Contributor: Aaron Lessen, MD

Educational Pearls:

How long do we need to watch patients with a presumed overdose who were treated with naloxone in the field?

• A 2025 study in the Annals of Emergency Medicine took a look at this question
• Methods
  • Prospective, multi-institutional cohort study
  • Included ED patients with suspected acute opioid overdose with biologic testing to confirm substances.
  • This paper performed a secondary analysis evaluating the risk of "delayed intubation," defined as intubation occurring >4 hours after ED arrival.
• Results
  • 1,591 patients with presumed opioid overdose were included.
  • Delayed intubation occurred in only 9 patients (0.6%).
  • 8 of the 9 cases had non-respiratory causes contributing to intubation.
  • Only 1 patient had respiratory-related deterioration, presenting with respiratory acidosis after receiving 6.4 mg naloxone prior to intubation.
• Key Takeaway
  • Delayed respiratory deterioration requiring intubation after 4 hours of ED monitoring is extremely rare, suggesting prolonged monitoring may not be necessary for most stabilized overdose patients.

How else can we mitigate risk?

• Give patients take-home naloxone at discharge and educate them on how to use it (See Episode 673: Leaving the ED with Naloxone).

When are naloxone drips necessary?

• If a patient requires repeated naloxone boluses, consider a drip
• To get the dose, take the total naloxone dose that restored adequate breathing and give two-thirds of that dose per hour
• Typically these patients are admitted to the ICU

References

1. McCabe DJ, Gibbs H, Pratt AA, Culbreth R, Sutphin AM, Abston S, Li S, Wax P, Brent J, Campleman S, Aldy K, Falise A, Manini AF; ToxIC Fentalog Study Group. Risk of Delayed Intubation After Presumed Opioid Overdose in the Emergency Department. Ann Emerg Med. 2025 Jun;85(6):498-504. doi: 10.1016/j.annemergmed.2025.01.022. Epub 2025 Mar 4. PMID: 40047773; PMCID: PMC12955731.

Summarized and edited by Jeffrey Olson MS4

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Contributor: Travis Barlock, MD

Educational Pearls:

• D-dimer: fibrin degradation product used to evaluate for clot formation and breakdown
  • Threshold:
  • Elevated D-dimer indicates recent or ongoing intravascular coagulation and fibrinolysis
• YEARS score: algorithm to assess PE risk using three clinical criteria
  • Criteria: signs of DVT, hemoptysis, and PE as the most likely diagnosis
  • YEARS score of 0 with D-dimer
  • YEARS score of ≥1 with D-dimer
  • A study found that YEARS score accurately predicted the presence or absence of PE in 80% of enrolled patients with 90% sensitivity and 65% specificity
• D-dimer may also help exclude aortic dissection: Aortic Dissection Detection Risk Score (ADD-RS)
  • When ADD-RS = 0 or 1 and D-dimer
  • When ADD-RS >1, patients are considered high probability for aortic dissection and CT should be performed

References

1. Fayiad, H., Moussa, H., Nosair, Y. et al. Predictive accuracy of years score in diagnosis of pulmonary embolism. Egypt J Bronchol 18, 18 (2024). https://doi.org/10.1186/s43168-024-00269-y
2. Weitz JI, Fredenburgh JC, Eikelboom JW. A Test in Context: D-Dimer. J Am Coll Cardiol. 2017 Nov 7;70(19):2411-2420. doi: 10.1016/j.jacc.2017.09.024. PMID: 29096812.
3. Yichao Ma,Zhenjiang Ding,Yunong Zhao,Paijiao Zhang,Bo Du,Ye Shen,Junmei Hu,Luqi Zhu,Honghong Zhao,Chunrong Jin,Yuhong Wang,Lizhen Gao,Research progress on multi-marker detection technology for cardiovascular diseases (review), Journal of Electroanalytical Chemistry, 1008, (119969), (2026).

Summarized by Meg Joyce, MS2 | Edited by Meg Joyce & Jorge Chalit, OMS4

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Contributor: Taylor Lynch MD Educational Pearls:

• Melatonin is an endogenous hormone released primarily by the pineal gland
  • Also released by extrapineal regions in the retina, the GI tract, and some immune cells
• Peak secretion occurs at night and is suppressed during the day
  • Secretion and production decrease with age
  • Older patients experience the greatest improvement in sleep latency and sleep quality
• Mechanism of action in the suprachiasmatic nucleus of the hypothalamus
  • MT1 receptor
    • Reduces normal firing
  • MT2 receptor
    • Shifts the circadian rhythm
• FDA approved for insomnia
  • Decreases sleep latency by 7 minutes
  • Increases total sleep time by 8 minutes
• FDA approved for circadian sleep-wake disorders
  • Jet lag
    • Most effective in west-to-east travel
    • Best if crossing at least 5 time zones
  • Shift work
    • A study examined ED physicians and nurses with rotating shifts
    • Modest increase in deep sleep percentage
    • No difference in cognition or reaction time the day after taking melatonin
    • Nurses on rotating night shifts experienced increased total sleep time by 20 minutes
• Dosing
  • 0.5 - 3 mg is the most evidence-based dosing
  • Higher doses increase the risk of rebound grogginess but do not improve outcomes

References

1. Ahmad SB, Ali A, Bilal M, et al. Melatonin and Health: Insights of Melatonin Action, Biological Functions, and Associated Disorders. Cell Mol Neurobiol. 2023;43(6):2437-2458. doi:10.1007/s10571-023-01324-w
2. Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev. 2002;(2):CD001520. doi:10.1002/14651858.CD001520
3. Morgenthaler TI, Lee-Chiong T, Alessi C, Friedman L, Aurora RN, Boehlecke B, Brown T, Chesson AL Jr, Kapur V, Maganti R, Owens J, Pancer J, Swick TJ, Zak R; Standards of Practice Committee of the American Academy of Sleep Medicine. Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. An American Academy of Sleep Medicine report. Sleep. 2007 Nov;30(11):1445-59. doi: 10.1093/sleep/30.11.1445. Erratum in: Sleep. 2008 Jul 1;31(7):table of contents. PMID: 18041479; PMCID: PMC2082098.
4. Thottakam BMVJ, Webster NR, Allen L, Columb MO, Galley HF. Melatonin Is a Feasible, Safe, and Acceptable Intervention in Doctors and Nurses Working Nightshifts: The MIDNIGHT Trial. Front Psychiatry. 2020;11:872. Published 2020 Aug 27. doi:10.3389/fpsyt.2020.00872

Summarized and edited by Jorge Chalit, OMS4

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Contributor: Travis Barlock, MD

Educational Pearls:

• Foul-smelling urine and cloudy urine are commonly misinterpreted as indicators of a UTI. However, these findings alone are not diagnostic.
• Criteria for UTI:
  • Presence of localized urinary symptoms:
  • Suprapubic pain
  • Dysuria
  • Hesitancy
  • Urgency
  • Urinalysis with WBC > 10
  • Urine culture with > 100,000 CFU/mL
• Colonization differs from infection - many patients harbor asymptomatic bacteria but do not have a true infection.
• Consequences of overtreatment
  • One review showed 45% of patients treated with antibiotics for a presumed UTI actually had asymptomatic bacteriuria and were incorrectly treated.
  • Unnecessary antibiotic treatment can have deleterious effects on the gut microbiome, increasing the risk of multidrug-resistant infections.
  • Another problem with overdiagnosing UTI is missing the real diagnosis by explaining symptoms away as "just a UTI."
• Be mindful of the risk of overtesting versus not testing at all.
  • Clinicians must navigate a balance between moving patients efficiently through the ER and testing appropriately when a UTI is truly suspected.

References:

1. Baghdadi JD, Korenstein D, Pineles L, et al. Exploration of primary care clinician attitudes and cognitive characteristics associated with prescribing antibiotics for asymptomatic bacteriuria. JAMA Netw Open. 2022;5(5):e2214268. doi:10.1001/jamanetworkopen.2022.14268
2. Colgan R, Williams M. Acute uncomplicated urinary tract infections in adults. Am Fam Physician. 2024;109(2):167-174. Accessed February 21, 2026. https://www.aafp.org/pubs/afp/issues/2024/0200/acute-uncomplicated-utis-adults.html#afp20240200p167-ta1

Summarized by Ashley Lyons OMS3 | Edited by Ashley Lyons & Jorge Chalit OMS4

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Contributor: Aaron Lessen, MD Educational Pearls:

What is anaphylaxis and what are its treatments?

• Anaphylaxis is a broad term for potentially life threatening allergic reactions that can progress to cardiovascular collapse (anaphylactic shock).
• It is triggered by IgE and antigen cross-linking on mast cells to induce degranulation and the release of histamines, which can cause diffuse vasodilation and respiratory involvement with end-organ hypoperfusion.
• First line treatment is the immediate administration of epinephrine at 0.01 mg/kg (max dose for pediatrics is 0.3 mg and for adults is 0.5 mg) as well as removal of the offending agent causing the reaction.
• Additional pharmacologic treatments such as anti-histamines and steroids should be considered but not used instead of epinephrine when anaphylactic shock is evident as the sole therapy.

What is biphasic anaphylaxis and what is its occurrence?

• Biphasic anaphylaxis is the return of anaphylactic symptoms after the initial anaphylactic event. Previous studies have reported an incidence ranging from 1-20% of patients having an initial anaphylactic reaction having biphasic anaphylaxis, at a range of time from 1-72 hours.
• The mechanism of biphasic anaphylaxis is not completely known, but can be contributed to by initial interventions wearing off (and why patients will be monitored for 2-4 hours after initial symptoms and treatment), or delayed immune mediators beginning to take effect.
• Recent studies show that the rate of biphasic anaphylaxis may be closer to 16% occurrence with a median time of occurrence being around 10 hours.

What is the key take away and patient education on biphasic anaphylaxis?

• After patients have been observed for the initial 2-4 hours in the emergency room, they are generally safe to go home.
• Patients should be informed of the need to carry an Epi-Pen for similar anaphylactic reactions, and informed that there is a chance within the next day (10-20 hours) that they may have the symptoms occur once again.
• The biphasic reaction may be more mild, and patients should be educated on how to treat it and to seek immediate emergency care if the symptoms do not improve.

References

1. Golden DBK, Wang J, Waserman S, et al. Anaphylaxis: A 2023 practice parameter update. Annals of Allergy, Asthma & Immunology. 2024;132(2):124-176. doi:10.1016/j.anai.2023.09.015
2. Rubin S, Drowos J, Hennekens CH. Anaphylaxis: Guidelines From the Joint Task Force on Allergy-Immunology Practice Parameters. afp. 2024;110(5):544-546.
3. Weller KN, Hsieh FH. Anaphylaxis: Highlights from the practice parameter update. CCJM. 2022;89(2):106-111. doi:10.3949/ccjm.89a.21076
4. Gupta RS, Sehgal S, Brown DA, et al. Characterizing Biphasic Food-Related Allergic Reactions Through a US Food Allergy Patient Registry. The Journal of Allergy and Clinical Immunology: In Practice. 2021;9(10):3717-3727. doi:10.1016/j.jaip.2021.05.009

Summarized by Dan Orbidan OMS2 | Edited by Dan Orbidan & Jorge Chalit OMS4

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Contributor: Alec Coston, MD

Educational Pearls:

Disclaimer: this has nothing to do with the ER but is too cool to not talk about.

• Condition: Carbamoyl phosphate synthetase 1 (CPS1) deficiency

• Rare inborn error of metabolism

• Inability to properly break down ammonia

• Leads to severe hyperammonemia and hepatic encephalopathy

• Natural history:

• Without treatment, typically fatal within the first few weeks of life

• Even with current standard treatments, life expectancy is often limited to ~5–6 years

• Breakthrough treatment:

• A team of researchers at the Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania developed the CRISPR-based targeted gene therapy for this patient.

• First-of-its-kind precision approach tailored to the patient's specific mutation

• Key components of the therapy:

• Whole-genome sequencing to identify the exact CPS1 mutation

• Creation of a custom base-editing enzyme designed to correct that specific mutation

• Design of a guide RNA to direct the base editor to the precise genomic location

• Delivery method:

• Lipid nanoparticles used to deliver the gene-editing machinery

• Nanoparticles can be targeted to specific tissues

• Why the liver works well:

• CPS1 is primarily expressed in hepatocytes

• The liver is relatively easy to target with lipid nanoparticles

• Hepatocytes divide frequently, allowing edited genes to be passed on as cells replicate

• Long-term impact:

• Once edited, cells continue producing functional CPS1 enzyme

• Potential for durable, possibly lifelong correction from a single treatment

References

• https://www.nih.gov/news-events/news-releases/infant-rare-incurable-disease-first-successfully-receive-personalized-gene-therapy-treatment

• Choi Y, Oh A, Lee Y, Kim GH, Choi JH, Yoo HW, Lee BH. Unfavorable clinical outcomes in patients with carbamoyl phosphate synthetase 1 deficiency. Clin Chim Acta. 2022 Feb 1;526:55-61. doi: 10.1016/j.cca.2021.11.029. Epub 2021 Dec 29. PMID: 34973183.

• Bharti N, Modi U, Bhatia D, Solanki R. Engineering delivery platforms for CRISPR-Cas and their applications in healthcare, agriculture and beyond. Nanoscale Adv. 2026 Jan 5. doi: 10.1039/d5na00535c. Epub ahead of print. PMID: 41640466; PMCID: PMC12865601.

Summarized and edited by Jeffrey Olson MS4

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Contributors: Travis Barlock MD, Ian Gillman PA, Jacob Altholz MD, Jeffrey Olson MS4

In this episode, EM attending Travis Barlock and medical student Jeffrey Olson listen in to the two remaining cases presented from EMM's recent event, Tox Talk 2025.

Talk 1- Methemoglobinemia- Ian Gillman

• Cyanosis + chocolate-colored blood + normal PaO₂ + pulse ox stuck at ~85% = Methemoglobinemia → Treat with methylene blue

• The medications that can cause it can be remembered with…

• Watch out with methylene blue as it can cause serotonin syndrome

• While treating with methylene blue the pulse ox can drop dramatically but this is not a real drop in oxygenation but rather an effect of how the methylene blue affects the sensor

• BADNAPS: causes of methemoglobinemia

• Benzocaine

• Aniline Dyes

• Dapsone

• Nitrites/Nitrates (Found in meds, preservatives, and well water)

• Antimalarials

• Pyridium

• Sulfonamides

Talk 2- Intratecal TXA and Hierarchy of Controls for Error Avoidance - Jacob Altholz

• Hierarchy of Controls in terms of error prevention includes all of the layers of protection which can be categorized as elimination, substitution, engineering controls, administration controls, and PPE

References

• Centers for Disease Control and Prevention. (2022, April 28). Hierarchy of controls. National Institute for Occupational Safety and Health. https://www.cdc.gov/niosh/learning/safetyculturehc/module-3/2.html

• Pushparajah Mak RS, Liebelt EL. Methylene Blue: An Antidote for Methemoglobinemia and Beyond. Pediatr Emerg Care. 2021 Sep 1;37(9):474-477. doi: 10.1097/PEC.0000000000002526. PMID: 34463662.

Produced by Jeffrey Olson, MS4

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Contributor: Alec Coston, MD

Educational Pearls:

• BiPAP is often effective in severe asthma, but many patients struggle with mask tolerance due to intense air hunger–driven anxiety, often compounded by hypoxia.

• Benzodiazepines are commonly used for anxiety, but they can depress respiratory drive, making clinical improvement difficult to interpret (a lower RR may reflect sedation rather than true physiologic improvement).

• Low-dose fentanyl is a useful alternative when patients cannot tolerate BiPAP despite coaching.

• Opioids blunt the perception of dyspnea and are well established for treating air hunger.

• When carefully titrated, fentanyl provides anxiolysis without significant respiratory suppression.

• It is rapidly titratable (e.g., 25 mcg IV every 5 minutes).

• Evidence primarily comes from palliative and oncology literature, but growing clinical experience supports its use in severe asthma to improve BiPAP tolerance.

• Failure of fentanyl should prompt escalation to ketamine, often signaling impending need for intubation.

References

1. Pang GS, Qu LM, Tan YY, Yee AC. Intravenous Fentanyl for Dyspnea at the End of Life: Lessons for Future Research in Dyspnea. Am J Hosp Palliat Care. 2016 Apr;33(3):222-7. doi: 10.1177/1049909114559769. Epub 2014 Nov 25. PMID: 25425740.

Summarized and edited by Meg Joyce, MS2

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Contributor: Aaron Lessen, MD

Educational Pearls

BRASH Syndrome:

• Bradycardia

• Renal Failure

• AV Nodal Blockade

• Shock

• Hyperkalemia

Clinical Features:

• Profound bradycardia and shock in patients on AV nodal blockers:

• Commonly, Beta Blockers or Calcium Channel Blockers

Etiology:

• Caused by an inciting kidney injury:

• Common triggers include precipitating illness, dehydration, or medications

• Results in hyperkalemia

• The enhanced effect of the combination of AV nodal blockade and hyperkalemia leads to a more profound presentation of shock.

Treatment:

• IV Fluids, unless volume overloaded

• Epinephrine for bradycardia

• Lasix for volume overload, only if the patient is still making urine

• Low threshold to dialyze for hyperkalemia

• Focus on treating early and more aggressively.

References:

Farkas JD, Long B, Koyfman A, Menson K. BRASH Syndrome: Bradycardia, Renal Failure, AV Blockade, Shock, and Hyperkalemia. J Emerg Med. 2020 Aug;59(2):216-223. doi: 10.1016/j.jemermed.2020.05.001. Epub 2020 Jun 18. PMID: 32565167.

Summarized by Ashley Lyons OMS3

Editting by Ashley Lyons OMS3 and Jeffrey Olson MS4

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Contributor: Taylor Lynch, MD

Educational Pearls:

• Tramadol is a Schedule IV opioid analgesic used for moderate pain and is often perceived as safer than other opioids due to lower abuse potential.

• It is a prodrug with weak direct μ-opioid receptor activity.

• The parent compound also inhibits serotonin and norepinephrine reuptake, giving it SSRI/SNRI-like properties.

• Tramadol is metabolized by CYP2D6 into O-desmethyltramadol (ODT), which has significantly stronger μ-opioid receptor agonism than the parent drug.

• Ultrarapid CYP2D6 metabolizers (more common in Middle Eastern and North African populations) rapidly convert tramadol to ODT, increasing the risk of opioid toxicity.

• Poor CYP2D6 metabolizers generate little ODT and may experience primarily serotonergic effects, increasing the risk of serotonin syndrome, especially when combined with SSRIs or SNRIs.

• CYP2D6 inhibitors (e.g., bupropion, paroxetine, terbinafine, celecoxib) can block tramadol's conversion to ODT, potentially precipitating opioid withdrawal or increasing serotonergic toxicity.

• Tramadol is also associated with an increased risk of first-time seizures, even at therapeutic doses.

• Tramadol's effects are highly unpredictable, varying from minimal analgesia to exaggerated opioid effects depending on metabolism.

• Drug–drug interactions can lead to serotonin syndrome or opioid withdrawal.

• Despite its Schedule IV classification and reputation for safety, alternative analgesics may be preferable in many patients.

References

1. DailyMed - TRAMADOL HYDROCHLORIDE tablet, coated. Accessed January 10, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=61fb5ba7-6896-4ee4-83de-caee69b06a8e#ID57

2. Dean L, Kane M. Tramadol Therapy and CYP2D6 Genotype. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, eds. Medical Genetics Summaries. National Center for Biotechnology Information (US); 2012. Accessed January 10, 2026. http://www.ncbi.nlm.nih.gov/books/NBK315950/

3. Aly SM, Tartar O, Sabaouni N, Hennart B, Gaulier JM, Allorge D. Tramadol-Related Deaths: Genetic Analysis in Relation to Metabolic Ratios. J Anal Toxicol. 2022;46(7):791-796. doi:10.1093/jat/bkab096

Summarized and edited by Dan Orbidan OMS2

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