The Tox Cave
The Tox Cave will dissect interesting ED cases from the perspective of a toxicologist, focusing on applying up-to-date management of the poisoned patient.
The name Tox Cave was coined by a former toxicology fellow to describe our small office space, likening it to the Bat Cave. The Tox Cave is where Drexel toxicology fellows and attendings have gathered to discuss the nuances of toxicology over the years.
Monday, February 02, 2015
A 27-year-old woman with no past medical history presented to the ED by EMS after being found unresponsive at home by her partner. EMS reported that she was unresponsive with a GCS of 3, pinpoint pupils, and sonorous breath sounds. Naloxone 0.4 mg IV was administered, and the patient became responsive. The patient was delirious, agitated, and tachycardic upon arrival to the ED. She was administered lorazepam 2 mg IV without improvement. Her agitation and delirium were so severe that she was intubated, paralyzed with rocuronium, and started on a midazolam infusion.
What is the appropriate dose of IV naloxone?
No consensus exists on the appropriate starting dose of naloxone, but many toxicologists recommend a starting dose of naloxone 0.04 mg IV in opioid-dependent patients, quickly titrating up every two minutes to a maximum of 10 mg. If no effects are seen after 10 mg, the patient’s respiratory or CNS depression are unlikely to be a result of opioid toxicity. Special considerations should be taken in certain populations, including opiate-naive patients and children where larger doses of Narcan can be used initially to reverse the respiratory depression.
Adverse effects have been reported at doses as low as 0.4 mg IV, which support a starting dose of 0.04 mg. It is important to remember that most adverse effects are from acute opioid withdrawal rather than to the naloxone itself.
To administer naloxone 0.04 mg IV, dilute a naloxone preparation of 0.4 mg/1ml ampule in a 10 ml syringe of normal saline, and then administer the medication 1 ml at a time.
What is the relationship between naloxone and pulmonary edema?
Pulmonary edema and acute lung injury following naloxone administration for opioid-toxic patients has been described, but it remains controversial whether acute lung injury is from acute withdrawal precipitated by naloxone or to opioid-induced complications.
Several mechanisms relating naloxone to pulmonary complications have been proposed, such as naloxone to reverse the profound respiratory depression leading to more apparent opioid-induced pulmonary findings. Another mechanism of action for naloxone-induced pulmonary edema is the catecholamine surge. A study by Kienbaum, et al., in 1998 demonstrated a 30-fold increase in epinephrine levels after naloxone administration in opioid-dependent patients. (Anesthesiology 1998;88:1154.) Interestingly, this catecholamine surge has been shown to be exacerbated by hypoventilation or hypercapnia in canines.
Other explanations for pulmonary edema that occurs in the opioid-toxic or anesthesia patients who received naloxone include inherent toxicity of opioids themselves, co-administered drugs, or other underlying disease processes.
What serious cardiovascular complications have been reported in association with the administration of naloxone?
Serious cardiovascular effects include arrhythmias such as ventricular tachycardia, myocardial infarction, cardiomyopathy, and heart failure. These complications are rarely reported, and may actually be the result of hypoxia, inherent toxicity of the opioids themselves, co-intoxication with another agent (such as cocaine), or pre-existing cardiac disease. The mechanism is thought to be from catecholamine release induced by precipitated opioid withdrawal or unmasking of sympathomimetic agents.
What are other adverse effects related to the administration of naloxone?
Many of the adverse effects related to the administration of naloxone are from acute opioid withdrawal.
Managing patients who have received naloxone for opioid intoxication.
Prior to administering naloxone, one may consider providing sufficient ventilation to potentially reduce the catecholamine surge that is believed to be exacerbated by elevated CO2, and therefore possibly decrease the incidence of the more serious adverse effects listed above.
Patients who received naloxone for opioid intoxication should be closely monitored for recurrence of respiratory depression and sedation, particularly in patients who have ingested long-acting opiates or opioids (methadone) or transdermal patches. These patients should be on continuous cardiac and pulse oximetry monitoring because the half-life of naloxone (30-80 minutes) is generally shorter than most opioids. Redevelopment of respiratory depression requires repeat administration of naloxone. Oxygen should only be administered if the patient becomes hypoxic because it may delay detecting hypoventilation as a normal pulse oximetry reading and will not reflect developing hypercapnia. Some physicians for this reason recommend continuous end-tidal CO2 monitoring in these patients because this is a more accurate indicator of a patient’s ventilatory effort.
Symptomatic support should be provided to help alleviate the uncomfortable symptoms if opioid withdrawal occurs. Clonidine, an alpha-2 adrenergic receptor agonist, has been shown to be effective in cases of autonomic instability (i.e., tachycardia, hypertension).
Disposition of a patient who received naloxone for opioid intoxication.
The disposition of a patient who has received naloxone in the ED must be carefully considered. The pharmacological effects of naloxone are shorter than most opioids used, and some patients are at risk for re-sedation or respiratory depression after the effects of naloxone have worn off. It is prudent to monitor patients for at least six hours after they have been administered naloxone for redeveloping symptoms and to consider admission of patients who have required two or more doses of naloxone.
A special consideration must be made in patients who have ingested long-acting opioids/opiates. Patients who have ingested sustained-release formulations (e.g, MS Contin), long-acting opioids (methadone), or one or more fentanyl patches require admission for 24-hour observation.
This patient required sedation and eventually intubation because of her severe delirium and agitation, but the majority of patients rarely experience adverse effects as a result of naloxone administration.
1. Clarke SF, Dargan PI, Jones AL. Naloxone in opioid poisoning: Walking the tightrope. Emerg Med J 2005;22(9):612.
2. Lameijer H, Azizi N, et al. Ventricular tachycardia after naloxone administration: A drug related complication? Case report and literature review. Drug Safety-Case Reports 2014;1:1.
3. Spadotto V, Zorzi A, et al. Heart failure due to ‘stress cardiomyopathy’: A severe manifestation of the opioid withdrawal syndrome. Eur Heart J Acute Cardiovasc Care 2013;2(1):84.
Friday, January 02, 2015
A 44-year-old-man with a past medical history of alcohol abuse was brought to the emergency department by EMS. He was found sleeping on a bench and appeared intoxicated. His initial vital signs were temperature 90.9°F, heart rate 62 bpm, blood pressure 130/84 mm Hg, respiratory rate 16 bpm, and pulse oximetry 98% on room air. He is disheveled patient, and has a depressed level of consciousness, slurred speech, and the distinct odor of mint and urine. Pertinent lab findings include an ethanol level of 340 mg/dL.
The minty odor is tipoff in this case that he is inebriated from mouthwash. The ethanol concentration in mouthwashes commercially available in the United States varies widely. The highest ethanol concentration reported is 26.9%. Alcohol-free products are also available.
The risk of toxicity from the nonalcoholic ingredients is minimal in most ingestions of mouthwash:
One standard drink is equivalent to 2.2 fluid ounces of 27% alcohol/volume mouthwash:
National Institute on Alcohol Abuse and Alcoholism; http://1.usa.gov/12ifXGW.
It is important to recognize the signs of ethanol intoxication in patients who have ingested any alcohol-containing mouthwash. Management strategies for ethanol-intoxicated patients are:
n Supportive care is the mainstay of treatment.
n Exclude other causes of altered mental status such as hypoglycemia, trauma, infection, co-ingestants, and stroke.
n Evaluate and treat complications of ethanol intoxication such as hypothermia, hypoglycemia, and alcoholic ketoacidosis.
n Nutritional support as needed: intravenous fluids with multivitamins, thiamine, and folic acid.
n Monitor for ethanol withdrawal symptoms.
n Monitor until clinically sober:
□ The estimated rate of metabolism of ethanol ranges from 15 to 20 mg/dL per hour in the non-tolerant drinker, but may be as high as 25 to 35 mg/dL per hour in the tolerant drinker.
Lachenmeier DW, et al. What happens if people start drinking mouthwash as surrogate alcohol? A quantitative risk assessment. Food Chem Toxicol 2013;51:173.
Shulman JD, Wells LM. Acute ethanol toxicity from ingesting mouthwash in children younger than 6 years of age. Pediatr Dent 1997;19(6):404.
Soo Hoo GW, Hinds RL, et al. Fatal large-volume mouthwash ingestion in an adult: A review and the possible role of phenolic compound toxicity. J Intensive Care Med 2003;18(3):150.
Tuesday, December 02, 2014
A 25-year-old man presents to the emergency department with palpitations. He reports injecting heroin, which he obtained from a new source, and is concerned that it was “not just heroin.” His initial vital signs include blood pressure 150/90 mm Hg, heart rate 130 bpm, respiratory rate 16 breaths per minute, and pulse oximetry 99% on room air. The patient appears uncomfortable, but is alert and oriented. His physical exam is remarkable for tachycardia and agitation.
The concern for an altered illicit drug is not uncommon in the ED. Cases and epidemics of tainted illicit drugs have been reported historically; the first reported heroin adulterant was quinine. A New York City outbreak of malaria in the 1930s was linked to IV drug abuse, and quinine, the mainstay of treatment at the time, was added to heroin to protect heroin
An epidemic of heroin adulterated with scopolamine occurred in the Northeast in the 1990s. Hamilton, et al. described patients who presented with respiratory depression after using heroin and then manifested signs of anticholinergic toxicity following naloxone administration. Another epidemic on the East Coast in 2005 involved heroin adulterated with clenbuterol. These patients presented with tachycardia, tremor, diaphoresis, hyperglycemia, hypokalemia, and lactic acidosis secondary to the beta-2 agonist effects of clenbuterol instead of manifesting a pure opiate toxidrome.
Xylazine, an alpha-2 agonist, was found as an adulterant in heroin in the early 2000s, and was thought to potentiate the high of heroin. It also resulted in more severe respiratory depression, hypotension, and bradycardia. More recently, emergency departments have had an increase in the number of heroin overdose patients resistant to the standard doses of naloxone. Adulterants like fentanyl and acetyl fentanyl are more potent than heroin, requiring a larger effective dose of naloxone and also causing numerous deaths in the United States.
Substances Often Used to Alter Illicit Drugs
□ Unwanted substances, such as by-products of the manufacturing process
□ Pharmacologically inert substance
□ Bulking agents
□ Pharmacologically active substance
□ Enhance the drug effect or protect against a deleterious effect of the drug
□ Replacement by another substance
□ May have similar properties
Physicians should be aware of possible additives in illicit drugs used by patients with atypical presentations. Laboratory confirmation for additives is not readily available. Clinical presentation and regional trends may help guide identification and management.
Toxicologist Matthew Salzman, MD, of Cooper University Hospital assisted with this column.
Hoffman, RS, Kirrane BM, Marcus SM. A Descriptive Study of an Outbreak of Clenbuterol-Containing Heroin. Ann Emerg Med 2008;52(5):548.
Wong SC, Curtis JA, Wingert WE. Concurrent Detection of Heroin, Fentanyl, and Xylazine in Seven Drug-related Deaths Reported from the Philadelphia Medical Examiner’s Office. J Forensic Sci 2008;53(2):495.
Hamilton RJ, Perrone J, et al. A Descriptive Study of an Epidemic of Poisoning Caused by Heroin Adulterated with Scopolamine. Clin Toxicol 2000;38(6):597.
Monday, November 03, 2014
An 88-year-old man with a history of congestive heart failure, hypertension, and diabetes mellitus presented to the ED from a nursing home with altered mental status. EMS reported that the patient has had a decreased appetite, diarrhea, and weakness for three days. His initial vital signs were temperature 97.9°F, heart rate 79 bpm, blood pressure 116/64 mm Hg, respiratory rate 16 bpm, and pulse oximetry 98% on room air. His physical exam was remarkable for a depressed level of consciousness. Lab findings showed a creatinine of 2.6 mg/dl, a BUN of 60 mg/dl, and normal potassium and magnesium. His ECG is shown below.
The nursing home transfer sheet said the patient had reported yellow-tinted vision several days earlier. The patient’s medications include Lasix, digoxin, lisinopril, and insulin. Digoxin was last administered as prescribed six hours previously. A digoxin level was ordered and came back at 5.1 ng/ml.
Given the patient’s medication history, serum digoxin level, and altered mental status, digoxin-specific antibody fragments were administered for digoxin toxicity. The medical toxicologist and the emergency physician discussed the appropriate dose for this patient for full vs. partial reversal. Based on the serum digoxin concentration and his weight (80 kg), the calculated dosage for full reversal was four vials and for partial reversal was two vials of digoxin-specific antibody fragments. The dosage for full reversal was administered. One hour later, the patient became acutely short of breath.
The ECG in this case is consistent with digoxin toxicity, which may include T wave flattening, QT interval shortening, scooped ST segments with ST depression in the lateral leads (Salvador Dali sign [red arrow]), and increased amplitude of the U waves.
Other ECG findings include:
n Premature ventricular contractions are the most common rhythm disturbances caused by digitalis toxicity.
n Bradycardia, atrial tachyarrhythmias with AV block, various degrees of AV nodal blockade, ventricular tachycardia, ventricular fibrillation, and junctional rhythms.
n Bidirectional ventricular tachycardia, which is pathognomonic, is a rare finding. (See below.)
Image obtained from Edward Burns, MD. http://lifeinthefastlane.com.
The indications for digoxin-specific antibody fragments are:
n Life-threatening or unstable arrhythmias.
n Hyperkalemia in the acute setting (serum K >5 to 5.5 meq/L).
• In a classic study, no patient with K >5.5 meq/L survived without antidotal therapy and no patient with K<5 meq/L died.
n Chronic elevation of serum digoxin concentration (SDC) with dysrhythmias, significant GI symptoms, or altered mental status.
n SDC ≥ to 15 ng/ml at any time ≥ 10 ng/ml six hours post ingestion regardless of symptoms.
n Acute ingestion of 10 mg of digoxin in an adult.
n Acute ingestion of 4 mg of digoxin in a child.
n End-organ dysfunction from hypoperfusion.
How are digoxin-specific antibody fragments dosed?
n Digoxin level
• Acute digoxin level should be checked six hours post-ingestion.
• Chronic digoxin concentration can be checked on presentation keeping in mind the time of last dose.
Note: Partial reversal should be considered in patients on chronic digoxin for CHF because they require the inotropic effects of digoxin for cardiac output.
Potential adverse effects of digoxin-specific antibody fragments administration and reversal of digoxin intoxication:
n Hypersensitivity reactions.
n Reversal of digoxin’s therapeutic effects resulting in cardiac deterioration manifesting as CHF exacerbation or tachydysrhythmias.
n Hypokalemia may result from intracellular shifting of potassium.
n Possible recurrence of digoxin toxicity in patients with renal failure resulting from failure to eliminate the digoxin-immune fragment complexes and release of unbound digoxin.
n Interference of digoxin-immune fragment complexes with routine total digoxin immunoassay measurements may result in falsely elevated levels.
Note: It is important to consider discussing the plan for reversal with the patient’s cardiology in anticipation for adverse effects associated with reversal.
The patient developed flash pulmonary edema, was started on BIPAP, and received dobutamine and epinephrine infusions for hypotension. The patient was admitted to the ICU and received treatment for decompensated heart failure secondary to digoxin reversal. The patient clinically improved within 48 hours. Repeat EKG is shown below.
1. Bismuth C, Gaultier M, et al. Hyperkalemia in Acute Digitalis Poisoning: Prognostic Significance and Therapeutic Implications. Clini Toxicol 1973;6(2):153.
2. Nelson L, Lewin N, et al, eds. Goldfrank's Toxicologic Emergencies. 9th Edition. New York: McGraw Hill; 2011.
3. Chan BS, Buckley NA. Digoxin-specific Antibody Fragments in the Treatment of Digoxin Toxicity. Clin Toxicol 2014;52(8):824.
Thursday, October 02, 2014
A 33-year-old-male bodybuilder with a history of polysubstance abuse presents with agitation and combativeness. He was wearing sunglasses and shadow boxing in the air.
His initial vital signs were temperature 98°F, heart rate 120 bpm, blood pressure 140/90 mm Hg, respiratory rate 16, pulse oximetry 100% on room air. His physical exam is remarkable for tachycardia, agitation, and delirium, and his ECG is remarkable for sinus tachycardia with normal intervals. CBC and BMP are within normal limits; CPK is mildly elevated at 402 IU/L.
What is the differential diagnosis for this patient?
n Sympathomimetics (amphetamine, cocaine, PCP, synthetic cathinones [bath salts], synthetic cannabinoids)
n CNS infection
n Head injury
n Thyroid storm
n Alcohol withdrawal syndrome
n Sedative-hypnotic withdrawal (baclofen, barbiturates, benzodiazepines, ethanol, gamma-hydroxybutyric acid [GHB] or GHB precursors gamma butyrolactone [GBL] and 1,4 butanediol [BD], volatile solvents)
The patient’s mental status and agitation improved with diazepam 10 mg IV x 2. He admits to using “2 to 3 mL of GHB every few hours around the clock to self-treat withdrawals.” The patient reports GHB use for bodybuilding, but he recently ran out and was unable to obtain more.
What are the GHB use or abuse scenarios?
n Medical uses (sodium oxybate for narcolepsy, cataplexy, and excessive daytime sleepiness symptoms)
n Recreational use
n Club or rave scenes
n Sports and athletics (bodybuilding)
n Date rape
n Use of GHB analogs/precursors (gamma butyrolactone or 1,4 butanediol)
How does GHB withdrawal present?
GHB withdrawal typically manifests within one to six hours, and may progress rapidly to refractory agitation, hallucinations, delirium, and death within 24 hours after last use. Clinical manifestations are similar to alcohol withdrawal syndrome with the exception of the autonomic instability being mild or absent and the agitation and delirium having a prolonged course.
Symptoms generally last four to 15 days with a mean of nine days. Clinical findings of GHB withdrawal include:
Central Nervous System
n Agitated delirium with confusion, anxiety, agitation, diaphoresis, insomnia, and tremors in early withdrawal
n Hallucinations, paranoid delusions, and profound delirium
n Increased muscle tone, myoclonic jerks, rigidity, and seizures
n Rotary or horizontal nystagmus
n Mild or absent autonomic instability
n Hypertension and tachycardia due to sympathetic stimulation
n Nausea and vomiting
n Abdominal cramps
n Diarrhea or constipation
n Urinary retention
n Psychomotor agitation predisposes the patient to hyperthermia and rhabdomyolysis
n Clinical course may be unpredictable with improvement followed by rapid deterioration
How is GHB withdrawal managed?
The mainstay of treatment includes supportive care and aggressive use of benzodiazepines for agitation.
n Monitoring: Cardiac monitoring and trend CPK in patients with agitation at risk for rhabdomyolysis
n Symptom control: agitation, delirium, seizures, hyperthermia. Recommend diazepam 10 mg IV every five to 10 minutes and titrate to restfulness. Rapid onset of action and presence of active metabolites (temazepam and oxazepam) increase the duration of action. In benzodiazepine-refractory cases, consider the use of barbiturates or propofol, but avoid the use of antipsychotics for agitation because they are often ineffective and may lower seizure threshold. Physical restraints may be cautiously used but should be removed quickly because they may worsen hyperthermia and rhabdomyolysis.
n Hypertension management: Treat with benzodiazepines. Beta-blockers are contraindicated because they may worsen hypertension and coronary ischemia. Fluids, nutritional support, and electrolyte repletion (thiamine, folic acid, and magnesium) may be indicated, similar to alcohol-withdrawal patients.
n Disposition: Admission to a critical care setting may be indicated for patients manifesting severe or progressive symptoms.
The patient was admitted to a monitored setting with a diagnosis of GHB withdrawal. He had multiple episodes of agitation and combativeness during his admission. He was administered escalating doses of diazepam, a total of 480 mg of diazepam IV during his eight-day hospital stay. The patient recovered in eight days, and was referred to drug rehabilitation.
1. Dyer JE, Roth B, Hyma BA. Gamma-hydroxybutyrate withdrawal syndrome. Ann Emerg Med 2001;37(2):147.
2. Tarabar AF, Nelson LS. The gamma-hydroxybutyrate withdrawal syndrome. Toxicol Rev 2004;23(1):45.
3. Craig K, Gomez HF, et al. Severe gamma-hydroxybutyrate withdrawal: A case report and literature review. J Emerg Med 2000;18(1):65.