ACMT Toxicology Visual Pearl: Questions about green pee? Urine luck!
Which of the following medications is likely responsible for this urine discoloration in an intubated and sedated ICU patient?
- Fentanyl
- Ketamine
- Lorazepam
- Midazolam
- Propofol
Bupropion Overdose: Factors Associated with Seizures
Background
Bupropion ingestions are one of the scarier poisonings due to a relatively narrow therapeutic index and the numerous adverse effects that may occur. Medical toxicologist Dr. Dan Rusyniak details his hatred of this drug in overdose in a Tox & Hound blog post aptly-titled Illbutrin. When bupropion was first approved in the 1980s, the max dose was 600 mg/day [1]. However, reports of seizures, particularly in patients with bulimia, caused its temporary removal from the market [2]. It was reintroduced a few years later with a max dose of 450 mg/day [3]. Common signs and symptoms noted in overdose include seizures, agitation, sinus tachycardia, and QRS/QTc prolongation. Seizures occur in up to 40% of overdose cases, are often refractory to initial therapy, and can happen as long as 24 hours after an overdose with extended release formulations [4, 5].
Evidence
A study of 256 patients from the Toxicology Investigators Consortium (ToxIC) Registry identified three factors associated with seizure development after bupropion overdose [6, 7].
- QTc prolongation > 500 msec (OR = 3.4, 95% CI: 1.3-8.8)
- Tachycardia (heart rate > 140) (OR = 1.9, 95% CI: 1-3.6)
- Age 13–18 years (OR = 2.4, 95% CI: 1.3-4.3)
Agitation and tremors are more common in patients who develop seizures with bupropion compared to those who do not [4]. Additionally, presence of tachycardia (heart rate >100 bpm) has a sensitivity of 91% and a negative predictive value of 93% for development of seizures [4].
Bottom Line
- Seizures are common following bupropion overdose and patients who seize are generally tachycardic.
- Patients should be observed at least 24 hours after a extended release bupropion overdose, as seizures can be significantly delayed.
Want to learn more about EM Pharmacology?
Read other articles in the EM Pharm Pearls Series and find previous pearls on the PharmERToxguy site.
References
- Davidson J. Seizures and bupropion: a review. J Clin Psychiatry. 1989;50(7):256-261. PMID: 2500425.
- Horne RL, Ferguson JM, Pope HG, et al. Treatment of bulimia with bupropion: a multicenter controlled trial. J Clin Psychiatry. 1988;49(7):262-266. PMID: 3134343.
- Huecker MR, Smiley A, Saadabadi A. Bupropion. In: StatPearls. StatPearls Publishing; 2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470212/.
- Starr P, Klein-Schwartz W, Spiller H, Kern P, Ekleberry SE, Kunkel S. Incidence and onset of delayed seizures after overdoses of extended-release bupropion. Am J Emerg Med. 2009;27(8):911-915. doi: 10.1016/j.ajem.2008.07.004. PMID: 19857406.
- Al-Abri SA, Orengo JP, Hayashi S, Thoren KL, Benowitz NL, Olson KR. Delayed bupropion cardiotoxicity associated with elevated serum concentrations of bupropion but not hydroxybupropion. Clin Toxicol (Phila). 2013;51(10):1230-1234. doi: 10.3109/15563650.2013.849349. PMID: 24131328.
- Wax PM, Kleinschmidt KC, Brent J, ACMT ToxIC Case Registry Investigators. The toxicology investigators consortium (Toxic) registry. J Med Toxicol. 2011;7(4):259-265. doi: 10.1007/s13181-011-0177-z. PMID: 21956161.
- Rianprakaisang TN, Prather CT, Lin AL, Murray BP, Hendrickson RG, Toxicology Investigators Consortium (ToxIC). Factors associated with seizure development after bupropion overdose: a review of the toxicology investigators consortium. Clin Toxicol (Phila). Published online April 21, 2021:1-5. doi: 10.1080/15563650.2021.1913180. PMID: 33878992.
One-Time Vancomycin Doses in the Emergency Department
Background
A previous ALiEM post from 2013 by an EM pharmacist colleague argued the case against one-time vancomycin doses in the ED prior to discharge. The take-home points from this post were:
- No evidence that a one-time vancomycin has any benefit
- This practice is not recommended by the Infectious Diseases Society of America (IDSA)
- May extend the patient’s ED stay by at least an hour for the IV infusion, depending on the dose
- Increases the cost of the ED visit (e.g., IV line, medication, RN time)
- Pharmacokinetically 1 dose of vancomycin doesn’t make sense
- Vancomycin 1 gm IV x1 provides sub-therapeutic levels for patients with normal renal function
- Efficacy is based on overall exposure (e.g., AUC/MIC) achieved with repeated dosing over several days
- Subtherapeutic vancomycin concentrations lead to development of resistance
Despite the above points, a one-time dose of vancomycin prior to the patient being discharged on an oral regimen is a common practice [1].
Evidence
As stated above, a single dose of vancomycin is unlikely to provide a therapeutic benefit and may only serve to reassure clinicians. The 2020 consensus guidelines regarding vancomycin monitoring for serious MRSA infections reinforce the recommendation of achieving an AUC0-24/MIC ratio of ≥400, as a ratio <400 increases resistance and has inferior efficacy [2]. Since the AUC is dependent on overall time of exposure plus concentration, a single dose for an average patient with normal renal function is not adequate (Figure 1). The graph below also demonstrates how long it generally takes for vancomycin to reach steady state when patients receive a dose every 8 hours.
*The estimated AUC above assumes a 30 yo male that weights 70kg and is 6′ tall with a serum creatinine of 1.0 mg/dL.
A randomized trial conducted at Christiane Care Health System compared patients who received a vancomycin loading dose of 30 mg/kg or 15 mg/kg [3]. Just twelve hours after this initial dose, 34.6% of patients who received 30 mg/kg had vancomycin levels in the therapeutic range (trough >15 mg/L) vs. 3% of patients who received 15 mg/kg (p < 0.01).
Bottom Line
Even large vancomycin loading doses rarely achieve therapeutic levels after one dose. Therefore, if the plan is to discharge, skip the one-time dose altogether and choose an antimicrobial regimen that will be continued in the outpatient setting (e.g., doxycycline or sulfamethoxazole/trimethoprim if concerned for MRSA or cephalexin for most other patients).
Want to learn more about EM Pharmacology?
Read other articles in the EM Pharm Pearls Series and find previous pearls on the PharmERToxguy site.
References
- Mueller K, McCammon C, Skrupky L, Fuller BM. Vancomycin use in patients discharged from the emergency department: a retrospective observational cohort study. J Emerg Med. 2015;49(1):50-57. doi: 10.1016/j.jemermed.2015.01.001. PMID: 25802166.
- Rybak MJ, Le J, Lodise TP, et al. Therapeutic monitoring of vancomycin for serious methicillin-resistant staphylococcus aureus infections: a revised consensus guideline and review by the american society of health-system pharmacists, the infectious diseases society of america, the pediatric infectious diseases society, and the society of infectious diseases pharmacists. Am J Health Syst Pharm. 2020;77(11):835-864. doi: 10.1093/ajhp/zxaa036. PMID: 32191793.
- Rosini JM, Laughner J, Levine BJ, Papas MA, Reinhardt JF, Jasani NB. A randomized trial of loading vancomycin in the emergency department. Ann Pharmacother. 2015;49(1):6-13. doi: 10.1177/1060028014556813. PMID: 25358330.
Safety and Efficacy of Clevidipine for Acute Blood Pressure Control
Background
Rapid and precise control of blood pressure is vital for patients with a hypertensive emergency or an acute stroke. Commonly, nicardipine is utilized in these situations, with nitroprusside being a less appealing alternative. The most recent AHA/ASA Acute Ischemic Stroke Guidelines, updated in 2019, also recommend clevidipine as a first-line antihypertensive option [1]. Clevidipine is a dihydropyridine calcium channel blockers, similar in mechanism to nicardipine and amlodipine. The main advantage of clevidipine over nicardipine is related to its pharmacokinetics (Table 1). Given its shorter half-life of elimination, clevidipine can be titrated every 1-2 minutes. Additionally, if hypotension does occur, stopping the clevidipine infusion allows blood pressure to rebound quickly.
| Medication | Onset | Duration | Half-Life |
|---|---|---|---|
| Clevidipine | 2-4 mins | 5-15 mins | 1-15 mins |
| Nicardipine | 10-20 mins | 1-2 hours | 2-4 hours |
| Nitroprusside | 1-2 mins | 1-10 mins | 2 mins |
Table 1: Pharmacokinetics of Common Antihypertensive Infusions [Micromedex; Lexicomp]
Evidence
Most studies demonstrate equivalent outcomes between clevidipine and other agents (e.g., nicardipine, nitroprusside, nitroglycerin) [2-5]. The ECLIPSE trial is the largest to assess the safety and efficacy of clevidipine [6]. The authors randomized cardiac surgery patients to clevidipine, nicardipine, nitroprusside, or nitroglycerin and found no difference in the incidence of myocardial infarction, stroke, or renal dysfunction. They noted that mortality was higher in patients receiving nitroprusside vs clevidipine, but equivalent compared to the the other medications. Additionally, clevidipine treated patients had significantly fewer excursions outside the prespecified blood pressure range than patients treated with any of the other agents.
Safety
Clevidipine is formulated in a 20% lipid emulsion and packaged in a glass vial. This causes clevidipine to appear similar to propofol, which could lead to safety issues. Also, care should be taken when using both clevidipine and propofol concomitantly, especially at high doses, as both provide clinically significant amounts of lipids, so triglycerides should be monitored.
Bottom Line
Clevidipine is a safe and effective antihypertensive to use in patients that require rapid and strict blood pressure control, specifically in patients with an aortic dissection or an acute ischemic/hemorrhagic stroke.
Want to learn more about EM Pharmacology?
Read other articles in the EM Pharm Pearls Series and find previous pearls on the PharmERToxguy site.
References
- Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the american heart association/american stroke association. Stroke. 2019;50(12):e344-e418. doi: 10.1161/STR.0000000000000211. PMID: 31662037.
- Allison TA, Bowman S, Gulbis B, Hartman H, Schepcoff S, Lee K. Comparison of clevidipine and nicardipine for acute blood pressure reduction in patients with stroke. J Intensive Care Med. 2019;34(11-12):990-995. doi: 10.1177/0885066617724340. PMID: 28820038.
- Rosenfeldt Z, Conklen K, Jones B, Ferrill D, Deshpande M, Siddiqui FM. Comparison of nicardipine with clevidipine in the management of hypertension in acute cerebrovascular diseases. J Stroke Cerebrovasc Dis. 2018;27(8):2067-2073. doi: 10.1016/j.jstrokecerebrovasdis.2018.03.001. PMID: 29627171.
- Ulici A, Jancik J, Lam TS, Reidt S, Calcaterra D, Cole JB. Clevidipine versus sodium nitroprusside in acute aortic dissection: A retrospective chart review. Am J Emerg Med. 2017;35(10):1514-1518. doi: 10.1016/j.ajem.2017.06.030. PMID: 28669696.
- Brehaut SS, Roche AM. Abstract W P65: Clevidipine Outperforms Other Agents in Emergent Acute Hypertension Treatment in Ischemic Stroke Pre-rt-PA. 2015;46:AWP65. doi: 10.1161/str.46.suppl_1.wp65.
- Aronson S, Dyke CM, Stierer KA, et al. The ECLIPSE trials: comparative studies of clevidipine to nitroglycerin, sodium nitroprusside, and nicardipine for acute hypertension treatment in cardiac surgery patients. Anesth Analg. 2008;107(4):1110-1121. doi:10.1213/ane.0b013e31818240db. PMID: 18806012.
Droperidol for Agitation in Older Adults in the Emergency Department
Droperidol is safe and effective for the treatment of severely agitated patients in the ED [1-3]. But what about its use for agitation in elderly patients specifically?
Droperidol Efficacy
Two Australian studies evaluated droperidol in more than 200 older adults (≥ 65 years old) in the prehospital and ED settings [4,5]. Both studies found droperidol to be effective in elderly patients with acute behavioral disturbances. The median time to sedation was ~20-30 minutes with doses ranging from 2.5-10 mg (Table 1).
| Characteristic | Page, et al (n=162) | Calver, et al (n=47) |
|---|---|---|
| Median Age | 78 years | 81 years |
| Initial Droperidol IM Dose | 5 mg | 10 mg (n=30) 5 mg (n=15) 2.5 mg (n=2) |
| Median Time to Sedation | 19 mins | 10 mg: 30 mins 5 mg: 21 mins 2.5 mg: NA |
| Patients Sedated with ≤ 10 mg Droperidol | 144 (89%) | 34 (72%) |
Table 1: Efficacy of droperidol in older adults
Droperidol Safety
Additionally, each study broke down each time a patient experienced an adverse event (Table 2). Overall, these adverse events were uncommon (4.5%), mild in nature, and resolved spontaneously or with minor interventions. No patients developed Torsades de Pointes.
| Study | Age/Sex | Droperidol Dose | Adverse Events | Management | Time Post-Droperidol |
|---|---|---|---|---|---|
| Page, et al (n=162) | 76 yo Male | 5 mg | SBP <90 (88/54) | Spontaneous Resolution | – |
| 87 yo Female | 10 mg | SBP <90 (80/46) | Spontaneous Resolution | – | |
| 79 yo Female | 5 mg | SBP <90 (83/48) O2 sat <90% (80%) | Supplemental Oxygen 500 mL IV Fluid | – | |
| 82 yo Male | 5 mg | RR <12 (RR 10) | Spontaneous Resolution | – | |
| 86 yo Male | 5 mg | O2 sat <90% (88%) | Supplemental Oxygen | – | |
| Calver, et al (n=49) | 75 yo Male | 10 mg | SBP <90 | – | 30 mins |
| 68 yo Female | 10 mg | SBP <90 | – | 5 mins | |
| 73 yo Male | 10 mg | Airway Obstruction | – | 100 mins | |
| 87 yo Female | 2.5 mg | Oversedation | – | 480 mins |
Table 2: Safety of droperidol in older adults
Bottom Line
Taking the above points into account, droperidol appears to be both effective and safe in agitated adults ≥ 65 years of age for the treatment of agitation. The study authors recommend starting with 5 mg and repeating, if necessary, rather than initially using a dose of 10 mg.
Want to learn more about EM Pharmacology?
Read other articles in the EM Pharm Pearls Series and find previous pearls on the PharmERToxguy site.
References
- Perkins, J., Ho, J. D., Vilke, G. M., & DeMers, G. (2015). American academy of emergency medicine position statement: Safety of droperidol use in the emergency department. The Journal of Emergency Medicine, 49(1), 91–97. doi: 10.1016/j.jemermed.2014.12.024. PMID: 25837231.
- PharmERToxGuy. Onset of IM Medications for Severe Agitation. Posted Dec 12, 2019.
- PharmERToxGuy. QTc Prolongation and Torsades de Pointes with Droperidol in the Emergency Department. Posted Aug 30, 2020.
- Calver, L., & Isbister, G. K. (2013). Parenteral sedation of elderly patients with acute behavioral disturbance in the ED. The American Journal of Emergency Medicine, 31(6), 970–973. doi: 10.1016/j.ajem.2013.03.026. PMID: 23685060.
- Page, C. B., Parker, L. E., Rashford, S. J., Kulawickrama, S., Isoardi, K. Z., & Isbister, G. K. (2020). Prospective study of the safety and effectiveness of droperidol in elderly patients for pre-hospital acute behavioural disturbance. Emergency Medicine Australasia: EMA, 32(5), 731–736. doi: 10.1111/1742-6723.13496. PMID: 32216048.
Is Lactated Ringer’s Solution Safe for Hyperkalemia Patients?
Background
There are three primary fluids used for resuscitation, each contains varying amounts of potassium per liter (Table 1):
- 0.9% Sodium Chloride (normal saline)
- Lactated Ringer’s solution
- Plasma-Lyte A
Additionally, these fluids contain markedly different amounts of other electrolytes, some of which directly influence their pH (Table 1).
| Solution | Na* | Cl* | K* | Ca* | Lactate* | Acetate* | Osmolarity^ | pH |
|---|---|---|---|---|---|---|---|---|
| Sodium Chloride 0.9% (normal saline) | 154 | 154 | – | – | – | – | 308 | 5.5 |
| Lactated Ringer’s | 130 | 109 | 4 | 2.7 | 28 | – | 273 | 6.5 |
| Plasma-Lyte A | 140 | 98 | 5 | – | 27 | 294 | 7.4 | |
| Blood | 135-145 | 96-106 | 3.5-5 | 8.5-10.5 | 0-1 | NA | 275-295 | 7.35-7.45 |
Table 1: Characteristics of IV fluids vs blood [1-3] (* = mEq/L; ^ = mOsmol/L); note: this is not an exhaustive list of fluid contents
A common question is if the balanced fluids containing potassium (Lactated Ringer’s and Plasma-Lyte A) are safe to use in hyperkalemia patients. The answer is YES! Despite containing potassium, these fluids will still decrease the serum potassium level of a hyperkalemic patient. This is because the potassium concentration in these fluids is lower relative to the patient’s serum potassium level and dramatically lower than the patient’s intracellular potassium concentration.
Evidence
A secondary analysis of the SMART trial did not find a difference in severe hyperkalemia (K ≥7 mEq/L) in hyperkalemic patients that received a balanced fluid (8.5%) vs those that received normal saline (14%) (p=0.24) [4]. The authors concluded that:
Our results suggest that the acid-base effects of isotonic crystalloids are more important for potassium homeostasis than the relatively small amount of potassium in these fluids.
A breakdown of the SMART Trial secondary analysis by Journal Feed summarizes other major findings and concludes, “It’s reasonable to choose LR to treat hyperkalemia over NS.” Lastly, Dr. Josh Farkas provides a succinct summary of this topic in a 2014 EMCrit/Pulmcrit post which is helpful in understanding the interplay between fluid balance and the different replacement options. Additionally, he discusses the potential for normal saline to cause a non-anion gap metabolic acidosis thereby leading to increased serum potassium levels.
Bottom Line
Balanced fluids (Lactated Ringer’s and Plasma-Lyte A) containing potassium can safely be used in patients with hyperkalemia. Given their more neutral pH, they may be preferred over normal saline in some patients.
Want to learn more about EM Pharmacology?
Read other articles in the EM Pharm Pearls Series and find previous pearls on the PharmERToxguy site.
References
- Sodium Chloride Injection. Package Insert. Baxter Healthcare Corporation; 2013.
- Lactated Ringers Injection. Package Insert. Baxter Healthcare Corporation; 2019.
- Plasma-Lyte A Injection. Package Insert. Baxter Healthcare Corporation; 2019.
- Toporek, A. H., Semler, M. W., Self, W. H., Bernard, G. R., Wang, L., Siew, E. D., Stollings, J. L., Wanderer, J. P., Rice, T. W., Casey, J. D., & SMART Investigators and the Pragmatic Critical Care Research Group. (2021). Balanced crystalloids versus saline in critically ill adults with hyperkalemia or acute kidney injury: Secondary analysis of a clinical trial. American Journal of Respiratory and Critical Care Medicine. doi: 10.1164/rccm.202011-4122LE. PMID: 33503391.
ACMT Toxicology Visual Pearls – In “Spore” Taste
A 15-year-old male presents symptomatic several hours after inhaling spores of this mushroom as a home remedy for epistaxis. What is the presentation and pathophysiology of the toxic syndrome associated with this mushroom?
For a video of this mushroom in action: https://youtu.be/G_DXTlvvsco
- Dyspnea and cough from hypersensitivity alveolitis
- Flushing, nausea and vomiting from acetaldehyde accumulation
- Nausea, vomiting and hepatoxicity from RNA synthetase inhibition
- Seizures from reduced GABA production in the central nervous system