meningitis, hypoglycemia etc should also be considered. To assist with diagnosis you can use the Hunter toxicity
criteria. See Table 58–15: Hunter toxicity criteria.
Table 58–15
Hunter toxicity criteria for serotonin syndrome.
Hunter Toxicity Criteria
To fulfill the criteria, the patient must have ingested a serotonergic agent and meet one of the stipulated conditions:
spontaneous clonus inducible clonus plus agitation

of diaphoresis
ocular clonus plus agitation or diaphoresis tremor plus hyperreflexia
hypertonia plus temperature abobe 38°C plus ocular clonus or inducible clonus
The Hunter Toxicity Criteria Decision Rules are 84% sensitive and 97% specific when compared with the gold
standard of diagnosis by a medical toxicologist.7
Treatment/Work Up
agitation and seizures and management of any subsequent complications (see general principles of overdose and poisoning). In cases of deliberate
overdose, decontamination with activated charcoal should be initiated, if presentation is within 1 hour of ingestion.
Specific Therapy
1. In mild cases of serotonin syndrome simply discontinuing the medication will result in resolution of symptoms in 24 hours. Of note neuroleptic
malignant syndrome may take days to resolve.
2. Prolonged QT and Torsades de pointes should be managed with magnesium sulfate 1-2 g IV over 15 minutes.
3. Hyperthermia should be closely monitored. When temperature exceeds 39 degrees Celsius urgent cooling is required. Numerous techniques exist
and initially should include the use of fans, antipyretics, cold IV fluids, and ice baths. More specialized methods include the use of intravenous
cooling catheters and cooling pads applied to the skin. Those with excessive agitation, recurrent seizures or increased muscular tone may require
paralysis to prevent excessive heat production. Renal function and CK levels should be followed closely.
4. Benzodiazepines not only help with agitation and seizures but also help improve autonomic symptoms such as tachycardia, hypertension, and
hyperthermia.
5. If supportive care and benzodiazepines are ineffective then cyproheptadine may be used. This is an antihistamine that has some anti-serotonergic
properties. The initial dose is 4-12 mg orally, repeated at 12-hour intervals if no response. Propranolol, bromocriptine, chlorpromazine,
olanzapine, and dantrolene are not recommended.
poisoning.
Antipsychotics
Antipsychotic, also known as neuroleptics and major tranquilizers, are used to treat a variety of conditions including psychosis, movement disorders,
nausea, and agitation. Typical antipsychotics were first developed in 1951 and work by non-specific antagonism of central dopamine receptors.
Atypical antipsychotics were developed in 1998 and are much more specific therefore produce much fewer side effects. They selectively antagonize
mesolimbic D2 receptors. All classes of antipsychotic medications drugs also have varying degrees of antihistaminic, antiadrenergic, antiserotonergic,
and anticholingeric properties leading to numerous side effects, especially in overdose. Aripiprazole is a newer atypical antipsychotic that has a low
affinity for serotonin, alpha-1 adrenergic, and histamine-1 receptors and as a result a more favorable side effect profile.
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Antipsychotics
Antipsychotic, also known as neuroleptics and major tranquilizers, are used to treat a variety of conditions including psychosis, movement disorders,
nausea, and agitation. Typical antipsychotics were first developed in 1951 and work by non-specific antagonism of central dopamine receptors.
Atypical antipsychotics were developed in 1998 and are much more specific therefore produce much fewer side effects. They selectively antagonize
mesolimbic D2 receptors. All classes of antipsychotic medications drugs also have varying degrees of antihistaminic, antiadrenergic, antiserotonergic,
and anticholingeric properties leading to numerous side effects, especially in overdose. Aripiprazole is a newer atypical antipsychotic that has a low
affinity for serotonin, alpha-1 adrenergic, and histamine-1 receptors and as a result a more favorable side effect profile.
Antipsychotic use is very common in the United States where deliberate and accidental overdose occurs. Mortality from overdose is low. A specific but
rare and potentially fatal complication to be aware of is neuroleptic malignant syndrome.
Clinical Features
Symptoms and signs are related to the numerous receptors that are blocked. Histamine receptor antagonism produces lethargy, sedation and coma.
Other central effects include ataxia, dysarthria, myoclonus and seizures. Alpha-adrenergic antagonism may produce miosis, tachycardia and
orthostatic hypotension. Anticholingeric effects can produce the classic anticholingeric toxidrome of blurry vision, dry mouth, flushed skin,
constipation, dilated pupils and urinary retention.
On examination patients may have extrapyramidal signs such as acute dystonic reactions and akathisia. These are common side effects of typical
antipsychotics and normal therapeutic doses. These effects can be seen with overdose but are rare. Antipsychotics can also affect cardiac sodium ion
channels producing EKG changes including QT, PR and QRS prolongation, ST and T wave abnormalities and right axis deviation. The most common
EKG finding is sinus tachycardia.
Neuroleptic Malignant Syndrome (NMS)—NMS is a potentially life threatening neurological emergency due to an idiosyncratic reaction to
antipsychotics with a mortality of 10%-20%. It presents with a tetrad of fever (38°C-40°C), muscular rigidity (lead pipe), autonomic dysfunction
(tachycardia, diaphoresis, and labile blood pressure), and altered mental status (confusion, delirium and catatonia).
Death usually occurs from complications from autonomic dysfunction including rhabdomyolysis and cardiac and respiratory failure. Onset of
symptoms is usually gradual over 3-7 days. CK levels are often significantly elevated > 100,000 IU/L.
Due to the fact that antipsychotics interact with multiple different receptors producing several clinical toxidromes, diagnosis can be difficult.
Anticholingeric toxicity, TCA overdose, sympathomimetic abuse, and sedative-hypnotic overdose can produce similar signs.
Treatment/Work Up
Specific Therapy
1. Prolonged QT or torsade de pointes should be treated with intravenous magnesium sulfate 1-2 g IV over 15 minutes.
2. Vasopressors such as norepinephrine may be required for hypotension that does not respond to fluid resuscitation.
3. Mild hyperthermia should be treated with conventional cooling methods. When temperature exceeds 39°C urgent cooling is required. Numerous
techniques exist and initially should include the use of fans, antipyretics, cold IV fluids, and ice baths. More specialized methods include the use of
intravenous cooling catheters and cooling pads applied to the skin.
4. Neuroleptic malignant syndrome is treated as above. In addition high dose benzodiazepines can help muscle rigidity. Dantrolene 1-2.5 mg/kg IV
load may be useful when rigidity is pronounced. Bromocriptine, a dopamine agonist, may be administered orally to counter the dopamine
antagonism.
poisoning.
CHOLINERGIC AND ANTI-CHOLINERGIC TOXICITY
Acetylcholine is the most abundant neurotransmitter in the peripheral and central nervous system with actions on both somatic and autonomic nerves
via nicotinic and muscarinic receptors.
load may be useful when rigidity is pronounced. Bromocriptine, a dopamine agonist, may be administered orally to counter the dopamine
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antagonism.
poisoning.
CHOLINERGIC AND ANTI-CHOLINERGIC TOXICITY

Acetylcholine is the most abundant neurotransmitter in the peripheral and central nervous system with actions on both somatic and autonomic nerves
via nicotinic and muscarinic receptors.
Anti-cholinergic toxicity is produced by blocking the effects of acetylcholine. Anticholinergic drugs competitively inhibit binding of the
neurotransmitter acetylcholine to post synaptic muscarinic acetylcholine receptors found in smooth muscle but not nicotinic acetylcholine receptors
found in the neuromuscular junction.
Numerous drugs and classes of drugs have anticholingeric properties at therapeutic levels and in overdose. See Table 58–16: Classes of anticholingeric
drugs.
Table 58–16
Classes of drugs with known anticholinergic properties.
Drug Class/Plant
Antihistamines
Antipsychotics
Antispasmodics
Tricyclic antidepressants
Deadly nightshade
Cholinergic toxicity is produced by an excess of acetylcholine usually by inhibition of the enzyme acetylcholinesterase on the post synaptic membrane.
This enzyme is responsible for the breakdown of acetylcholine, which then terminates the nerve signal transmission. This produces nicotinic,
muscarinic and CNS effects. Cholinergic toxicity is usually due to exposure to organophosphates in the form of insecticides, herbicides or nerve agents
used in chemical warfare or terrorism. Organophosphates cause irreversible inactivation, through phosphorylation, of acetylcholinesterase.
Acetylcholinesterase inhibitors are used in medicine for reversal of neuromuscular blockade in general anesthesia and to treat certain neuromuscular
disorders such as myasthenia gravis but toxicity from these agents is rare.
Anticholingerics
Clinical Features
Anticholinergic toxicity is usually caused by accidental or deliberate overdose of a prescribed medication and produces a characteristic toxidrome.
Patients have tachycardia, mydriasis, urinary retention, dry flushed skin, blurred vision, absent bowel sounds, hyperthermia and can have hypo or
hypertension. Mental status changes include confusion, agitation, hallucinations and disorientation. The classic symptoms and signs are described
below: See Table 58–17: Classic anti-cholinergic symptoms and signs.
Table 58–17
Classic anti-cholingeric symptoms and signs.
Symptom/Sign Etiology
Dry skin (dry as a bone) Anhidrosis
Hyperthermia (hot as a hare)
Chapter 58: Overdose, Poisoning, and Withdrawal, Edward Mossop; Fred DiBlasio Anhidrosis Page 26 / 42
AMS (mad as a hatter) CNS effects
Anticholinergic toxicity is usually caused by accidental or deliberate overdose of a prescribed medication and produces a characteristic toxidrome.
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Patients have tachycardia, mydriasis, urinary retention, dry flushed skin, blurred vision, absent bowel sounds, hyperthermia and can have hypo or
hypertension. Mental status changes include confusion, agitation, hallucinations and disorientation. The classic symptoms and signs are described
below: See Table 58–17: Classic anti-cholinergic symptoms and signs.
Table 58–17
Classic anti-cholingeric symptoms and signs.
Symptom/Sign Etiology
Dry skin (dry as a bone) Anhidrosis
Hyperthermia (hot as a hare) Anhidrosis
AMS (mad as a hatter) CNS effects
Flushed (red as a beet) Vasodilatation
Blurred vision (blind as a bat) Mydriasis
Abdominal pain (full as a flask) Urinary retention
Tachycardia Atropine effect
Serious complications of toxicity include status epilepticus, rhabdomyolysis, and cardiovascular collapse.
Drugs or abuse, psychiatric disorders, encephalitis and withdrawal states can produce similar symptoms and signs. Numerous medications have anti-
cholinergic properties as part of their toxic profile; therefore clinicians should look for other symptoms and signs associated with other classes of
medication.
Treatment/Work Up
Specific Therapy
1. If toxicity is related to underlying tricyclic overdose then sodium bicarbonate may be required (see TCA overdose).
2. If toxicity is related to anti-psychotics then watch for signs of neuroleptic malignant syndrome (see anti-psychotic overdose).
3. Mild hyperthermia should be treated with conventional cooling methods. When temperature exceeds 39°C urgent cooling is required. Numerous
techniques exist and initially should include the use of fans, antipyretics, cold IV fluids, and ice baths. More specialized methods include the use of
intravenous cooling catheters and cooling pads applied to the skin.
poisoning.
5. Physostigmine (acetylcholinesterase inhibitor) use is controversial and may be indicated if conventional supportive care is not effective and should
only be used in pure anti-cholinergic toxicity. Dose as 0.5-2 mg IV slowly over 5 minutes. Please consult specialist advice before administering.
Organophosphates
Clinical Features
Organophosphate toxicity can be from oral, inhalational (nerve gas) or dermal exposure. This causes an excess of acetylcholine producingPage
Chapter 58: Overdose, Poisoning, and Withdrawal, Edward Mossop; Fred DiBlasio a 27 / 42
cholinergic crisis and characteristic toxidrome with symptoms due to muscarinic, nicotinic and CNS stimulation.
Peripheral muscarinic effects include bronchorrhea, bronchospasm, salivation, blurred vision, diaphoresis, lacrimation, urinary incontinence,
only be used in pure anti-cholinergic toxicity. Dose as 0.5-2 mg IV slowly over 5 minutes. Please consult specialist advice before administering.
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Organophosphates
Clinical Features
Organophosphate toxicity can be from oral, inhalational (nerve gas) or dermal exposure. This causes an excess of acetylcholine producing a
cholinergic crisis and characteristic toxidrome with symptoms due to muscarinic, nicotinic and CNS stimulation.
Peripheral muscarinic effects include bronchorrhea, bronchospasm, salivation, blurred vision, diaphoresis, lacrimation, urinary incontinence,
vomiting, and defecation. Nicotinic effects include muscle fasciculations, weakness and paralysis, which can lead to respiratory failure. CNS effects
cause headaches, blurred vision, confusion, coma, and seizures. A useful mnemonic for the muscarinic effects is SLUDGE/BBB: salivation, lacrimation,
urinary incontinence, defecation and gastric emesis, bradycardia, bronchorrhea and bronchospasm. If muscarinic effects predominate then patients
may be bradycardic with miosis versus tachycardic with mydriasis if nicotinic effects predominate. Blood pressure can be either high or low.
Diagnosis of organophosphate poisoning is a clinical diagnosis. Myasthenia gravis patients who take an excessive amount of their medications can
present with a cholinergic crisis.
Treatment/Work Up
agitation and seizures and management of any subsequent complications (see general principles of overdose and poisoning). Organophosphate
poisoning is often from dermal exposure making surface decontamination important. Personal protective clothing should be worn by medical staff to
prevent secondary contamination. The patient should be washed with soap and water and any clothing worn by the patient should be disposed of.
Other decontamination and enhanced elimination techniques are ineffective.
Specific Therapy
1. If intubation is required avoid succinylcholine due to the prolonged paralysis effects.
2. Atropine antagonizes the peripheral muscarinic effects of excess acetylcholine and should be given if muscarinic symptoms predominate. Give 1
mg IV every 5 minutes until symptoms improve (most importantly tracheobronchial secretions should slow down). Large doses of atropine may be
required. Of note atropine has no effect on nicotinic receptor function therefore will not effect paralysis or muscle weakness. Tachycardia and
mydriasis are not a contraindication to atropine.
3. Pralidoxime is effective at restoring the activity of acetylcholinesterase by reversing the phosphorylation. It predominantly improves the nicotinic
effects, such as weakness, and therefore should be used in conjunction with atropine. Give 1-2 g mixed with normal saline over 5 to 10 minutes.
Repeat dosing or an infusion may be required.
CARDIAC MEDICATION OVERDOSE

Introduction
Cardiac medications are very commonly prescribed medications with antihypertensives frequently featured in the top 10 most prescribed drugs in the
United States. Accidental or deliberate overdose is common and potentially fatal. Cardiac medication toxicity usually presents with hypotension, due to
either vasodilatation or decreased myocardial contractility, and arrhythmias, however non-cardiac effects can also present a management challenge.
Cardiac medications discussed here include, beta-blockers, calcium channel blockers, and digoxin.
Beta-Blockers
Beta-blockers are competitive antagonists of the B-receptors, with B1-receptors found in the heart, and B2-receptors found in the bronchial tree and
blood vessels. They are used to manage acute coronary syndrome, hypertension, thyrotoxicosis, glaucoma, and arrhythmias. Toxicity leads to negative
inotropy and chronotropy causing hypotension and bradycardia. Some agents (acebutolol, betaxolol, pindolol, propranalol) demonstrate myocardial
membrane stabilizing activity that can cause QRS widening and decrease myocardial contractility as well as potentiate dysrhythmias.
Clinical Features
Patients with significant toxicity present with bradycardia and depressed myocardial contractility causing significant hypotension, which can
Chapter 58: Overdose, Poisoning, and Withdrawal, Edward Mossop; Fred DiBlasio Pageprogress
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to cardiogenic shock. EKG changes can include atrioventricular blocks, a widened QRS/ventricular arrhythmias and asystole. Global hypoperfusion
may cause elevated lactic acid and changes in mental status including seizures. Onset is within 6 hours for immediate release preparations and can be
delayed up to 12 hours with extended release. Propranolol may cause more CNS effects independent of hypoperfusion. Other effects include
blood vessels. They are used to manage acute coronary syndrome, hypertension, thyrotoxicosis, glaucoma, and arrhythmias. Toxicity leads to negative
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inotropy and chronotropy causing hypotension and bradycardia. Some agents (acebutolol, betaxolol, pindolol, propranalol) demonstrate myocardial
membrane stabilizing activity that can cause QRS widening and decrease myocardial contractility as well as potentiate dysrhythmias.
Clinical Features
Patients with significant toxicity present with bradycardia and depressed myocardial contractility causing significant hypotension, which can progress
to cardiogenic shock. EKG changes can include atrioventricular blocks, a widened QRS/ventricular arrhythmias and asystole. Global hypoperfusion
may cause elevated lactic acid and changes in mental status including seizures. Onset is within 6 hours for immediate release preparations and can be
delayed up to 12 hours with extended release. Propranolol may cause more CNS effects independent of hypoperfusion. Other effects include
bronchospasm (rare) and hypoglycemia.
Diagnosis is based on history and physical signs. Beta-blocker overdose may be hard to distinguish from calcium channel blocker (CCB) overdose.
Beta-blocker toxicity usually causes hypoglycemia whereas CCB toxicity induces hyperglycemia. Barbiturates can also produce similar signs however
patients usually have a significantly depressed mental status.
Treatment/Work Up
activated charcoal should be initiated, if presentation is within 1 hour of ingestion. Late administration of activated charcoal may be beneficial for
sustained release preparations if a potentially toxic amount has been ingested. Gastric lavage performed within 1 hour of ingestion has been used.
Whole bowel irrigation, for cases of sustained release preparations, may be affective, however is generally not recommended. Hemodialysis may be
beneficial in cases of atenolol, nadolol or sotalol overdose.
Specific Therapy
1. Atropine 0.5-1 mg should be administered for bradycardia.
2. Glucagon has both chronotropic and inotropic effects independent of beta-receptors and should be administered as an IV bolus of 3-5 mg followed
by a continuous infusion of 0.25 ml/kg/min. The main side effect is vomiting which can lead to aspiration.
3. Norepinephrine, epinephrine, or dobutamine can be administered in high doses, for refractory hypotension and bradycardia, to overcome the
competitive blockade.
4. Hyperinsulinemia-euglycemia therapy has been shown to improve myocardial contractility and hypotension. Initially administer 50 ml of 50%
dextrose. Start high dose regular insulin 1 unit/kg IV bolus followed by a continuous infusion of 0.5-1 unit/kg/hr with dextrose 10% in water at 200
ml/hr. Serum glucose should be monitored every 20 min and the dextrose infusion rate adjusted to maintain serum glucose between 150-300
mg/dL.
5. Calcium supplementation is of limited benefit however should be considered in refractory cases. Calcium chloride is preferred.
6. Intravenous lipid emulsion (ILE) may be considered and administered with a bolus of 1.5 ml/kg followed by a continuous infusion of 0.25
ml/kg/min.
7. For severe cases refractory to the above measures consider transvenous pacing, placement of an intra-aortic balloon pump or veno-arterial
extracorporeal membrane oxygenation (VA-ECMO) as a bridge to recovery.
Calcium Channel Blockers
Calcium channel blockers (CCB) are used primarily in the treatment of hypertension, angina pectoris, and supraventricular arrhythmias. CCB all block
L-type calcium channels which are known to control myocardial contractility (inotropy), vascular smooth muscle contractility and conduction and
pacemaker cells (chronotropy). These agents hold the potential for substantial toxicity and can be fatal in overdose. There are 2 main classes of CCB;
dihydropyridines and non-dihydropyridines. At therapeutic dosage, dihydropyridines are potent vasodilators with only a slight negative effect on
cardiac contractility and conduction, whereas non-dihydropyridines are weak vasodilators, but exert a depressive effect on cardiac conduction and
contractility. See Table 58–18: Classes of calcium channel blockers.
Table 58–18
Classes of calcium channel blockers. Page 29 / 42
Dihydropyridines Non-Dihydropyridines
L-type calcium channels which are known to control myocardial contractility (inotropy), vascular smooth muscle contractility and conduction and
pacemaker cells (chronotropy). These agents hold the potential for substantial toxicity and can be fatal in overdose. There are 2 main classes of CCB;
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dihydropyridines and non-dihydropyridines. At therapeutic dosage, dihydropyridines are potent vasodilators with only a slight negative effect on
cardiac contractility and conduction, whereas non-dihydropyridines are weak vasodilators, but exert a depressive effect on cardiac conduction and
contractility. See Table 58–18: Classes of calcium channel blockers.
Table 58–18
Classes of calcium channel blockers.
Dihydropyridines Non-Dihydropyridines
Amlodipine Verapamil
Felodipine Diltiazem
Nifedipine
Nicardipine
Nimodipine
Clinical Features
Patients ingesting more than 5 to 10 times the usual dose can develop severe intoxication within 6 hours, or up to 12 hours in extended release
formulations. Toxicity causes bradycardia, depressed myocardial contractility and vasodilatation leading to significant hypotension. Dihydropyridines
cause more vasodilatation and sometimes induce a reflex tachycardia. Non-dihydropyridines have more myocardial depressing affects however both
classes have significant overlap at high doses. Global hypoperfusion may cause drowsiness and elevated lactic acid. Hyperglycemia may develop due to
inhibition of calcium-mediated insulin release. EKG findings include PR prolongation and 2nd and 3rd degree atrioventricular block.
Diagnosis is based on history and physical signs. Beta-blocker overdose may be hard to distinguish from CCB overdose. Beta-blocker toxicity usually
causes hypoglycemia whereas CCB toxicity induces hyperglycemia. Barbiturates can also produce similar signs however patients usually have a
significantly depressed mental status.
Treatment/Work Up
activated charcoal should be initiated, if presentation is within 1 hour of ingestion. Late administration of activated charcoal may be beneficial for
sustained release preparations if a potentially toxic amount has been ingested. Gastric lavage performed within 1 hour of ingestion has been used.
Whole bowel irrigation, for cases of sustained release preparations, may be affective, however is generally not recommended.
Specific Therapy
1. Atropine 0.5-1 mg should be administered for bradycardia, however this is usually ineffective.
2. Calcium should be replaced with calcium gluconate or chloride (10 ml of 10%), however this may also be ineffective. Calcium chloride is preferred
because it contains more elemental calcium however may cause irritation and should ideally be given through a central line.
3. Norepinephrine, epinephrine or dobutamine can be administered for refractory hypotension and bradycardia but have varying results.
mg/dL.
5. Glucagon can be both chronotropic and inotropic and should be administered as an IV bolus of 3-5 mg followed by a continuous infusion of 0.25
ml/kg/min. The main side effect is vomiting which can lead to aspiration.
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mg/dL.
5. Glucagon can be both chronotropic and inotropic and should be administered as an IV bolus of 3-5 mg followed by a continuous infusion of 0.25
ml/kg/min. The main side effect is vomiting which can lead to aspiration.
ml/kg/min.
7. For severe cases refractory to the above measures consider transvenous pacing, placement of an intra-aortic balloon pump or veno-arterial
extracorporeal membrane oxygenation (VA-ECMO) as a bridge to recovery.
Digoxin
Cardiac glycosides are derived from the foxglove plant and are used to treat supraventricular tachyarrhythmia and cardiac heart failure. They increase
vagal tone resulting in decreased chronotropy and competitively inhibit the sodium potassium ATPase pump to increase inotropy and extracellular
potassium. Toxicity can develop from acute ingestion, drug interactions (amiodarone, diuretics, spironolactone, macrolides, and CCB) leading to
elevated digoxin levels or from chronic use in the setting of renal failure and electrolyte abnormalities. Low potassium and magnesium may precipitate
toxicity by lack of competition for the sodium potassium ATPase pump.
Clinical Features
Toxicity produces non-specific cardiac, GI, CNS, and electrolyte abnormalities. CNS effects include dizziness, headache, confusion, and visual
complaints. The patient may report yellow or green vision or halos. GI effects include nausea and vomiting. Hyperkalemia is a potentially serious
complication of digoxin toxicity. EKG changes include tachy and bradyarrhythmias, atrioventricular block, and changes associated with hyperkalemia.
Ventricular arrhythmias can occur in severe toxicity. Other non-specific findings include weakness, anorexia, and fatigue.
Digoxin toxicity may be hard do diagnose clinically due to the numerous non-specific effects. Hyperkalemia is frequently seen in acute toxicity but may
be normal in cases of chronic toxicity. EKG changes can help to distinguish toxicity form other more benign conditions. Specific drug levels may be
helpful in acute toxicity but may be only minimally elevated in chronic toxicity and therefore the diagnosis may be overlooked by false reassurance.
Barbiturate, beta-blocker and CCB overdose may produce similar features.
Treatment/Work Up
agitation and seizures and management of any subsequent complications (see general principles of overdose and poisoning). In cases of acute toxicity
activated charcoal should be administered if presentation is within 1 hour of ingestion.
Specific Therapy
1. DC cardioversion should be used for any unstable supraventricular or ventricular tachy-arrhythmias.
2. Brady-arrhythmias should initially be treated with atropine 0.5-1 mg IV or temporary pacing if severe.
3. Stable supraventricular tachy-arrhythmias can be treated with magnesium sulfate IV 1-2 g over 15 minutes. Stable ventricular arrhythmias may be
treated with lidocaine IV or phenytoin.
4. Correct any underlying electrolyte abnormalities. Hyperkalemia should be treated with insulin and dextrose, resins or hemodialysis if severe.
5. Digoxin-specific Fab (antigen binding fragment) should be administered to patients who have an unstable arrhythmia that has not responded to
conventional therapy, in those who have a potassium of greater than 5 mEq/L after an ingestion of more than 10 mg of digoxin and in patients who
have a blood digoxin level of greater than 10 ng/ml.
OVER THE COUNTER ANALGESIC OVERDOSE

Over-the-counter (OTC) drugs as a whole were are the second leading substance type used in suicides representing approximately 10% ofPage
Chapter 58: Overdose, Poisoning, and Withdrawal, Edward Mossop; Fred DiBlasio suicides
31 / due
42
to substance overdose. Prescription drugs are the leading type of drug used in suicides representing 79% of suicides due to substance overdose.
Analgesics such as acetaminophen and aspirin (ASA) are easily available cover the counter and at low cost. They can be fatal in overdose but early
identification and appropriate treatment can significantly improve outcomes.
4. Correct any underlying electrolyte abnormalities. Hyperkalemia should be treated with insulin and dextrose, resins or hemodialysis if severe.
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5. Digoxin-specific Fab (antigen binding fragment) should be administered to patients who have an unstable arrhythmia that has not responded to
conventional therapy, in those who have a potassium of greater than 5 mEq/L after an ingestion of more than 10 mg of digoxin and in patients who
have a blood digoxin level of greater than 10 ng/ml.
OVER THE COUNTER ANALGESIC OVERDOSE

Over-the-counter (OTC) drugs as a whole were are the second leading substance type used in suicides representing approximately 10% of suicides due
to substance overdose. Prescription drugs are the leading type of drug used in suicides representing 79% of suicides due to substance overdose.
Analgesics such as acetaminophen and aspirin (ASA) are easily available cover the counter and at low cost. They can be fatal in overdose but early
identification and appropriate treatment can significantly improve outcomes.
Acetaminophen
Background
Acetaminophen is the most widely used antipyretic and analgesic available OTC in the United States and can be found in numerous different
preparations. It is rapidly absorbed in the GI tract and metabolized by the liver. At therapeutic doses a very small percentage of acetaminophen is
metabolized to a toxic intermediate called N-acetyl-p-benzoquinoneimine (NAPQI), which is rapidly conjugated with hepatic glutathione forming non-
toxic compounds. In overdose the metabolic pathways become saturated leading to higher levels of NAPQI, which causes depletion of glutathione
stores. NAPQI then begins to react with hepatocytes causing necrosis. The antidote, N-Acetylcysteine (NAC), acts by enhancing glutathione stores and
providing a substitute to allow for detoxification. Acetaminophen poisoning has become the most common cause of acute liver failure in the United
States.
Clinical Features
Patients can overdose in several different ways: 1. Single acute overdose in < 1 hour, 2. Staggered overdose where doses are taken over more than 1
hour, 3. Therapeutic excess where patients ingest multiple smaller doses over a 24 hour period, 4. Uncertain or unclear knowledge of overdose. For
single acute overdose patients may present in less than 4 hours, between 4 and 8 hours or after 24 hours.
Toxic exposure is likely to occur if patients ingest > 150 mg/kg in a single dose or over a 24 hour period. Rarely, toxicity can occur with ingestions
between 75 and 150 mg/kg within any 24-hour period in some patients. Clinical features of acetaminophen overdose are detailed in the Table below:
See Table 58–19: Four stages of acetaminophen toxicity.
Table 58–19
Four stages of acetaminophen toxicity.
Stage Manifestations
Stage I: Nausea, vomiting diaphoresis, lethargy, and malaise, though some remain asymptomatic. Lab studies are typically normal. CNS depression
0.5 to 24 and elevated anion gap metabolic acidosis can rarely be observed following massive overdose, and if present are likely due to coingestants.
hours
Stage II: Clinical and laboratory evidence of hepatotoxicity +/- nephrotoxicity become evident. While appearing to improve clinically, elevations of from
24 to 72 those who develop hepatic injury, over half will demonstrate aminotransferase elevations within 24 hours and all have elevations by 36
hours hours.32 Patients develop right upper quadrant pain with liver enlargement and tenderness. Elevations of prothrombin time (PT) total
bilirubin, oliguria and renal function abnormalities become evident.
Stage Marked by a peak in liver function abnormalities, systemic symptoms of stage I reappear in conjunction with jaundice, confusion due to
I I I : 72 to hepatic prolongation of PT or INR, hypoglycemia, lactic acidosis, and a total bilirubin concentration above 4.0 mg/dL (primarily indirect). Acute
96 hours renal failure occurs in 10% to 25% of patients with significant hepatotoxicity and > 50% of those with hepatic failure.33
post
ingestion
Stage Patients that survive stage III enter a recovery phase by day four that completed by day seven. Symptoms and laboratory abnormalities may
IV: 4 to not abate for several weeks. When recovery occurs, it is complete; chronic hepatic dysfunction is not a seqyaelae of acetaminophen poising.
14 days
single acute overdose patients may present in less than 4 hours, between 4 and 8 hours or after 24 hours.
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Toxic exposure is likely to occur if patients ingest > 150 mg/kg in a single dose or over a 24 hour period. Rarely, toxicity can occur with ingestions
between 75 and 150 mg/kg within any 24-hour period in some patients. Clinical features of acetaminophen overdose are detailed in the Table below:
See Table 58–19: Four stages of acetaminophen toxicity.
Table 58–19
Four stages of acetaminophen toxicity.
Stage Manifestations
Stage I: Nausea, vomiting diaphoresis, lethargy, and malaise, though some remain asymptomatic. Lab studies are typically normal. CNS depression
0.5 to 24 and elevated anion gap metabolic acidosis can rarely be observed following massive overdose, and if present are likely due to coingestants.
hours
Stage II: Clinical and laboratory evidence of hepatotoxicity +/- nephrotoxicity become evident. While appearing to improve clinically, elevations of from
24 to 72 those who develop hepatic injury, over half will demonstrate aminotransferase elevations within 24 hours and all have elevations by 36
hours hours.32 Patients develop right upper quadrant pain with liver enlargement and tenderness. Elevations of prothrombin time (PT) total
bilirubin, oliguria and renal function abnormalities become evident.
Stage Marked by a peak in liver function abnormalities, systemic symptoms of stage I reappear in conjunction with jaundice, confusion due to
I I I : 72 to hepatic prolongation of PT or INR, hypoglycemia, lactic acidosis, and a total bilirubin concentration above 4.0 mg/dL (primarily indirect). Acute
96 hours renal failure occurs in 10% to 25% of patients with significant hepatotoxicity and > 50% of those with hepatic failure.33
post
ingestion
Stage Patients that survive stage III enter a recovery phase by day four that completed by day seven. Symptoms and laboratory abnormalities may
IV: 4 to not abate for several weeks. When recovery occurs, it is complete; chronic hepatic dysfunction is not a seqyaelae of acetaminophen poising.
14 days
A full history and physical is important to help establish diagnosis. Acetaminophen levels should be drawn for all patients after a single acute overdose
if they present between 4-24 hours post ingestion. The serum level can then be plotted on the Rumack-Matthew normogram to ascertain patient risk of
toxicity (see Figure 58–1). If possible levels should be drawn and resulted before 8 hours because NAC is most effective given within the first 8 hours.
Levels drawn before 4 hours are unreliable at predicting toxicity. Levels drawn after 24 hours are usually not useful because treatment is likely to be
ineffective. This normogram can only be used for acute single overdose between 4-24 hours. Acetaminophen levels in staggered overdose, therapeutic
excess or unknown time of ingestion are misleading and usually not recommended however, some centers recommend treating if acetaminophen
levels are over 10 mcg/ml in the setting of an unknown time of ingestion. See Figure 58–1: Acetaminophen treatment protocol normogram.
Figure 58–1
Acetaminophen treatment protocol normogram. (Adapted with permission from Rumack BH, et al. Acetaminophen overdose: 662 cases
with evaluation of oral acetylcystein treatment. Arch Intern Med. 1981; 141:382 [PMID: 7469629].)
Figure 58–1 Access Provided by:
Acetaminophen treatment protocol normogram. (Adapted with permission from Rumack BH, et al. Acetaminophen overdose: 662 cases
with evaluation of oral acetylcystein treatment. Arch Intern Med. 1981; 141:382 [PMID: 7469629].)
Treatment/Work Up
activated charcoal should be initiated if presentation is within 1 hour of ingestion. Activated charcoal may also inadvertently absorb oral NAC in which
case the oral dose may need to be adjusted or converted to IV.
Specific Therapy
1. NAC, the antidote, is most effective if given within the first 8 hours after a single acute overdose. Indications for NAC are detailed below (see Table
58–20). NAC can be given intravenously over 21 hours or orally over 72 hours. Intravenous dosing involves an initial load of 150 mg/kg given over
15-60 minutes, followed by 50 mg/kg given over 4 hours, followed by 100 mg/kg in 16 hours. NAC is infused in 5% dextrose in water. Oral dosing
involved a loading dose of 140 mg/kg once, followed by 70 mg/kg every 4 hours for 17 doses. NAC can induce histamine release, especially in the
intravenous form, resulting in urticaria and bronchoconstriction. See Table 58–20: Indications for NAC.
2. Liver failure and resulting multi-organ failure should be managed in a specialist liver transplant center. Significant complications include
coagulopathy, cerebral edema, renal failure, and acidosis.
Table 58–20
Indications for NAC therapy.
Indications for NAC Therapy
1 Serum acetaminophen level, drawn after 4 hours after a single ingestion, above the treatment line on the normogram
2 Suspected single ingestion of > 150 mg/kg where serum levels will not be available until after 8 hours of ingestion
3 Staggered overdose
4 Unknown time of ingestion and a serum level of > 10 mcg/ml
5 History of acetaminophen ingestion with ANY evidence of liver injury
involved a loading dose of 140 mg/kg once, followed by 70 mg/kg every 4 hours for 17 doses. NAC can induce histamine release, especially in the
intravenous form, resulting in urticaria and bronchoconstriction. See Table 58–20: Indications for NAC. Access Provided by:
2. Liver failure and resulting multi-organ failure should be managed in a specialist liver transplant center. Significant complications include
coagulopathy, cerebral edema, renal failure, and acidosis.
Table 58–20
Indications for NAC therapy.
Indications for NAC Therapy
1 Serum acetaminophen level, drawn after 4 hours after a single ingestion, above the treatment line on the normogram
2 Suspected single ingestion of > 150 mg/kg where serum levels will not be available until after 8 hours of ingestion
3 Staggered overdose
4 Unknown time of ingestion and a serum level of > 10 mcg/ml
5 History of acetaminophen ingestion with ANY evidence of liver injury
6 Delayed presentation of > 24 hours but with evidence of liver injury
Salicylates
Background
Salicylic acid derivatives are non-steroidal anti-inflammatories used commonly to treat fever, inflammation, and pain. Aspirin is cheaply and easily
available over the counter and is present in many different preparations from cold and flu medications to topical gels. Aspirin is also a widely
prescribed antiplatelet therapy as prophylaxis in patients with cardiovascular and cerebrovascular disease. Salicylates are rapidly absorbed,
undergoing hepatic metabolism and renal excretion. They exert their effects primarily by inhibition of cyclooxygenase with decreased production of
prostaglandins, prostacyclin, and thromboxanes. Aspirin causes a direct stimulation of the respiratory center in the medulla leading to respiratory
alkalosis. Aspirin can also interfere with metabolism and oxidative phosphorylation leading to increased oxygen consumption, hyperthermia and an
anion gap metabolic acidosis due to increased production of endogenous acids, ketone bodies and lactate.
Clinical Features
Aspirin toxicity can occur from an acute intentional overdose or be more chronic from unintentional gradual misuse. Chronic poisonings tend to occur
in the elderly and are associated with a higher mortality. Acute toxicity can be mild < 150 mg/kg ingested, moderate 150-300 mg/kg, or severe > 300
mg/kg. Mild symptoms include nausea, vomiting, tinnitus, and dizziness. Moderate symptoms include hyperventilation, hyperthermia, ataxia, and
anxiety. Severe toxicity can result in coma, seizures, agitation, renal failure, cardiac arrhythmia, pulmonary edema, and shock. Chronic toxicity may
initially have vague subtle signs that are missed and gradually progress to severe toxicity with behavioral changes, neurological signs, hyperthermia,
tachypnea and evidence of pulmonary edema. Acid base disturbances initially show a respiratory alkalosis then a coexisting anion gap metabolic
acidosis.
Aspirin toxicity is a clinical diagnosis supported by acid base changes. Salicylate levels in acute toxicity can be helpful with mild toxicity associated with
levels of < 300 mg/L and severe toxicity with > 700 mg/L. However, chronic toxicity develops gradually with lower drug levels, which correlate poorly
with toxicity, therefore drug levels may provide false reassurance and should be viewed with caution. Differential diagnosis includes sepsis,
encephalitis, stimulant toxicity, and other causes of anion gap metabolic acidosis.
Treatment/Work Up
agitation and seizures and management of any subsequent complications (see general principles of overdose and poisoning). Salicylate levels should
be checked every 2 hours. Decontamination with activated charcoal should be initiated if presentation is within 1 hour of ingestion. Consider whole
bowel irrigation should be considered with large overdoses or sustained release preparations. Enhanced elimination techniques are discussed below.
Specific Therapy
encephalitis, stimulant toxicity, and other causes of anion gap metabolic acidosis. Access Provided by:
Treatment/Work Up
agitation and seizures and management of any subsequent complications (see general principles of overdose and poisoning). Salicylate levels should
be checked every 2 hours. Decontamination with activated charcoal should be initiated if presentation is within 1 hour of ingestion. Consider whole
bowel irrigation should be considered with large overdoses or sustained release preparations. Enhanced elimination techniques are discussed below.
Specific Therapy
1. If endotracheal intubation is required care must be taken to prevent worsening acidosis from apnea during intubation or hypoventilation due to a
low set respiratory rate. Salicylate is less protein bound in acid environments, with more tissue penetration, and therefore more toxic.
2. Ion trapping with alkaline therapy is effective at removing salicylates. In an alkaline environment weak acids, like salicylates, remain ionized and
protein bound, therefore do not penetrate the tissues, and are more easily excreted and trapped in the urine. Administer a bolus of 1-2 mEq/kg of
sodium bicarbonate then begin an infusion to maintain urine pH of > 7.5. Potassium levels may need to be supplemented.
3. Hemodialysis should be considered for severe toxicity when levels are > 1000 mg/L in acute poisoning or > 600 mg/L in chronic or in patients who
fail to improve despite the above measures.
TOXIC ALCOHOLS
Any alcohol can be toxic if ingested in large enough quantities. The term “toxic alcohol” has traditionally referred to isopropanol, methanol, and
ethylene glycol. Compared to ethanol use, toxic alcohol use is relatively uncommon, however can be significantly more poisonous.
Alcohols are organic compounds characterized by one or more hydroxyl (-OH) groups attached to a carbon chain. Alcohol as a solute acts as an osmole
and increases the serum osmolality. This can be detected by calculating the osmolal gap. This is determined by subtracting the calculated serum
osmolality from the measured osmolality. Alcohols are not included in the calculated osmolality; therefore there will be a gap proportionate to the
serum concentration of the alcohol and inversely proportionate to the molecular weight.
Calculated Osmolality (mOsm/kg) = 2x Na+ (mEq/L) + Glucose (mg/dL)/18 + BUN (mg/dL)/2.8
Osmolal gap = Measured osmolality – calculated osmolality
Ethanol Toxicity
Ethanol use is very common in the United States. Approximately 10% of adults abuse alcohol to become intoxicated with numerous health and social
problems associated. The national institute of health reports that in 2013 86.8% of people ages 18 or older reported that they drank alcohol (ethanol)
at some point in their lifetime; 70.7% reported that they drank in the past year and 56.4% reported that they drank in the past month. Ethanol use is
present in 15% to 40% of unselected emergency department patients. Death can occur from acute overdose but is most likely from trauma associated
with being intoxicated. Ethanol is not only found in alcoholic beverages but is present in mouthwash, OTC cold and flu medications, perfume and some
cleaning products. Ethanol is rapidly absorbed and metabolized in the liver via alcohol dehydrogenase.
Clinical Features
Over 5 standard alcoholic drinks on one occasion can produce intoxication. Signs and symptoms include slurred speech, nystagmus, disinhibited
behavior, incoordination, unsteady gait, memory impairment, stupor, or coma. Hypotension and tachycardia may result from ethanol-induced
peripheral vasodilation, or volume loss. Multiple metabolic derangements including hypoglycemia, lactic acidosis, hypokalemia, hypomagnesemia,
hypocalcemia and hypophosphatemia may be seen. Intoxicated patients may present with a wide range of traumatic injuries. Alcohol is also a very
common coingestant with other drugs of abuse and OTC medications.
Ethanol intoxication can mimic many causes of altered mental status. Serum ethanol levels will confirm the diagnosis, however due to frequent
presence of alcohol in emergency visits, other causes must still be excluded. Acute intoxication will cause an elevated osmolal gap without affecting the
anion gap. However chronic alcoholics can develop a starvation ketoacidosis that will lead to an elevated anion gap acidosis. Ethanol levels are
diagnostic.
Treatment/Work Up
agitation and seizures and management of any subsequent complications (see general principles of overdose and poisoning). Activated charcoal does
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Ethanol intoxication can mimic many causes of altered mental status. Serum ethanol levels will confirm the diagnosis, however due to frequent
presence of alcohol in emergency visits, other causes must still be excluded. Acute intoxication will cause an elevated osmolal gap without affecting the
anion gap. However chronic alcoholics can develop a starvation ketoacidosis that will lead to an elevated anion gap acidosis. Ethanol levels are
diagnostic.
Treatment/Work Up
agitation and seizures and management of any subsequent complications (see general principles of overdose and poisoning). Activated charcoal does
not bind alcohols.
Specific Therapy
1. If the patient is suspected to be a chronic alcoholic then administer thiamine 100 mg, folic acid 1 mg and a multivitamin to help prevent Wernicke's
encephalopathy. These can be given orally or added to IV fluids.
2. Hypoglycemia should be corrected. There is no evidence to suggest delaying glucose administration until thiamine has been repleted.
3. Any other electrolyte abnormalities should be corrected.
Alcohol Withdrawal
The complications related to alcohol withdrawal create a significant demand on healthcare resources and are associated with an increased morbidity
and mortality. Alcohol withdrawal syndrome occurs in up to 31% of trauma patients and 16% of postsurgical patients, and there are proximally 500,000
episodes of alcohol withdrawal per year severe enough to require pharmacologic treatment.
Minor symptoms of autonomic hyperactivity can occur within 6 hours of cessation of drinking. This can include tremor, anxiety, palpitations,
diaphoresis, and insomnia. Delirium tremens and seizures can develop 12-48 hours after the last alcohol intake and can be accompanied by
arrhythmias with a mortality of 5%. Multiple other electrolyte abnormalities can be present. Management should target symptom control and
supportive care with correction of metabolic derangements. Escalating doses of long acting benzodiazepines, such as diazepam, are used to control
psychomotor agitation and prevent seizures. Patients usually require close observation in an ICU with a symptom triggered approach using the Clinical
Institute Withdrawal Assessment for Alcohol Scale (CIWA). This scale provides medication only when required. Thiamine (B1) and other vitamins
should always be repleted in chronic alcoholics to help prevent Wernicke-Korsakoff syndrome. Wernicke's classically causes a triad of opthalmoplegia,
ataxia, and confusion. Left untreated this can progress to irreversible Korsakoff syndrome of memory loss and confabulation.
Ethylene Glycol and Methanol Toxicity
Ethylene glycol and methanol are toxic alcohols causing CNS depression and multiple other systemic complications. They are toxic in very small
amounts (30-60 ml) and can be rapidly fatal. Both these alcohols are present in antifreeze/coolant, paint solvents, and windshield washer fluid or are
produced illicitly as an ethanol substitute. Both parent alcohols are relatively non-toxic, however are rapidly absorbed and undergo hepatic
metabolism by alcohol dehydrogenase to form severely toxic metabolites. Methanol is converted into formate/formic acid and ethylene glycol is
metabolized to glycolate/glycolic acid and oxalate/oxalic acid. Formic acid is toxic to the optic nerve and will eventually cause permanent blindness.
Glycolic acid and oxalic acid are toxic to the kidney and can lead to acute tubular necrosis, oxalate crystalluria and calcium oxalate stones. As with all
alcohols, the osmolal gap will be elevated early, however as the alcohol is metabolized this may normalize. As the toxic metabolites are produced a
severe anion gap metabolic acidosis will develop. Acute ingestions may have a normal anion gap with an elevated osmolal gap because the toxic
metabolites have not yet accumulated. Unlike with ethanol, methanol and ethylene glycol do not produce a characteristic odor. Of note the alcohol
dehydrogenase enzyme preferentially metabolizes ethanol, so if ethanol has been ingested at the same time this may delay presentation.
Clinical Features
Methanol—Methanol has a half-life of 14-18 hours so toxicity may not develop for 12-24 hours until enough time has passed for toxic metabolites to
develop. Presentation may be further delayed if ethanol has also been ingested. Initially patients present with inebriation. Once toxic metabolites have
developed patients complain of visual changes including cloudy, blurred vision or the appearance of a snowstorm. Other symptoms include headache,
nausea, vomiting and abdominal pain. Fundoscopic exam may reveal retinal edema and a hyperemic optic disc.
Ethylene Glycol
Ethylene glycol has a half-life of 3-8 hours and has 3 distinct clinical phases as toxic metabolites accumulate. Again presentation may be delayed if
ethanol has been ingested. The initial stage (CNS) occurs in 12 hours and is characterized by CNS signs including inebriation, slurred speech,
Chapter 58: Overdose, Poisoning, and Withdrawal, Edward Mossop; Fred DiBlasio Pageataxia,
37 / 42
and coma. The second stage (cardiopulmonary) develops from 12-24 hours and is characterized by tachycardia, tachypnea and hypertension, which
can progress to circulatory collapse. The third and final stage (renal) includes flank pain, costovertebral angle tenderness and acute renal failure.
Hypocalcemia can develop from calcium oxalate deposition. The urine may show calcium oxalate crystals however this is rarely diagnostic. Of note,
developed patients complain of visual changes including cloudy, blurred vision or the appearance of a snowstorm. Other symptoms include headache,
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nausea, vomiting and abdominal pain. Fundoscopic exam may reveal retinal edema and a hyperemic optic disc.
Ethylene Glycol
Ethylene glycol has a half-life of 3-8 hours and has 3 distinct clinical phases as toxic metabolites accumulate. Again presentation may be delayed if
ethanol has been ingested. The initial stage (CNS) occurs in 12 hours and is characterized by CNS signs including inebriation, slurred speech, ataxia,
and coma. The second stage (cardiopulmonary) develops from 12-24 hours and is characterized by tachycardia, tachypnea and hypertension, which
can progress to circulatory collapse. The third and final stage (renal) includes flank pain, costovertebral angle tenderness and acute renal failure.
Hypocalcemia can develop from calcium oxalate deposition. The urine may show calcium oxalate crystals however this is rarely diagnostic. Of note,
ethylene glycol is commonly used in engine coolant where fluorescein may be added to allow the mechanic to use a UV light to detect coolant/radiator
leaks. If ethylene glycol is ingested fluorescein may be excreted in the urine causing it to fluoresce under UV light. This is however very rarely helpful.
Lactic acid levels may be falsely elevated due to glycolate cross-reacting with lactate in lab assays.
Diagnosis of toxic alcohol ingestion is clinical with supportive laboratory findings. Initially the osmolal gap will be significantly elevated and will
gradually decrease. After several hours patients will begin to develop a progressive anion gap metabolic acidosis. Ethylene glycol toxicity usually shows
leukocytosis, elevated lactic acid (not a true lactic acidosis) and hypocalcemia with evidence of renal dysfunction and a normal fundoscopic exam.
Urine testing for crystals or florescence is not recommended. Methanol and ethylene glycol levels are diagnostic but may take several hours to result.
Other causes of altered mental status and a high anion gap metabolic acidosis should always be considered.
Treatment/Work Up
agitation and seizures and management of any subsequent complications (see general principles of overdose and poisoning). Activated charcoal is
ineffective at binding alcohols. Enhanced elimination techniques include hemodialysis to remove both the parent alcohols and toxic metabolites and
urine alkalization are discussed below.
Specific Therapy—
Treatment is based on: blocking the production of toxic metabolites, removing toxic metabolites and correcting the metabolic acidosis.
1. Sodium bicarbonate 1-2 mEq/kg should be administered and titrated to correct the acidosis and maintain a normal pH. Formic acid and glycolic
acid may have enhanced renal clearance by this method.
2. Fomepizole, a competitive inhibitor of alcohol dehydrogenase, can block the formation of toxic metabolites. The AACT recommends starting
fomepizole if the ethylene glycol or methanol levels are > 20 mg/dL or if there is a high clinical suspicion. Administer 15 mg/kg IV load followed by 10
mg/kg every 12 hours. If unavailable or contra-indicated then ethanol can be used to preferentially block metabolism. Administer 10 ml/kg IV load
of 10% ethanol, followed by 1.2 ml/kg/h. The infusion rate is adjusted to maintain a blood ethanol level of 100-150 mg/dL. Oral dosing can also be
used with commercial 80% proof alcohol and dosed to keep the patient mildly inebriated.
3. Hemodialysis is effective at removing the parent compounds and the toxic metabolites and should be initiated in cases of severe poisoning with
evidence of renal failure, optic toxicity, refractory acidosis or deteriorating vital signs. Of note if ethanol is being used as a treatment this will also be
removed by hemodialysis.
4. Treatment with fomepizole, alcohol and hemodialysis until the levels of toxic alcohol are below 20 mg/dL. Once ethylene glycol levels are < 20
mg/dL administer pyridoxine 100 mg IV and thiamine 100 mg IV. Once methanol levels are < 20 mg/dL administer folate 40 mg IV. This will shift the
metabolism of to less toxic metabolites.
5. Calcium gluconate supplementation may be required in cases of ethylene glycol poisoning.
Isopropyl Alcohol Toxicity
Isopropyl alcohol is commonly used in rubbing alcohol, as a disinfectant, antifreeze, and in solvents. The usual goals of ingestion are intoxication or
self-harm but fatality is rare. Isopropyl functions primarily as a central nervous system inebriant and depressant and presents much like ethanol
toxicity. It is also a gastric irritant and has been associated with upper GI bleeding. Isopropyl alcohol is metabolized by alcohol dehydrogenase to
acetone, a ketone that does not cause acidosis or an elevated anion gap. Urine ketones will be positive and patients may have a fruity odor to their
breath. As with all alcohols the osmolal gap will be elevated. Treatment is supportive. Dialysis is rarely required. See Table 58–21: Comparison of
different alcohols.
Table 58–21
Comparison of different alcohols.
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Isopropyl alcohol is commonly used in rubbing alcohol, as a disinfectant, antifreeze, and in solvents. The usual goals of ingestion are intoxication or
self-harm but fatality is rare. Isopropyl functions primarily as a central nervous system inebriant and depressant and presents much like ethanol
toxicity. It is also a gastric irritant and has been associated with upper GI bleeding. Isopropyl alcohol is metabolized by alcohol dehydrogenase to
acetone, a ketone that does not cause acidosis or an elevated anion gap. Urine ketones will be positive and patients may have a fruity odor to their
breath. As with all alcohols the osmolal gap will be elevated. Treatment is supportive. Dialysis is rarely required. See Table 58–21: Comparison of
different alcohols.
Table 58–21
Comparison of different alcohols.
Ethanol Methanol Ethylene Glycol Isopropanol
Metabolites Acetaldehyde Formaldehyde Glycoaldehyde Acetone

Acetate Formate Glycolate
Oxalate
Anion gap Normal (unless Early: normal Early: normal Normal

develops Late: elevated Late: elevated
ketoacidosis)
Osmolal Elevated (25% more Early: elevated Early: elevated Elevated

gap than predicted) Late: normal Late: normal
Signs Inebriation Inebriation, Inebriation, acute kidney injury, Falsely elevated lactate, Oxalate Inebriation, Urine
blindness crystals (urine), Fluorescein presence in urine, Hypocalcemia ketones, Fruity breath
(ketones)
OTHER POISONS
Acquired Methemoglobinemia
Methemoglobin is an abnormal state of hemoglobin and that can be induced by numerous medications. It occurs when the iron in heme is oxidized
from Fe2+ (ferrous) to Fe3+ (ferric) which is unable to bind oxygen resulting in a functional anemia due to decreased oxygen carrying capacity and
availability to tissues causing the hemoglobin dissociation curve to shift to the left. Topical local anesthetics (benzocaine, lidocaine), dapsone,
antimalarials, amyl nitrate, and nitroglycerin are commonly implicated. Patients present with headache, nausea, fatigue and SOB with a slate grey or
blue cyanotic discoloration. Symptoms usually occur when methemoglobin levels reach 20%. Levels over 50% can cause loss of consciousness and be
life threatening. Levels over 70% can be fatal. Clinically the cyanosis will not respond to increased oxygen administration. Blood will appear a chocolate
brown color and cause inaccurate pulse oximetry. Typically the pulse oximeter will always produce a reading of 85%. Arterial blood gas (ABG) analysis
will reveal very high PaO2 (if placed on supplemental oxygen) as this is only a measure of dissolved oxygen, not oxygen bound to hemoglobin. SaO2 on
an ABG may also be 100%, however this only measures saturation of normal ferrous hemoglobin. Newer ABG machines can also measure the
percentage of methemoglobin, which is diagnostic. Patients with levels over 25% should be treated with methylene blue, a reducing agent that will
convert ferric Fe3+ heme back into ferrous Fe2+. The initial dose is 1-2 mg/kg as a 10% solution given IV over 15 minutes.
Cyanide
Cyanide is a highly toxic substance that causes death via mitochondrial cytochrome dysfunction preventing oxidative phosphorylation. Cyanide
exposure is uncommon and usually from the result of fires involving synthetic materials including wool, silk, and plastics. In the hospital setting
patients treated with sodium nitroprusside, for hypertension over a prolonged period of time can develop cyanide toxicity. Clinically patients present
with headache, anxiety, confusion, vomiting, and abdominal pain. Vital signs may reveal tachycardia, bradycardia, hypotension, hypertension, and
hyperventilation. This can progress rapidly to cardiovascular collapse and coma. On exam patients may have flushed skin causing a cherry red
appearance. ABG analysis may reveal a severe anion gap metabolic acidosis and elevated lactate due to increased anaerobic metabolism. Diagnosis is
based on history and clinical signs. Cyanide levels are not rapidly available. Rapid assessment and treatment is essential to prevent decline. Supportive
care with oxygen and fluids should be given. There are different antidotes available that can reduce toxicity by 3 different mechanisms: 1. Binding to
cyanide directly, 2. Inducing methemoglobin, and 3. Providing a sulfur donor. Hydroxocobalamin binds directly to intracellular cyanide producing a
stable molecule. It is administered as 2 vials, 2.5 grams in 100 ml of saline. Amyl nitrite, an oxidizing agent, can induce formation of methemoglobin.
Cyanide can bind to methemoglobin, instead of to mitochondrial cytochromes and forms a less toxic molecule. Amyl nitrate is normally given pre
hospital inhaled from a vial over 30 seconds. Sodium thiosulfate provides a source of sulfur that promotes enzymatic formation of less toxic
patients treated with sodium nitroprusside, for hypertension over a prolonged period of time can develop cyanide toxicity. Clinically patients present
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with headache, anxiety, confusion, vomiting, and abdominal pain. Vital signs may reveal tachycardia, bradycardia, hypotension, hypertension, and
hyperventilation. This can progress rapidly to cardiovascular collapse and coma. On exam patients may have flushed skin causing a cherry red
appearance. ABG analysis may reveal a severe anion gap metabolic acidosis and elevated lactate due to increased anaerobic metabolism. Diagnosis is
based on history and clinical signs. Cyanide levels are not rapidly available. Rapid assessment and treatment is essential to prevent decline. Supportive
care with oxygen and fluids should be given. There are different antidotes available that can reduce toxicity by 3 different mechanisms: 1. Binding to
cyanide directly, 2. Inducing methemoglobin, and 3. Providing a sulfur donor. Hydroxocobalamin binds directly to intracellular cyanide producing a
stable molecule. It is administered as 2 vials, 2.5 grams in 100 ml of saline. Amyl nitrite, an oxidizing agent, can induce formation of methemoglobin.
Cyanide can bind to methemoglobin, instead of to mitochondrial cytochromes and forms a less toxic molecule. Amyl nitrate is normally given pre
hospital inhaled from a vial over 30 seconds. Sodium thiosulfate provides a source of sulfur that promotes enzymatic formation of less toxic
thiocyanate. It is usually administered as 50 ml of a 25% solution IV.
Iron
Iron toxicity usually results from intentional or accident ingestion of iron tablets or multivitamins and is most common in the pediatric population. The
amount of elemental iron varies between different preparations. For example ferrous sulfate 325mg tablets only contain 20% of elemental iron. Pre-
natal vitamins typically contain the most iron. Ingestions of 60 mg/kg usually will result in blood levels of > 500 mcg/dL causing severe toxicity. Iron
toxicity goes through several stages. The first stage (GI) develops within the first 6 hours and causes abdominal pain, nausea, vomiting, and diarrhea
and GI bleeding due to the direct toxic effects of iron on the GI mucosa. The second stage (latent) occurs when GI symptoms resolve and there is
relative stability or lack of symptoms for up to 24 hours. The third stage (cardiovascular) develops up to 72 hours and is characterized by shock and
cardiovascular collapse. The etiology of this stage can be multifactorial from hypovolemia due to diarrhea or blood loss, direct vasodilatation and
cardiac dysfunction from direct toxic effects of iron on smooth muscle and the myocardium. Patients can also develop a coagulopathy (direct effect of
iron on prothrombin) and metabolic acidosis. This stage is the most common cause of death. The fourth stage (hepatic) involves evidence of
hepatotoxicity and develops 2-5 days after ingestion. This can progress to liver failure. The fifth and final stage (delayed) occurs 4-6 weeks after
ingestion and involves gastric outlet obstruction caused by scarring of the gastric mucosa. Treatment of iron toxicity initially involves supportive
resuscitation. Patients may require aggressive fluid resuscitation and vasopressors to correct hypotension. Decontamination with activated charcoal is
not recommended. Gastric lavage may be beneficial if patients present within 60 minutes. Whole bowel irrigation should also be attempted to clear the
GI tract. The coagulopathy should be corrected with fresh frozen plasma. Enhanced elimination techniques involve chelation of iron in the plasma with
deferoxamine. This can be administered IM or IV however the IV route is preferred. The initial infusion rate is 15 mg/kg/hour as tolerated to provide a
total of 1 gram in the first hour. The rate can then be adjusted to provide a total of 6 grams during the first 24 hours. Patients who develop liver failure
may require transplant evaluation.
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Chapter 58: Overdose, Poisoning, and Withdrawal

3. Consider decontamination and the use of antidotes.

5. Always seek help from your regional poison control center.

GENERAL PRINCIPLES OF OVERDOSE AND POISONING

History and Physical

Pupillary and motor reaction

Skin examination (moisture, cyanosis, rashes)

Assessement of bowel sounds

Category Vital Signs Mental Status Physical Signs Agent/Drug

Opioid Hypotension, bradycardia, Stupor, Miosis, hyporeflexia Morphine,

Sedative-Hypnotic Hypotension, bradycardia, Stupor, coma, Hyporeflexia, ataxia, Benzodiazepines,

Category Vital Signs Mental Status Physical Signs Agent/Drug

Opioid Hypotension, bradycardia, Stupor, Miosis, hyporeflexia Morphine,

Sedative-Hypnotic Hypotension, bradycardia, Stupor, coma, Hyporeflexia, ataxia, Benzodiazepines,

Hallucinogenic Hyperthermia, Agitated but Mydriasis, synesthesia, nystagmus PCP, LSD,

SSRI: selective serotonin reuptake inhibitor;

TCA: tricyclic antidepressants;

LSD: Lysergic acid diethylamide;

Initial Hospital Care

Altered Mental State-Agitation or Coma

Common drugs associated with rhabdomyolysis

Lysergic acid diethylamide (LSD) HIV medications

Amphetamines Carbon monoxide

Antihistamines selective serotonin reuptek inhibitor (SSRIs)

Decontamination and Enhanced Elimination

Drugs amenable to repeat dosing of activated charcoal

Enhanced Elimination Techniques

Ion Trapping and Forced Diuresis

Agent Route of Administration Metals Bound

Dimercaprol IM with urine alkalizing agent Arsenic, gold, lead, mercury

Penicillamine Oral Copper, arsenic, lead

Deferoxamine IV, IM, or SC Iron

Poison/Condition Antidote/Treatment Dose

Anticholinergic Physostigmine 0.5-2 mg IV over 5 min

Benzodiazepines Flumazenil 0.2 mg/kg IV

Calcium channel antagonists Calcium chloride 10% 0.2-0.25 ml/kg IV

Chronic alcohol/Wernicke Thiamine 100 mg IV

Digoxin Digoxin Fab 5-10 vials IV

Heparin Protamine 25-50 mg IV

Iron Deferoxamine 2 g IM, or 15 mg/kg/hr IV (max dose, 6-8 g/day)

Methemoglobin/oxidizing Methylene blue 1-2 mg/kg IV

Methotrexate Folic acid 1-2 mg/kg IV every 4-6 hr

Neuroleptic malignant Dantrolene 1-2.5 mg/kg IV

Opioids Naloxone 0.1-2 mg IV Titrate to response

Serotonin syndrome Cyproheptadine 4-12 mg po Repeat every 2 hr

Tricyclic antidepressants Sodium bicarbonate 1-2 mEq/kg IV bolus Repeat as needed

Gamma Hydroxybutyrate (GHB)

Withdrawal and Dependence

Opioids Morphine, oxycodone, codeine, fentanyl, heroin

Opioids Morphine, oxycodone, codeine, fentanyl, heroin

Sympathomimetics Cocaine, methamphetamine, mephedrone, MDMA

Hallucinogens MDMA, mushrooms, PCP, LSD, cannabis

Sedatives Benzodiazepines, barbiturates, GHB

1. Transdermal opioids patches should be looked for and removed.

Norepinephrine, epinephrine, dopamine, midodrine Blood pressure support

Albuterol, levalbuterol Bronchodilation

Phenylephrine, pseudoephedrine Over the counter cold and flu preparations

Cocaine, MDMA, methamphetamine, mephedrone Most commonly used illicitly

Treatment summary of sympathomimetic overdose

Continuous vital signs and serial EKGs

Trend troponin, CK and electrolytes

Benzodiazepines titrated to response