This meta analysis of studies looking at thrombolytics and prostaglandins in treating significant frost bite offers some insight into the possibilities these therapeutics offer. Unfortunately, the studies available are not high quality and most are case reports.
“Our results suggest that thrombolysis or intravenous iloprost is effective when administered promptly to treat severe frostbite. For grade 3–4 frostbite the Wilderness Medical Society frostbite guidelines recommend the use of intravenous iloprost within 48 h of injury, and thrombolysis within 24 h of injury. The Helsinki protocol recommends the use of tPA for patients with grade 3–4 frostbite presenting within 48 h of injury with angiographic evidence of thrombosis."
“Iloprost is a synthetic prostaglandin I2 that has been used to treat frostbite . Like other prostacyclins, it inhibits platelet aggregation and promotes vasodilation. Iloprost may stimulate the release of endogenous tissue plasminogen activator or counteract its inhibitory effects [35]. Iloprost reduces vasoconstriction induced by thromboxane A2 , and may reduce oxidative stress from free radicals, moderating reperfusion injury [37, 38]. The effect on platelet aggregation may be reversed within two hours), but prostacyclin effects may disrupt the vicious cycle of activated platelets and leukocytes that damages endothelium .”
More research in this area is needed. Transfer to a center with these capabilities seems worth a discussion in the case of severe frostbite.
Background
Treatment of acute agitation often involves combining antipsychotics and benzodiazepines. Injectable olanzapine, a second-generation antipsychotic, uniquely carries a warning against concomitant use with parenteral benzodiazepines. The olanzapine prescribing information states that “concomitant administration of intramuscular (IM) olanzapine and parenteral benzodiazepines is not recommended due to the potential for excessive sedation and cardiorespiratory compromise”. The European Medicines Agency (similar to the United States FDA) cautions against use of the two within 60 minutes of each other using similar language.
The above warnings were based on a 2010 publication of 160 adverse event reports from a post-marketing database maintained by the drug manufacturer, and have resulted in many institutions prohibiting co-administration of IM olanzapine and parenteral benzodiazepines. The publication cited 29 fatal adverse events involving injectable olanzapine, concluding that caution should be exercised when using IM olanzapine and parenteral benzodiazepines simultaneously. However, 25 of the 29 patients received other sedating medications in addition to olanzapine and benzodiazepines, and the majority of fatalities were >12 hours after the last dose of olanzapine. Following this publication, a 2013 randomized controlled trial by Chan et al. found no difference in adverse event rates between patients receiving IV midazolam alone and patients receiving IV midazolam plus IV olanzapine for acute agitation.
This December 2024 study by Cole et al. aimed to re-evaluate the risks of cardiorespiratory compromise with concomitant injectable olanzapine and injectable benzodiazepine administration.
Study design
This was a single-center retrospective cohort study of 693 patients who received 2 parenteral doses of eligible sedating medications within 60 minutes of each other. A total of 549 patients received 2 doses of olanzapine, and 144 received olanzapine and a benzodiazepine (midazolam, lorazepam, or diazepam). To avoid cohorts with a higher baseline risk of sedation, patients who received other sedating medications and patients who received more than 2 doses of olanzapine or 1 dose of a benzodiazepine were excluded.
Patient Population
Results
*One death during hospitalization was due to missed occlusion myocardial infarction
Study Critique:
Key Takeaways
A recent review article highlighted the adverse effects that emergency physicians should know of with the novel antineoplastic agents. The adverse effects and the associated agents are briefly summarized from the article in the table below. A link to the full article is below.
Link to article: Antibody-Drug Conjugates: The Toxicities and Adverse Effects That Emergency Physicians Must Know - Annals of Emergency Medicine
Background:
Epinephrine administration is a critical component of treating severe allergic reactions, and delayed administration is associated with increased morbidity and mortality. Epinephrine auto-injectors are the current standard of care and allow for rapid administration in all care settings, but compliance issues can limit their use. The most common reason patient’s site for failure to administer or delayed administration of auto-injectors is needle phobia (particularly with pediatric patients). This has led to interest in developing needle-free epinephrine delivery devices that are easy to administer.
New Drug Approval:
This August, the FDA approved an epinephrine nasal spray (brand name: Neffy) for use as emergency treatment for Type 1 allergic reactions, including life-threatening anaphylaxis. The approval was based on four studies, including 175 total patients, comparing epinephrine 2 mg nasal spray with an epinephrine 0.3 mg intramuscular injection in healthy adults and children. These studies showed similar blood concentrations of epinephrine between treatment arms through 60 minutes after administration. In addition, both treatment arms showed similar elevations in heart rate and systolic blood pressure.
Bottom Line:
Epinephrine nasal spray is a newly approved option for the treatment of severe allergic reactions and anaphylaxis. While this approval was based on studies in healthy adults and children who did not currently have anaphylaxis, this medication may be worth considering for patients who have issues or concerns about using an injectable device to administer epinephrine.
The benefits of calcium treatment for hyperkalemia have historically been attributed to “membrane stabilization,” as it has been hypothesized to restore cardiac resting membrane potential. However, the true mechanism by which calcium improves cardiac function in this setting remains unclear. This has led to inconsistencies in the clinical threshold for treating hyperkalemia with calcium.
Piktel et al. recently conducted an experimental study investigating the adverse electrophysiologic effects of hyperkalemia and therapeutic effects of calcium treatment in isolated canine myocytes using ex vivo tissue and in vivo cellular techniques.
Key study findings:
Effects of hyperkalemia:
Effects of calcium treatment in the setting of hyperkalemia:
Limitation:
Bottom line: Findings of this study suggest that calcium's beneficial effects in hyperkalemia are not attributed to “membrane stabilization,” but rather to restoration of conduction velocity through L-type calcium channels and subsequent narrowing of the QRS complex. This supports calcium treatment in hyperkalemia when the ECG shows conduction slowing and QRS widening.
At our institution we have developed a guideline for the use of hypertonic saline in hyponatremia.
Administration of 3% sodium chloride for acute or symptomatic hyponatremia
Acute hyponatremia with severe symptoms
Acute hyponatremia with moderate symptoms
Hyponatremia Fluid Rate Calculations (**Be Careful with Online Calculators**)
FYI: 3% Sodium Chloride (1.95 mL/mEq; 513 mEq/1 L); 0.9% Sodium Chloride (6.5 mL/mEq; 154 mEq/1 L)
Equations for Calculations
***See Visual Diagnosis for an Example with Calculations***
Two recommendations from the recent GRACE 4 publication in Academic Emergency Medicine to consider:
1. Use phenobarbital along with benzodiazepines in patients with moderate to severe alcohol withdrawal. The evidence isn’t robust but is positive when compared to benzos alone.
2. Adults with alcohol use disorder can benefit from anti-craving medications such as naloxone and gabapentin at time of discharge.
A panel comprised of 21 participants selected by four clinical toxicology societies (America’s Poison Centers, American Academy of Clinical Toxicology, American College of Medical Toxicology, and Canadian Association of Poison Control Centers) sought to develop consensus guidelines for management of acetaminophen poisoning in the US and Canada. Highlights from this framework include:
Acetylcysteine Stopping Criteria
A common misconception is that acetylcysteine is administered for 21 hours then discontinued. The consensus statement codifies the practice of reassessing the patient at the end of the acetylcysteine infusion and only stopping acetylcysteine if all of the following criteria are met:
Ingestion of Extended-Release Acetaminophen Products
Extended release acetaminophen products are available on the US market. Management is largely the same as for instant release acetaminophen except for several exceptions:
Management of Repeated Supratherapeutic Acetaminophen Ingestion
When a patient presents following repeated acetaminophen ingestions over a period of greater than 24 hours the Matthew-Romack nomogram is no longer applicable for guiding decisions regarding treatment with acetylcysteine. The consensus statement recommends initiating treatment in this scenario if the patient’s acetaminophen concentration is > 20 mcg/mL or if patient’s AST/ALT are abnormal.
Final Thoughts:
These guidelines will function as a useful reference and officially codify a general framework with evidence-based recommendations for the management of acetaminophen poisoning. As always, a poison center or clinical toxicologist should be consulted for any complicated or serious acetaminophen poisoning.
Myasthenia gravis (MG) is an autoimmune neuromuscular disorder that affects an estimated 14 to 20 patients per 100,000 in the United States. Most patients with MG have autoantibodies against acetylcholine receptors (AChRs), which disrupt neuromuscular transmission through downregulation, destruction, blocking of AChRs or disrupting receptors in the postsynaptic membrane.
Several medications may worsen MG or precipitate myasthenic crisis, however, incidence is difficult to describe as literature is largely limited to case reports and there is often presence of other confounding factors. There are two proposed mechanisms for medications to cause or exacerbate MG:
Several medications commonly used in the emergency department are known to impair neuromuscular transmission and may induce or worsen MG. The following medications should be avoided, or used with extreme caution in patients with MG*:
*This list contains several common medications utilized in the emergency department, but is not an all-inclusive list of medications that may exacerbate MG. Please refer to the reference section for additional information.
Naloxone is given frequently in the emergency department to improve the respiratory rate in patients with suspected or known opioid ingestion. In order to minimize the risk of severe opioid withdrawal (nausea, vomiting, diarrhea, anxiety, piloerection, sweating, agitation, etc.), consider diluting naloxone and administering small aliquots of 0.04-0.08mg at a time. This requires IV access and a patient with a present, but low respiratory rate.
Dilution instructions:
Supplies:
Instructions:
Administer 1 -2 mL (0.04 – 0.08 mg) naloxone every 2 minutes and assess response.
Don't forget to prescribe/give naloxone upon discharge from the emergency department.
MYTH: Bactrim cannot be used as monotherapy for nonpurulent skin and soft tissue infections.
Not True!
Organisms of concern: Streptococcus spp.
Here’s why:
TRUTH: Bactrim CAN be used as monotherapy for nonpurulent skin and soft tissue infections.
Prepared by Rianna Fedora, PharmD on 2/26/24
Empiric antimicrobial treatment for necrotizing soft tissue infections (NSTIs) should include coverage of a wide range of pathogens including Staphylococcus spp, Streptococcus spp, anaerobic bacteria and gram negative bacteria. Treatment should also include an agent that suppresses toxin production by group A Streptococcus (GAS), with the Infectious Diseases Society of America (IDSA) guidelines recommending clindamycin plus penicillin for treatment of GAS causing necrotizing fasciitis and toxic shock syndrome. A typical empiric NSTI regimen would be vancomycin plus clindamycin plus piperacillin-tazobactam.
Linezolid is an appealing alternative to clindamycin and vancomycin, as it has anti-toxin effects via inhibition of exotoxin expression, potent in vitro activity against Streptococcus spp, activity against methicillin-resistant Staphylococcus aureus (MRSA), and potential for less adverse effects than clindamycin plus vancomycin. Several recent studies have looked at using linezolid in lieu of clindamycin plus vancomycin when treating NSTIs.
Published Studies:
Dorazio and colleagues published a retrospective single center study compared 62 matched pairs of patients who received linezolid vs. clindamycin plus vancomycin as part of their NSTI treatment.
Heil and colleagues published a retrospective single center cohort study examined patients who received either linezolid (n = 29) or clindamycin (n = 26) for treatment invasive soft tissue infection or necrotizing fasciitis with GAS isolated from blood and/or tissue.
Lehman and colleagues published a retrospective single center study compared patients who received linezolid (n = 21) versus clindamycin plus vancomycin (n = 28) in addition to gram-negative and anaerobic coverage for empiric treatment of NSTIs.
Bottom Line:
When added to an agent with good gram negative and anaerobic coverage (i.e. piperacillin-tazobactam), linezolid may be a more viable option for coverage of MRSA and GAS toxin production during empiric NSTI treatment when compared to clindamycin plus vancomycin. This is largely due to a more favorable side effect profile.
Nirmatrelvir-ritonavir (Paxlovid™) is a combination of two protease inhibitors used for the treatment of mild-moderate symptomatic COVID-19. Nirmatrelvir inhibits the SARS-CoV2 main protease, and ritonavir inhibits metabolism of nirmatrelvir, acting as a “booster” to increase nirmatrelvir concentrations.
The EPIC-HR trial, which included non-hospitalized adults with mild-moderate COVID-19 who were unvaccinated and at risk of progressing to severe disease, showed an 89% reduction in COVID-19-related hospitalization or 28-day all-cause mortality in patients treated with nirmatrelvir-ritonavir compared to placebo. The efficacy rates in this trial were similar to remdesivir (87% relative risk reduction), and greater than molnupiravir (31% relative risk reduction), two alternative agents used for treatment of mild-moderate COVID-19. However, these three agents have never been directly compared. Nirmatrelvir-ritonavir was initially approved by the FDA under Emergency Use Authorization (EUA), but is now fully FDA-approved as of May 2023.
Which patients benefit?
Drug-Drug Interactions:
Dosing:
Common side effects:
Bottom Line: Paxlovid is appropriate for patients with symptomatic mild-moderate COVID-19 with risk factors for progression to severe disease. Ask your pharmacist for assistance evaluating drug-drug interactions!
For the agitated geriatric patient, if verbal deescalation, distraction, and providing a safe quiet area do not work and you require chemical sedation use oral antipsychotics first. Follow this with IV or IM antipsychotics. Avoid benzodiazepines due to often worsening delirium or respiratory depression. For dosing, start low and go slow.
Bottom Line: Droperidol is an effective alternative to haloperidol in the treatment of gastroparesis although most patients will also receive prokinetic agents as well such as metoclopramide. It may also have some analgesic benefit.
Prior studies have demonstrated the efficacy and safety of haloperidol in the management of gastroparesis. A recent retrospective study was conducted to assess the impact of droperidol as it is an effective antiemetic similar to haloperidol.
This study enrolled 233 patients. Visits were matched with their most recent ED visit > 7 prior where droperidol was not administered.
Most patients were female, 51% African American, and the median age was 40. Doses ranged from 0.625 mg – 2.5 mg with the most common dose being 1.25 mg.
Results:
Background: It is estimated that nearly 6% of U.S. adults and children report having a food allergy.1,2 Epinephrine autoinjectors are used to provide life-saving pre-hospital treatment for patients experiencing anaphylaxis in the community, but can have serious consequences if administered incorrectly. Accidental finger-stick injuries with epinephrine auto-injector can result in significant pain and ischemia due to vasoconstriction and decreased blood flow to the digit. Treatments for digital epinephrine injection include supportive care, topical vasodilators, and injectable vasodilators.3
Supportive care3,4:
DOACs (dabigatran*, apixaban, rivaroxaban) each have different dosing strategies based on indication and patient characteristics. While there is no official term for the doses, the higher initial doses for apixaban (10 mg BID for 7 days) and rivaroxaban (15 mg BID for 21 days) for the treatment of venous thromboembolism (VTE) are commonly referred to as “loading doses.” However, the term “loading dose” is actually a misnomer.
Loading doses are used to reach therapeutic drug levels quicker with medications such as vancomycin and phenytoin/fosphenytoin. However, this is not the purpose of the higher initial doses of apixaban and rivaroxaban. The purpose of the higher doses is to provide increased levels of anticoagulation during the acute phase of VTE when patients are hypercoagulable. For this reason, VTE and heparin-induced thrombocytopenia are the only indications where a higher dose is used initially, all other indications start with the standard dose. The difference in duration of these higher doses between apixaban (7 days) and rivaroxaban (21 days) are due to the durations used in trials by the drug company, versus any pharmacokinetic reasons.
To apply this concept:
Apixaban/Rivaroxaban: For the treatment of VTE, a higher dose is only required for the initial 7- (apixaban) or 21-day period (rivaroxaban). After this period, if there is any interruption in therapy, the standard dose can be restarted because therapeutic levels are rapidly achieved and higher doses are not needed outside of the acute phase.
One caveat to this would be if the patient developed a new VTE while therapy is interrupted, in which case another period of the higher dosing could be considered.
*Remember: Dabigatran cannot be used for initial treatment of VTE and must be started only after at least 5 days of a parenteral anticoagulant. (Dabigatran and the parenteral anticoagulant should not be overlapped).
ACLS guidelines state that thrombolytics may be considered for suspected pulmonary embolism during cardiac arrest. There is limited data supporting the recommendation; however, it is noted that the benefits likely outweigh the risks. There is also no consensus on the appropriate thrombolytic timing, drug, or dose.
Our institution recently implemented the use of tenecteplase for acute ischemic stroke, ST-elevation myocardial infarction (STEMI), and pulmonary embolism (PE). When using tenecteplase for suspected PE during cardiac arrest, we use the same weight-based dose used for STEMIs. We include a label on the outside of the tenecteplase box that lists all the doses for the various indications.
Tenecteplase Dose
<60 kg: 30 mg
≥60 to <70 kg: 35 mg
≥70 to <80 kg: 40 mg
≥80 to <90 kg: 45 mg
≥90 kg: 50 mg
The tenecteplase dose is administered as an IV bolus over 5 seconds.
There is also limited data for the duration of CPR after thrombolytic administration, with no recommendations being made in most literature. Our current institutional guidelines recommend to consider continuing CPR for 60-90 minutes before resuscitation efforts are terminated. The only guideline that makes any mention of duration of CPR is the European Resuscitation Council Guidelines 2021, which makes the same recommendation.
Citrate is an anticoagulant added to blood products to maintain stability for storage. With the administration of large volumes of blood products, citrate binds to ionized calcium, which can cause hypocalcemia. Evidence for specific calcium administration during massive transfusion protocols is limited; however, a proposed strategy has been to administer calcium gluconate 2 grams for every 2-4 units of red blood cells.
Robinson, et al. performed a retrospective analysis attempting to determine the optimal Citrate:Ca ratio (a novel ratio created for this study) to reduce 30-day mortality. They did not find any differences in mortality; however, they found a Citrate:Ca ratio of 2-3 produced a normalized ionized calcium level with 24 hours of a massive transfusion protocol.
Based on their calculations, this would equate to supplementing 1 g of calcium gluconate for every 3 units of red blood cells given.
***Reminder: Based on the amount of elemental calcium in each gram of calcium gluconate (4.7 mEq) and calcium chloride (13.6 mEq); 3 g calcium gluconate=1 g calcium chloride.***
Bottom Line: Supplementing with calcium gluconate 1 g for every 3 units of red blood cells should be sufficient to maintain normal ionized calcium levels after a massive transfusion protocol.
Nitroglycerin easily migrates into polyvinyl chloride (PVC), a plastic commonly used in intravenous tubing due to its flexibility and low cost. A slow rate of flow and long tubing length increase the loss of nitroglycerin. While using less absorptive tubing (i.e. polyethylene or polypropylene) when administering nitroglycerin is recommended, most published clinical studies looking at nitroglycerin have used PVC tubing.
A 1989 study compared nitroglycerin delivery through PVC tubing and low sorbing tubing at various concentrations and flow rates.1 Samples were obtained from the nitroglycerin bottle and the distal end of the tubing at several time points.
A 2018 study enrolled 8 volunteers to receive nitroglycerin infusions through PVC tubing and low sorbing polyolefin tubing.2
Bottom Line: Most studies evaluating nitroglycerin use in various clinical scenarios have used PVC tubing. Doses based on use with PVC tubing may be too high when using less absorptive tubing. Employing more conservative dosing strategies when using low sorbing tubing can help mitigate the risk of adverse effects (i.e. hypotension, headache).
