Series Editor: Mike O’Brien, PharmD
Quick evidence-based pearls on all things pharmacology and pharmacy-related in Emergency Medicine
Series Editor: Mike O’Brien, PharmD
Quick evidence-based pearls on all things pharmacology and pharmacy-related in Emergency Medicine
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 . However, reports of seizures, particularly in patients with bulimia, caused its temporary removal from the market . It was reintroduced a few years later with a max dose of 450 mg/day . 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].
A study of 256 patients from the Toxicology Investigators Consortium (ToxIC) Registry identified three factors associated with seizure development after bupropion overdose [6, 7].
Agitation and tremors are more common in patients who develop seizures with bupropion compared to those who do not . Additionally, presence of tachycardia (heart rate >100 bpm) has a sensitivity of 91% and a negative predictive value of 93% for development of seizures .
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 .
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 . 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 . 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).
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).
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 . 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.
|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]
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 . 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.
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.
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.
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?
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
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%)
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
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.
There are three primary fluids used for resuscitation, each contains varying amounts of potassium per liter (Table 1):
Additionally, these fluids contain markedly different amounts of other electrolytes, some of which directly influence their pH (Table 1).
|Sodium Chloride 0.9% (normal saline)||154||154||–||–||–||–||308||5.5|
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.
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) . 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.
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.
A previous EM Pharm Pearl focused on the adverse events associated with the use of IV olanzapine for agitation. This pearl addresses concerns around using parenteral (IV or IM) olanzapine with parenteral benzodiazepines.
Olanzapine has two FDA boxed warnings, one for increased mortality when used long-term in older adults with dementia-related psychosis and another pertaining to adverse effects of extended release IM olanzapine. However, there exists a potential risk of excess sedation and respiratory depression when IM/IV olanzapine is administered with parenteral benzodiazepines for agitation. The European Medicines Agency recommends separating the administration of IM/IV olanzapine and parenteral benzodiazepines by at least 60 minutes. The FDA does not have a specific recommendation regarding separation of the 2 medications, but cautions against co-administration citing a lack of data. Currently, IM olanzapine is the only second generation antipsychotic with a precaution listed in its FDA prescribing information. This advisory is the result of 160 post-marketing adverse events, including 29 fatalities, associated with IM olanzapine .
When the above cases submitted to the FDA are thoroughly investigated, the problem appears to be related to polypharmacy rather than an olanzapine/benzodiazepines alone [2, 3]. This FOAMcast podcast provides an excellent summary of the data (Table 1). Additionally, the timing of fatalities after the last dose of olanzapine is prolonged in many cases (Table 2) and many of the causes of death are unattributable to olanzapine . Several ED studies have used IV/IM olanzapine in combination with parenteral benzodiazepines to treat agitated patients without an increased signal of airway compromise [4-6].
|Table 1: Summary of Fatalities Associated with Olanzapine (n=29)|
|Olanzapine Alone||Olanzapine |
+ Other Medications
|Table 2: Timing of Fatalities Following Last Olanzapine Dose (n=29)|
|≤ 1 hour||1-12 hours||12-24 hours||> 24 hours||Unknown|
Separating IV/IM olanzapine from parenteral benzodiazepines by 60 minutes is likely a safe practice, if co-administration of these medications is necessary or desired to treat agitated patients. Patients with ethanol on board are at a higher risk of adverse events [7, 8]. Monitoring should be commensurate with the patient situation and medication(s) chosen.
The ability to safely and effectively sedate agitated patients in the emergency department (ED) is paramount to provide prompt medical care and protect ED staff. Intravenous (IV) antipsychotics are frequently utilized, instead of other routes, given their more rapid onset of action. Similar to haloperidol, olanzapine can be used safely via the IV route despite both being FDA-approved for intramuscular (IM) administration only.
The table below summarizes the primary data evaluating IV olanzapine in the ED [1-5]. While IV olanzapine is a safe option for some agitated patients, some of these studies report a higher risk of respiratory complications or respiratory depression with the IV route compared to IM olanzapine or other IV treatment options. An Annals of Emergency Medicine commentary argues IV olanzapine might not be necessary for non-emergent cases of agitation or non-agitation indications and the IM route may suffice .
|Study||Olanzapine Dose||Adverse Event Rate – Olanzapine||Adverse Event Rate – Comparators||Notes|
|10 mg||8.3%|| IV Droperidol: 10.7%|
Placebo: 15.7 %
|1.25-20 mg||Minor: 11.4%|
|N/A||Adverse events were respiratory complications; 7 patients intubated|
|5-10 mg||20%||IV Midazolam + Droperidol: 22%|
IV Droperidol: 16.2%
|10 mg||21.4%|| IV Midazolam + Droperidol: 20.6%|
IV Droperidol: 6.7%
|1.25-20 mg||3.7%||IM olanzapine: 2.0%||Adverse events were respiratory depression|
Table: Adverse Events from IV Olanzapine for Agitation in the ED [1-5]
Treatment of agitated patients in the ED can be complex. Respiratory complications after medication administration may be related directly to the medication(s), the reduction of sympathetic drive, or both. All agitated patients should be monitored after receiving medications for sedation. The exact time course of this monitoring is not known and likely medication specific. Patients at high risk of neurologic, cardiovascular, or hemodynamic compromise should be monitored even more closely. This could include an ECG, pulse oxygenation, vital signs, and direct observation, as appropriate based on the patient-specific factors.
Medication selection for treating agitation in the ED requires thoughtful consideration of factors such as onset time (read more about “Onset of IM Medications for Severe Agitation“), duration, adverse events, and patient-specific variables. IV olanzapine is an option and monitoring should be commensurate with the situation and medication(s) chosen.
For further information, please read this in-depth literature review of IV olanzapine for the management agitation .