Medical Concept: Nicotine toxicity, a new trend in toxicology

The Case

A 2 year old male presents to the Emergency Department with his parents immediately after ingesting an unknown amount of Pina Colada e-cigarette (electronic cigarette) refill liquid (18mg/mL of nicotine).  It is a 30mL bottle and there is still some liquid inside.  His breath smells of Pina Colada.

Topic Overview

This case is becoming more and more familiar in Emergency Departments across North America and around the world.  E-cigarettes and other nicotine replacement products have become very popular in the past several years as an alternative to cigarettes and as smoking cessation aids.  Cases of nicotine overdose and accidental ingestion are following a similar rise in popularity.  In New Zealand, the increase in calls to poison control about pediatric exposure to nicotine replacement therapy products has mimicked the increase in sales (Figure 1) [1].  Mean age of pediatric exposure was 29 months and 99.5% of exposures occurred in the patient’s own home.  In the United States, calls to Poison Control about e-cigarette exposures increased from 1 to 215 per month from February 2010 to December 2014 (Figure 2) [2].

Pediatric nicotine therapy replacement therapy (NRT) product exposures per year (left) and sales of NRT products (right).

Pediatric nicotine therapy replacement therapy (NRT) product exposures per year (left) and sales of NRT products (right). [1]

Figure 2. Calls to poison centers for e-cigarette and cigarette exposures in the United States.

Figure 2. Calls to poison centers for e-cigarette and cigarette exposures in the United States. [2]

E-cigarettes contain a variety of substances and they are not guaranteed to be accurate to what is on the label.  Ingredients include nicotine, diethylene glycol, ethylene glycol, ethanol, formaldehyde, glycerin, flavouring, colouring, and much more. [3] The alcohols are usually used as solvents and generally the amounts are within approved FDA limits. [3] One brand, however, did contain an unknown amount of Oil of Wintergreen [3], which can cause salicylate toxicity in very small doses.  E-cigarette liquid can contain anywhere from 6-72mg/mL of nicotine, depending on the brand. [3]

Figure 3

Figure 3

E-cigarettes refills are particularly attractive to children.  They smell and taste delicious and they come in a wide variety of flavours and colours.  They have vibrant labels and some have cartoons on the packaging (Figure 3).  In Canada, advertisement or sale of liquids containing nicotine is illegal, but possession or consumption of them is not and it is easy to order products online.  In the United States, there are no FDA regulations regarding liquids containing nicotine.  Across North America, there is no legislation mandating child resistant packaging and most people do not know that nicotine can be toxic in small doses.

This brings us to the next question.  What is the lethal dose of nicotine?  Textbooks, safety datasheets, and poison control tend to cite 45-60mg of nicotine as the potentially lethal dose. [4,5]  It turns out that the original data was from a single paragraph in a textbook written in 1906 by Dr. R. Kobert. [6]  Kobert obtained his data by doing self-experiments and it conflicted with other data that was available at the time.  His reputation as a leading scholar in toxicology led to universal acceptance of 60mg as the lethal dose (LD50 of 0.5-1mg/kg). [6]  A comprehensive review by Mayer in 2014 suggests an LD50 of 6.5-13mg/kg (500-1000mg for adults), which is more consistent with actual fatalities and dog studies. [6]  Considering that e-cigarette liquid may contain up to 72mg/mL of nicotine, this lethal dose may still only be a millilitre of liquid for a child.  My interpretation of this data is that the lethal dose is probably higher than most textbooks state, but information is lacking and we should still err on the side of caution.  As ingestions become more frequent, more information will become available.

Nicotine can have a wide range of clinical signs and symptoms as it activates nicotinic receptors all over the body.  It primarily effects the autonomic, neuromuscular, and central nervous systems.  It is easier to remember if it is divided into early and late symptoms.  Early in toxicity (within the first hour or so) nicotine acts as a stimulant. [4,5]  Delayed effects (after an hour) are due to nicotinic receptor blockade (See Table 1).4,5  Nicotine has a short half life of 1-4 hours.4  Vomiting is an early sign and occurs in 50% of symptomatic cases. [4]  If symptoms are not seen within the first several hours, they are unlikely to occur.  However, the half life with large overdoses is not well studied and it may take up to 72 hours for symptoms to fully clear. [4]

SystemEarly Effects (<1hr)Delayed Effects (>1hr)
CardiovascularTachycardia, hypotensionBradyarrythmia, hypotension
RespiratoryBronchorrhea, hyperpneaHypoventilation, apnea
NeurologicTremor, headache, ataxiaSeizure, coma
MusculoskeletalFasiculationsParalysis
GastrointestinalVomitingDiarrhea

If you have a patient with suspected nicotine overdose, how should it be managed?  The patient should be on a cardiorespiratory monitor, have intravenous access, and be watched closely.  Symptomatic management should be initiated (ie: anti-emetics, atropine for bradycardia, respiratory support as needed, benzodiazepines for seizures, etc.) Bloodwork may be indicated if the patient is unstable, the history is unclear, it was an attempted suicide, or if the toxidrome is inconsistent.  The use of activated charcoal for tobacco ingestions is recommended, but the benefit in liquid nicotine overdoses is unclear. [4,5]  Activated Charcoal is usually recommended within the first two hours post ingestion. However, its efficacy is questionable due to rapid absorption of liquid nicotine. This needs further study.”  Multi-dose activated charcoal may be indicated in patients with significant toxicity due to the enterohepatic circulation of nicotine. [4]  As always, one must consider airway precautions when giving charcoal to a patient who is vomiting or has decreased level of consciousness.  Unfortunately, there is no antidote and dialysis is not effective.  The physician should call Poison Control in all cases of suspected nicotine overdose.  The patient should be observed in the Emergency Department.  If they are without symptoms for several hours they may be discharged without follow up.

As primary care physicians it is our job to educate patients and parents.  The general public may not be aware that nicotine is toxic.  Patients should be advised to store nicotine refill liquids away from children and in a locked area.  It should be treated as any other dangerous medication and any history of ingestion, no matter how small, should prompt an immediate visit to the Emergency Department.  Physicians should also advocate for changes that may reduce unintentional exposures, such as FDA regulations and child resistant packaging.

Back to the Case

The patient remained in the Emergency Department for 6 hours.  His vitals remained stable and he never developed any symptoms.  There were no investigations and he did not receive any treatment.  He was discharged home in the care of his parents, who were educated about the toxicity of e-cigarette liquid.

Take Home Points

  • Nicotine (in e-cigarette refill liquid) is a “one pill killer”
  • Clinical presentation is initially a stimulant, then a receptor blockade
  • The toxic dose of nicotine is unclear, but we should err on the side of caution and treat all ingestions as potentially toxic
  • Treatment is primarily symptomatic, but there may be a role for multi-dose activated charcoal
  • It is the physician’s responsibility to educate patients (and parents) about the dangers of nicotine toxicity

References

  1. Pediatric poisoning due to nicotine replacement therapy products: an emerging hazard.  JPCH 2014;50:164-165. PMID: 24528448
  2. Calls to poison centers for exposures to electronic cigarettes – United States, September 2010-February 2014. MMWR 2014;63(13):292-293. PMID: 24699766
  3. Toxicity assessment of refill liquids for electronic cigarettes. IJERPH 2015;12:4796-4815. PMID: 25941845
  4. Goldfrank, L. R., & Flomenbaum, N. (2006). Goldfrank’s toxicologic emergencies. New York: McGraw-Hill.
  5. Tintinalli, J. E., Kelen, G. D., & Stapczynski, J. S. (2010). Tintinalli’s emergency medicine: A comprehensive study guide. New York: McGraw-Hill, Medical Pub. Division.
  6. How much nicotine kills a human? Tracking back the generally accepted lethal dose to dubious self-experiments in the nineteenth century.  Arch Toxicol;88:5-7. PMID: 24091634

Author information

Alana Hawley

Alana Hawley

Resident Contributor at McMaster University

Resident Physician, McMaster University Royal College Emergency Medicine Program

The post Medical Concept: Nicotine toxicity, a new trend in toxicology appeared first on BoringEM and was written by Alana Hawley.

Valsalva 2.0

The Valsalva maneuver’s effectiveness for supraventricular tachycardia is, essentially, the reason adenosine exists.  With rates of non-pharmacologic cardioversion merely 5-20%, it’s not absent of value, but hardly reliable.

So, I appreciate these authors innovation in trialling a new, improved Valsalva maneuver.  The comparator in this study was the “traditional” maneuver, as applied via a forced exhalation of 40 mmHg for 15 seconds.  The “modified” maneuver was the same exhalation, but followed by immediately laying the patient supine and having a passive leg raise performed.

With 214 patients analyzed in the intention-to-treat population in a multi-center randomized trial, the success rate was, essentially: 43% vs. 17% in sinus rhythm one minute after Valsalva.  This boiled down to only 57% of patients in the modified Valsalva group ultimately requiring any pharmacologic therapy, compared with 80% of the traditional method.

I don’t see any particular reason to suspect the modified version would be more harmful than the otherwise safe traditional method, so there shouldn’t be any reason to avoid teaching and using this new alternative.  This may also be of more use to patients at home in preventing an Emergency Department visit in the first instance.

“Postural modification to the standard Valsalva manoeuvre for emergency treatment of supraventricular tachycardias (REVERT): a randomised controlled trial”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)61485-4/abstract (oa)

EM Mindset: Michael B. Weinstock – Not Like Reading a Book at the Beach

Author: Michael B. Weinstock, MD (Professor of Emergency Medicine (Adjunct), Department of Emergency Medicine, The Ohio State University College of Medicine; Emergency Department Chairman and Director of Medical Education, Mt. Carmel St. Ann’s Dept. of Emergency Medicine; Author: Bouncebacks! + Bouncebacks!: Medical and Legal + Bouncebacks!: Pediatrics) // // Editors: Alex Koyfman, MD (@EMHighAK) and Manpreet Singh, MD (@MPrizzleER)

I often compare working a busy ED shift to skiing a double black diamond run; for some it is stressful, for others it is intense. But whatever your perspective, we would all agree it is not like reading a book at the beach. The trick is to find a way to be successful and persevere for a whole career.

Being on the front lines on a busy shift is tough; sometimes the amount of work thrown our way seems insurmountable. We need to rapidly treat the sick and to recognize red flags of illness in the worried well, all while finding the sweet spot of connection with the human tragedy which so often filters into our day; the 18 month-old child who needs IV fluids for dehydration, the 42 year-old mother with a new diagnosis of ovarian cancer, the octogenarian who wanted to die at home but is now receiving chest compressions from the paramedics.

“I wish I’d have been a doctor. Maybe I’d have saved some life that had been lost…” -Bob Dylan, Don’t fall apart on me tonight

When you are buried deep in the ‘weak and dizzy’, there are 3 squads incoming, and your relief is not due for 3 more hours, remember that of all the people in the emergency department, you are the one who is healthy. You are the one who is getting paid for being there. You are the one who can gleam that special amount of satisfaction that you have made a difference in the life of another.

During the recent recession, I tried to remind myself, while walking into the double bay doors of the ED on a cold February morning or after leaving my kids on a hot summer day for a 2P shift, that I was going to work. A phrase that many of the able-bodied patients I would be seeing would have loved to be able to say.

What must it be like to want to work, to want to provide for your family, but be unable to find a job?

“You better start swimming or you’ll sink like a stone… for the times they are a changin’” – Bob Dylan, The times they are a changin’

You can spend 20 years of your life trying to find peace and wisdom, sitting on a mountain top in Nepal, or at your local yoga studio… but 20 minutes with a non-functioning electronic medical record (EMR) and you are reduced to a driveling idiot who wants to grab the monitor with both hands and throw it out the window!

Anticipate malfunctions and breakdowns and devise a ‘down-time’ plan for when they occur. How about continuing to use the voice activated software to dictate into a word processing program, then copy and paste into the EMR when it is back online? While waiting for the program to respond, can you take the time to see new patients, go over labs with patients waiting, or give bedside discharge instructions to those leaving?

I am old enough to remember when the labs were printed out at the main desk, the nurse had a clipboard of vital signs (usually with them in the break room during lunch), and the old charts were requested from the central medical records department which began an hour long process culminating in a pile of faded paper charts which caused sciatica just trying to lift them.

All in all, the EMR is easy to complain about, but those of us who have embraced the iPhone/texting generation would have it no other way. For those who are not there yet… don’t sink like a stone!

“Jokerman dance to the nightingale tune…” –Bob Dylan, Jokerman

Remember that super hilarious joke about the patient whose temperature always runs low: “99 is a fever for me!” Or the 50 year-old fibromyalgia victim with the positive ‘review of symptoms’? These stories are emblematic of the ridiculous nature of our jobs… but symbolic of the verbal filter which needs to exist at a dinner party. It is easy for us to separate patient’s human tragedy from human manipulation, which is why we use gallows humor… but remember that these jokes do not translate to the lay public. What is funny to a seasoned EP, is viewed as unfeeling to your dinner guests!

I have learned this lesson the hard way. ‘Walking back’ the uncompassionate comment only serves to make you feel spineless and cold. Save the comedy for the locker room…

“What looks large from a distance, close up is never that big” –Bob Dylan, Someone’s got a hold of my heart

Over the years I have learned on the job lessons which could not have been taught in residency:

  • Running the room is as important as getting the correct diagnosis. Continually re-evaluate and re-prioritize your tasks.
  • Concern for good medical care trumps a legal concern. Help your colleagues with those weird rashes and emergent procedures, as the favor will be soon repaid.
  • Get to work on time. After a busy night shift, you are the cavalry riding in to save the Alamo! Arriving even 2 minutes late is frustrating and demoralizing to the night-shift doctor.
  • Try and walk in your patient’s shoes. Even on the days when you are so tired and overworked that you can’t see straight, you are still the physician designated to see the patient. Their chief complaint does not always mirror their concern. Try and take them seriously, they are placing their trust in you.

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PEM Pearls: Migraine Treatment for Pediatric EM Patients

Migraine Treatment for Pediatric EM PatientsYou are working your evening shift at the pediatrics emergency department, and you walk into a darkened patient room with a distressed mother and her otherwise healthy 10-year old daughter who is curled in a ball, holding her head and crying. Her mother tells you that the around-the-clock ibuprofen has barely touched her 2-day headache.

After determining that your patient has no neurologic deficits and that this is most likely a primary headache, what can you do to break her symptoms?

The numbers

Headaches account for 1% of all pediatric emergency department visits. Of those presenting with headache, 40% of children are diagnosed with a primary headache, and 75% of these are migraines. Most research and medications have focused on children < 7 years ago as the average age of onset of migraines is 7 years old among boys and 11 years old among girls [1]. The diagnosis of pediatric migraine can be challenging, especially in younger children (<7 yo) who may not be able to describe their symptoms.

Should you stick the kid?

Children may have been vomiting and have decreased oral intake. If you are feeling bad about placing an IV in your patient, just know that about half of patients with migraines will need IV therapy [2].

Should you reach for that opioid?

According to the American Academy of Neurology, they recommend that opiate medications be avoided for the treatment of migraines in children. A study by DeVries found that among adolescents who received opioids, 28% had an emergency department revisit for their headache compared to only 14% who did not receive any opioids (P < 0.01) [3]. Dr. Amy Gelfand, a UCSF pediatric neurologist who specializes in pediatric headaches, says that by giving opioids, there is an associated decreased responsiveness to triptans in the future (See her Expert Peer Review comments below).

What should you try then?

By the time your patient present to the ED for migraines, they have been symptomatic for probably  24-72 hours already, and have taken some type of abortive medication, most often acetaminophen or ibuprofen [2][4]. The addition of caffeine to ibuprofen may increase ibuprofen’s analgesic properties [4].

Which dopamine-receptor antagonists to use?

Your choices of the phenothiazines for ages ≥7 years old include:

  • Prochlorperazine (1st choice)
  • Chlorpromazine
  • Metoclopramide

Pros:  Alleviates both pain and nausea/vomiting

Cons: Drowsiness, hypotension, and extrapyramidal reactions (EPS).

In a recent study in Pediatrics 2015, Bachur et al. performed a large retrospective study, using data collected on children aged 7-18 years from 35 pediatric EDs [5]. They examined any revisits within 3 days of initial encounter as their primary outcome. Common medications included:

  1. Non-opioid analgesics (66%)
  2. Dopamine receptor antagonists (50%)
  3. Ddiphenhydramine (33%)

Of those discharged at the initial encounter, 5.5% of children had a return visit within 3 days.

They found that children treated with prochlorperazine had a 31% decreased odds of returning to the emergency department, compared to those treated with metoclopramide. Kanis et al. found that proclorperazine was more effective than chlopromazine, with less admission, need for rescue medications, shorter disposition times, and hypotensive events [6].

Prophylactic diphenhydramine may be administered to patients receiving prochlorperazine to pre-treat akathisia and dystonic reactions. Diphenhydramine may cause additional sedation and drowsiness when co-administered with prochlorperazine. EPS may occur after ED discharge even in patients receiving prophylactic diphenhydramine, so parents should be cautioned about restlessness (akathesia)  and dystonia. [8]

Brousseau et al. showed better efficacy with a 50% reduction of pain at 1 hour in children who received prochlorperazine IV (84.8%) versus ketorolac IV (55.2%) though 30% of both groups had recurrences of some headache 48 hours after treatment [7]. Per Dr. Gelfand,  prochlorperazine should be considered first-line over ketorolac.

Other regimens

Triptans may be administered via oral and subcutaneous routes, or via intranasal spray. In the ED, triptans may be useful in kids with migraines who do not take triptans as abortive therapy. In general, patients should not receive more than two doses of triptans in a 24-hour period. They work effectively at the earlier stages of the migraine when the symptoms are more mild compared to when there are more moderate or severe. Zolmitriptan nasal spray has recently been approved for children 12 years old and older, while sumitriptan nasal spray is available for children 5 years and older. When compared to placebo, triptans have a 2-hour efficacy for 42-86% of patients. Combination medications of triptans and naproxen have also been shown to have good efficacy [1][4]. You can prescribe patients home with triptans, as long as there are no contraindications such as cardiac issues.  Keep in mind the cost impact of these medications. Many triptans are still non-generic and patients without insurance may not have access to them. There are four triptans that are FDA-approved for acute migraine treatment in the <18 age group (See below for the dosing table).

IV dihydroergotamine (DHE) is primarily used in the inpatient setting, but could be initiated in the ED for refractory cases, given that it typically takes several doses over several hours to administer. DHE can worsen nausea and lead to emesis,  therefore should be used in conjunction with an antiemetic or prochlorperazine (which also has anti-emetic properties). Avoid DHE and triptans together, especially for those patients with cardiovascular disease [1][4].

If the history is consistent with migraine, the algorithm by Sheridan et al may be useful in your pocket for patients ≥7 years old [1]:

Flowchart adapted from: Sheridan, Headache (2014)

Bottom Line

  1. Give hydration either by oral or by parenteral route.
  2. Dim the lights and turn down any loud sounds or alarms.
  3. Break the habit… Avoid opioids!
  4. Give prochlorperazine instead of metoclopramide or chlopromazine.
  5. Try a triptan.
  6. Refer to a neurologist. If your patient has migraines that are bad enough to have them land in the ED, they should be evaluated by a specialist, ideally one that has experience with managing pediatric migraines.

Dosages

Medications Dosage
Simple analgesics
Acetaminophen 15 mg/kg PO or PR (max 1 g/dose or 4 g/day)
Ibuprofen 10 mg/kg PO (max dose 800 mg/dose or 2400 mg/day)
Ketorolac 0.5 mg/kg IV (max dose 15 mg/dose)
Dopamine antagonists
Prochlorperazine 0.15 mg/kg IV (max dose 10 mg/dose)
Metoclopramide 0.1 mg/kg IV ( max dose 10 mg/dose)
5HT receptor agonists
Sumatriptan 5-20 mg IN
50-100 mg PO
3-6 subQ
Almotriptan  6.25 or 12.5 mg PO for ages 12-17 years
Rizatriptan MLT 5 mg (<40 kg) or 10 mg (≥40 kg) for >6 years old
Zolmitriptan  2.5-5 mg IN for ages 12-17 years
Treximet: Sumatriptan/Naproxen combination For ages 12-17 years:
85 mg/500 mg PO
30 mg/180 mg PO
10 mg/60 mg PO
Dihydroergotamine 0.5-1 mg SubQ, IM or IV
Other anti-emetics
Diphenhydramine 1 mg/kg (max dose 50 mg/dose)
Promethazine 0.25-1 mg/kg IV (max dose 25 mg/dose)
**Table adapted from Sheridan, Bulloch and Dr. Gelfand’s comments below

References

  1. Sheridan DC, Spiro DM, Meckler GD. Pediatric migraine: abortive management in the emergency department. Headache. 2014; 54(2): 235-45. PMID: 24512575
  2. Bulloch B, Tenenbein M. Emergency department management of pediatric migraine. Pediatr Emerg Care. 2000; 16(3): 196-201; quiz 203. PMID: 10888462
  3. DeVries A, Koch T, Wall E, Getchius T, Chi W, Rosenberg A. Opioid use among adolescent patients treated for headache. J Adolesc Health. 2014; 55(1): 128-33. PMID: 24581795
  4. Gelfand AA, Goadsby PJ. Treatment of pediatric migraine in the emergency room. Pediatr Neurol. 2012; 47(4): 233-41. PMID: 22964436
  5. Bachur RG, Monuteaux MC, Neuman MI. A comparison of acute treatment regimens for migraine in the emergency department. Pediatrics. 2015; 135(2): 232-8. PMID: 25624377
  6. Kanis JM, Timm NL. Chlorpromazine for the treatment of migraine in a pediatric emergency department. Headache. 2014; 54(2): 335-42. PMID: 24512578
  7. Brousseau DC, Duffy SJ, Anderson AC, Linakis JG. Treatment of pediatric migraine headaches: a randomized, double-blind trial of prochlorperazine versus ketorolac. Ann Emerg Med. 2004; 43(2): 256-62. PMID: 14747817
  8. Coralic Z. I am giving prochlorperazine. Should I give diphenhydramine too?. ALiEM. 2014.

Author information

Delphine Huang, MD

Delphine Huang, MD

Emergency Medicine resident

UCSF-San Francisco General Hospital Residency Program

The post PEM Pearls: Migraine Treatment for Pediatric EM Patients appeared first on ALiEM.