UMEM Educational Pearls - Pharmacology & Therapeutics

Category: Pharmacology & Therapeutics

Title: Naloxone: Low Dose, Quick Reassessment

Keywords: naloxone, opioid (PubMed Search)

Posted: 4/11/2024 by Ashley Martinelli (Updated: 4/24/2024)
Click here to contact Ashley Martinelli

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:

  • 10 mL vial of 0.9% sodium chloride
  • 1 vial of 0.4 mg/mL naloxone
  • 1 empty 10 mL syringe/needle

Instructions:

  1. Withdraw 9 mL of 0.9% sodium chloride into an empty syringe. 
  2. Add 1 mL of naloxone 0.4 mg/mL
  3. Label syringe as: Naloxone 0.04 mg/mL

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:

  • Sulfamethoxazole-Trimethoprim (Bactrim) disrupts folic acid synthesis & utilization.
  • This prevents the biosynthesis of the nucleic acid thymidine by bacteria and causes them to die. 
  • Some species of Strep, including S. pyogenes, are able to utilize exogenous sources of thymidine to continue their life cycle. 
  • Guess what? The laboratory media that was originally used to test Strep spp. susceptibility to Bactrim contained thymidine - therefore the bacteria were able to use it and did not die!
  • When tested using thymidine-depleted media, all 370 S. pyogenes isolates tested were highly susceptible to Bactrim!

TRUTH: Bactrim CAN be used as monotherapy for nonpurulent skin and soft tissue infections.

Prepared by Rianna Fedora, PharmD on 2/26/24

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Attachments

SMX-TMP Myth Buster Inservice-65f3561ae6df0.pdf (58 Kb)



Category: Pharmacology & Therapeutics

Title: Linezolid Versus Vancomycin Plus Clindamycin for Treatment of Necrotizing Soft Tissue Infections

Keywords: Necrotizing Fasciitis, Necrotizing Soft Tissue Infection, Skin and Soft Tissue Infection, clindamycin, linezolid, NSTI (PubMed Search)

Posted: 2/8/2024 by Matthew Poremba
Click here to contact Matthew Poremba

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.

  • Primary outcome was mortality at 30 days and secondary outcomes were the rates of C. difficile infection and rates of acute kidney injury (AKI). 
  • No statistically significant difference in any primary or secondary outcomes noted, although there was a trend towards more AKI with clindamycin plus vancomycin versus linezolid 
    • AKI rates: 9.68% in the clindamycin + vancomycin group vs 1.61% in the linezolid group; HR 6 [95% CI .73-276]

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.

  • There was no difference in any primary or secondary outcomes, which included inpatient mortality, duration of vasopressor requirement, hospital length of stay, rates adverse drug events and change in Sequential Organ Failure Assessment score from baseline through 72 hours of hospitalization.

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.

  • The primary outcome of duration of MRSA-active therapy was 2.9 days in the linezolid group versus 3.9 days in the vancomycin group (p = 0.04)
  • The only secondary outcome that reached statistical significance was new-onset AKI, with a rate of 38.1% in the vancomycin plus clindamycin group versus 0% in the linezolid group (0%)

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.

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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?

  • Mild – moderate COVID-19 symptoms
    • ED or outpatients
    • Hospitalized patients who are admitted for reasons other than COVID-19
  • Not requiring supplemental oxygen above baseline needs
  • Presenting within 5-7 days of symptom onset
  • Risk factor(s) for progression to severe disease
    • Age > 65
    • Comorbidities such as diabetes, chronic lung disease, asthma, malignancy, etc.
    • Immunocompromise

Drug-Drug Interactions:

  • Ritonavir strongly inhibits the CYP3A4 enzyme, which may significantly increase serum concentrations of medications metabolized by CYP3A4. Several common medications are metabolized by this enzyme and concomitant use may pose serious risk of toxicity.
  • In many cases, drug-drug interactions can be managed safely with close monitoring or dose adjustments. Some may require use of alternative COVID-19 therapies such as remdesivir or molnupiravir.

Dosing:

  • eGFR 60 mL/min or above: Nirmatrelvir 300 mg (2 tabs) + ritonavir 100 mg (1 tab) twice daily for 5 days
  • eGFR >30 - <60 mL/min: Nirmatrelvir 150 mg (1 tab) + ritonavir 100 mg (1 tab) twice daily for 5 days
  • eGFR <30 mL/min: Use is not recommended per the manufacturer, but retrospective studies have shown that reduced dosing is well-tolerated.

Common side effects:

  • Diarrhea (3%)
  • Altered sense of taste (5%)

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!

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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.

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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:

  • 46% of the droperidol visits received opioids compared to 60% when droperidol was not given (p=0.004)
  • Droperidol was noted to reduce pain scores from 9 (IQR 7-10) to 5 (IQR 0-8) (p=0.0001)
  • Droperidol visits were prescribed fewer antiemetic agents 60% vs 73% (p=0.0045)
  • There was no difference in the use of prokinetic agents (metoclopramide)
  • No difference in ED or hospital LOS or admission rates (~30%), cost, or adverse events

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Category: Pharmacology & Therapeutics

Title: A "Stick-y" Situation: Treatment of Epinephrine Autoinjector-Induced Digital Ischemia

Keywords: epinephrine, anaphylaxis, allergy, digital ischemia, phentolamine, nitroglycerin ointment, terbutaline (PubMed Search)

Posted: 10/12/2023 by Alicia Pycraft
Click here to contact Alicia Pycraft

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:

  • Warm compresses are preferred to increase local blood flow and enhance removal of the drug. Cold compresses may result in worsening ischemia. 
  • Apply for 15 minutes every 6 hours
 
Topical nitroglycerin3-6:
  • Increases production of nitric oxide which relaxes smooth muscles and causes vasodilation
  • Literature shows variable symptomatic improvement for adults and neonates, but safe use as an adjunct to injectable vasodilators or as monotherapy.
  • Apply a 1-inch strip of nitroglycerin 2% ointment over the affected area and repeat every 8 hours until symptoms resolve
  • Patients should be monitored for hypotension after application, as topical nitroglycerin is systemically absorbed.
 
Phentolamine4, 7-9:
  • Alpha-1 adrenergic antagonist that competitively blocks alpha-adrenergic receptors to produce brief antagonism of circulating epinephrine and norepinephrine. Phentolamine also promotes vasodilation and increases capillary blood flow. 
  • Evidence for use after accidental injection of epinephrine autoinjector is mostly described in case reports, but one study showed that phentolamine was more effective at vasodilation than either nitroglycerin or sodium nitroprusside for treatment of digital norepinephrine injection. In another study of epinephrine-injected patients, subjects reported normal fingertip sensation in an average of 120 minutes after injection of phentolamine compared to 549 minutes after injection of saline. It took an average of 85 minutes for the epinephrine-injected digits to return to normal color after phentolamine injection compared to an average of 320 minutes after injection with saline.
  • Preparation/application: Dilute 5 mg of phentolamine in 10 mL of 0.9% sodium chloride. Inject small amounts subcutaneously into the affected area.
 
Terbutaline6,10:
  • Beta-2 adrenergic agonist that causes vasodilation and attenuates the effect of alpha adrenoreceptor-mediated vasoconstriction.
  • Evidence shows that terbutaline has resulted in immediate and complete resolution of symptoms following accidental digital epinephrine injections if administered within 2 hours of the incident and it may be considered if phentolamine is not available.
  • Preparation/application: Dilute 1 mg of terbutaline with 1 mL of 0.9% sodium chloride and inject subcutaneously into the affected area.
  • May cause elevations in heart rate and blood pressure, as well as ECG changes. Terbutaline should be used cautiously in patients with cardiovascular disease.
 
Bottom line: Most cases of epinephrine autoinjector-induced digital ischemia can be conservatively managed with warm compresses and topical nitroglycerin, but phentolamine should be considered for patients with refractory pain or tissue ischemia. Terbutaline should be considered in the event of phentolamine shortage.

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Category: Pharmacology & Therapeutics

Title: DOAC "Loading Dose" = Misnomer

Keywords: DOAC, apixaban, rivaroxaban, loading dose (PubMed Search)

Posted: 9/14/2023 by Wesley Oliver (Updated: 4/24/2024)
Click here to contact Wesley Oliver

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).

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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.

 

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Category: Pharmacology & Therapeutics

Title: Optimal calcium repletion for massive transfusion protocol

Keywords: Calcium, Massive transfusion protocol, Citrate, Blood products (PubMed Search)

Posted: 7/13/2023 by Wesley Oliver (Updated: 4/24/2024)
Click here to contact Wesley Oliver

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.

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Category: Pharmacology & Therapeutics

Title: Effect of Administration Set on Nitroglycerin Infusion

Keywords: nitroglycerin, administration set, drug sorption, PVC tubing, polyethylene, SCAPE (PubMed Search)

Posted: 6/8/2023 by Matthew Poremba (Updated: 4/24/2024)
Click here to contact Matthew Poremba

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. 

  • An average of 39.7% (SD 12.7) of nitroglycerin was lost at the distal end of PVC tubing, while an average of 2.3% (SD 9.3) of nitroglycerin was lost with low sorbing tubing.

A 2018 study enrolled 8 volunteers to receive nitroglycerin infusions through PVC tubing and low sorbing polyolefin tubing.2 

  • The average max plasma concentration of nitroglycerin was 0.33 ng/ml (SD 0.19) in the PVC group, compared to 1.37 ng/ml (SD 0.89) with low sorbing tubing. 
  • This small study showed a trend towards greater lowering of mean arterial pressure from baseline with low sorbing tubing when compared to the PVC group, although this was not statistically significant.

 

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).

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Emergency contraception is highly effective at preventing unwanted pregnancies and has been on the market for 20+ years.

Levonogestrel (LNG) 1.5 mg PO x 1 dose  (OTC Available)

Ulipristal acetate (UPA) 30 mg PO x 1 dose (Requires RX)

Original studies with LNG was estimated to prevent up to 80% of expected pregnancies.  In the subsequent trials that brought UPA to the market and compared the two medications, LNG prevented 69% (95% CI, 46-82%) and 52.2% (95% CI, 25.1-69.5%).

While pregnancy rates are low with both options there is concern with patients of higher weight/BMI that the effectiveness of levonorgestrel decreases as weight rises. One large study of over 1700 patients specifically noted that a weight > 75 kg was associated with up to 6.5% pregnancy rate (95% CI 3.1-11.5) compared to 1.4% (95% CI 0.5-3.0) in patients weighing 65-75 kg.  Patients weighing > 85 kg had similarly high rates at 5.7% (95% CI 2.9-10.0).

The cost difference is minimal between products, especially when considering costs associated with treatment failures and subsequent need for care- the largest difference is with respect to access as LNG is OTC and UPA requires an RX.  Either can be administered in an ED setting as long as they are on formulary.

ACOG also recommends that ulipristal be utilized for it higher overall efficacy compared to levonorgestrel. 

Consider:

For patients above 75 kg, ulipristal can be used as first line emergency contraception for up to 5 days following unprotected intercourse.

Patients < 75 kg and < 72 hours following unprotected intercourse can use levonorgestrel or ulipristal as an appropriate emergency contraception method.

Patients < 75 kg and 72-120 hours following unprotected intercourse should use ulipristal due to its efficacy beyond 72 hours.

 

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Category: Pharmacology & Therapeutics

Title: Neuromuscular Blocker Dosing in Patients With Myasthenia Gravis

Keywords: Myasthenia gravis, Myasthenic crisis, neuromuscular blocker, paralytic, rocuronium, vecuronium, succinylcholine (PubMed Search)

Posted: 4/1/2023 by Matthew Poremba
Click here to contact Matthew Poremba

Myasthenia gravis is an autoimmune disease of the neuromuscular junction, most commonly due to antibodies attacking acetylcholine receptors in the postsynaptic membrane. Up to 30% of patients with myasthenia gravis will experience a myasthenic crisis during their disease course. If rapid sequence intubation is indicated, the unique characteristics of this patient population must be considered in the event use of a paralytic is necessary. All paralytic agents can be expected to last significantly longer, and an unpredictable response may be seen with depolarizing agents - therefore non-depolarizing agents are preferred in this population.

Non-Depolarizing Agents (Rocuronium, Vecuronium)

  • MG patients have increased sensitivity to non-depolarizing agents and require lower doses than typically used
  • It is reasonable to dose non-depolarizing agents at one-half the standard dose used. For example, rocuronium would be dosed at 0.5-0.6 mg/kg instead of the standard 1-1.2 mg/kg

Depolarizing Agents (Succinylcholine)

  • MG patients have decreased expression of normal acetylcholine receptors which are required for depolarizing agents to work effectively and require higher doses than typically used
  • Succinylcholine is typically dosed at 1.5-2.0 mg/kg (roughly double the dose used in other patient populations)

 

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Category: Pharmacology & Therapeutics

Title: Calcium may not prevent diltiazem-induced hypotension

Keywords: atrial fibrillation, atrial flutter, diltiazem, calcium (PubMed Search)

Posted: 3/3/2023 by Ashley Martinelli (Emailed: 3/4/2023) (Updated: 4/24/2024)
Click here to contact Ashley Martinelli

Non-dihydropyridine calcium channel blockers, verapamil and diltiazem, can induce hypotension when administered intravenously (IV) in approximately 4% of patients.  It has previously been taught that administering IV calcium before administering these medications may prevent the hypotension.  Previously, this theory was tested for verapamil and found success with reducing hypotension.  Only one study has been done exclusively with diltiazem and it found no benefit. 

In a new multicenter retrospective cohort study of adults in the ED, patients were randomized into two groups: those who received diltiazem alone and those who received calcium with diltiazem for atrial fibrillation/atrial flutter (AF/AFL) with a HR ≥ 120 bpm. Patients were excluded if they required electrocardioversion, had other agents prior to diltiazem, incomplete information, were pregnant or incarcerated. The primary outcome was change in SBP 60 minutes (+/-30 minutes) after diltiazem administration.

Baseline characteristics: 73 year old, equal male:female, predominantly white patients.  40% had new onset AF/AFL and the initial HR was 140 in both groups. There were 198 patients in the diltiazem group and 56 patients in the combination group.  Notably, patients in the combination group had a lower presenting SBP 109 (101-121) vs 123 (114-132) P<0.0001 which matches classical teaching for when to consider calcium use. Additionally, patients in the combination group received a lower diltiazem dose of 10mg vs 15mg in the monotherapy group p=0.004 with both group receiving doses lower than the standard 0.25 mg/kg dosing recommendation.

Outcomes:

  • Median change in SBP was not different between the monotherapy and combination therapy groups: (-2 mmHg vs -1.5 mmHg, p= 0.642)
  • There was no difference in:
    • Time to rate control (1.4 vs 1.8 hours, p= 0.141)
    • Time to sustained rate control (7.9 vs 7.7 hours, p=0.570)
    • Change in HR at 60 minutes: (-33 vs -34 bpm, p=0.428)
  • A subgroup analysis looking at timing of calcium (i.e. before or with diltiazem administration) also found no difference.


Take Home Point:

Administration of IV calcium may not be as beneficial as previously thought to prevent hypotension induced by diltiazem administration.  This particular study is confounded by the relatively low doses of diltiazem overall, but utilizing a lower dosing strategy in patients with low SBP is a reasonable safety strategy.

 

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Category: Pharmacology & Therapeutics

Title: C1-Esterase Inhibitor for ACE-Inhibitor Induced Angioedema

Keywords: Angioedema, ACE-inhibitor, C1-Esterase Inhibitor, ACEi, C1INH, Berinert (PubMed Search)

Posted: 2/3/2023 by Wesley Oliver (Emailed: 2/4/2023) (Updated: 2/4/2023)
Click here to contact Wesley Oliver

ACE-inhibitor (ACEi) induced angioedema is mediated by bradykinin and there are no proven medications for the treatment of this disease. Theoretically, a C1-esterase inhibitor (C1INH) could be beneficial; however, data has not demonstrated any efficacy for these agents.  

Strassen et al. recently published a double-blind, randomized, controlled, multicenter trial of 30 patients comparing C1NH (Brand Name: Berinert) to placebo. In addition to standard treatment, a dose of C1INH (Berinert) 20 IU/kg or placebo (0.95% NaCl) was administered intravenously.

The primary endpoint was the time to complete resolution of signs and symptoms of edema (TCER). When compared to placebo, the original primary analysis demonstrated that the placebo arm (15 hours) resolved faster than the C1INH arm (24 hours, p=0.046).

This study is further evidence against the use of C1INH for ACE-inhibitor induced angioedema. The primary focus in the treatment of ACEi induced angioedema should continue to be airway management.

For reference, at our institution we have both C1INH (Berinert) and icatibant on formulary and they are restricted to only being used for acute hereditary angioedema attacks and cannot be used for ACEi induced angioedema.

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Magnesium has been associated with function of serotonin and vascular tone regulation, both of which are mechanisms that implicate there may be a role in treatment of migraine. As this is a well-tolerated medication with a good safety profile, there is interest in utilizing this medication in the treatment of migraines. However, studies comparing magnesium to standard migraine treatments are lacking.

A recent single-center, double-blinded, randomized controlled trial compared magnesium, metoclopramide and prochlorperazine for treatment of migraine in the ED. Patients received either magnesium sulfate 2 grams, metoclopramide 10 mg or prochlorperazine 10 mg intravenously over 20 minutes. Adjunctive and rescue medications could be used at the providers discretion.

Pain was assessed with the 11-point Numeric Rating Scale at baseline and at several timepoints after completion of the infusion. Median change in pain score was found to be -3 in all groups at 30 minutes. Post-hoc analysis found magnesium to be non-inferior to prochlorperazine and metoclopramide at this time point. No difference in ED length of stay was found between groups. Adverse events were reported in 5% of patients receiving magnesium, 4.5% in patients receiving metoclopramide and 11.5% in prochlorperazine patients (p = 0.51). The most common adverse events were dizziness, akathisias, and anxiety.

 

Bottom Line: Magnesium can be used as an adjunctive agent in the treatment of migraines, and may also be considered as an alternative agent when other options such as prochlorperazine and metoclopramide are not appropriate. A reasonable dose would be 2 grams IV infused over 20 minutes. The team should follow-up 30-60 minutes after infusion to assess response to therapy.

 

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Category: Pharmacology & Therapeutics

Title: Let food be thy medicine

Keywords: dietary supplements, complementary nutritional products (PubMed Search)

Posted: 12/24/2022 by Brian Corwell, MD (Updated: 4/24/2024)
Click here to contact Brian Corwell, MD

Over half of U.S. adults in the United States consume dietary supplements. 

Study design:  A quality improvement study using data from the FDA’s Center for Drug Evaluation and Research, Tainted Products Marketed as Dietary Supplements

Dates:  2007 through 2016. 

Results:  Unapproved pharmaceutical ingredients were identified in 776 dietary supplements.

146 different dietary supplement companies were involved.

Most of these products were marketed for sexual enhancement (353 [45.5%]), weight loss (317 [40.9%]), or muscle building (92 [11.9%].

157 adulterated products (20.2%) contained more than 1 unapproved ingredient.

A 2015 NEJM study estimated that 23,000 ED visits per year are attributed to adverse effects associated with dietary supplements.

Estimated 2154 hospitalizations annually.

Frequently involve young adults between 20 and 34 years of age in addition to unsupervised children.

Excluding children, almost 66% of ED visits involve herbal or complementary nutritional products and 31.8% involved micronutrients.

Products for weight loss or increased energy were commonly implicated.

Finally, herbal and dietary supplements now account for 20% of cases of hepatotoxicity in the US.

The major implicated agents include anabolic steroids, green tea extract, and multi-ingredient nutritional supplements.

Anabolic steroids (marketed as bodybuilding supplements) typically induce a prolonged cholestatic, self-limiting liver injury.

Green tea extract and many other products, in contrast, tend to cause an acute hepatitis like injury.

 

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Sugammadex works by chelating non-depolarizing neuromuscular blocking agents (NMBA) such as rocuronium and vecuronium to reverse the effects of paralysis.  Dosing per package insert varies based on time from administration of the NMBA, and side effects, although rare, include severe bradycardia, hypotension, and asystole. While sugammadex is routinely used by our anesthesia colleagues, it is rarely utilized in the emergency department (ED) or intensive care unit (ICU) setting. 

A recent single-center study assessed 11 patients with either a traumatic brain injury (TBI) or intracranial hemorrhage (ICH) who received sugammadex for neurologic assessment in the ED or ICU.  The median dose was 240mg and the median time since last NMBA administration was 101 minutes.

In 6/11 patients, the neurosurgical plan changed and it affirmed a poor prognosis in 3/11 patients. In the ICU patients, sugammadex was associated with reduction in unnecessary tests.

All patients had a GCS of 3T prior to administration and 67% responded to sugammadex with a median increase to 8T (P=0.0156).  MAP reductions were common with a median of -8 mmHg.

Bottom Line:  Sugammadex can assist in determining a neurosurgical or clinical prognosis plan in patients with TBI and ICH.  Larger studies are needed in this patient population and caution should be used inpatients who are already hypotensive or bradycardic.  A reasonable dose, especially when given >1h from intubation would be 200mg.  The team should be available at administration to note changes in GCS.

 

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Category: Pharmacology & Therapeutics

Title: Beware of piperacillin-tazobactam dose reductions in septic shock

Keywords: sepsis, piperacillin-tazobactam (PubMed Search)

Posted: 9/29/2022 by Ashley Martinelli (Emailed: 10/3/2022) (Updated: 4/24/2024)
Click here to contact Ashley Martinelli

Piperacillin-tazobactam is one of the most commonly used antipseudomonal antibiotics in the empiric management of patients with septic shock. The package insert recommends dose reductions for renal impairment in other infectious etiologies, but the impact of dose reduction has not been previously studied in patients with septic shock.

A recent retrospective, observational cohort study compared outcomes of patients with septic shock who received ≥ 27 grams (at least 3.375 gm q6 hours x 48 h-“NORM”) versus those who received < 27 grams (“LOW”) over the initial 48 h of septic shock (defined as concomitant norepinephrine infusion).  

Patients were excluded if they had death or hospice disposition within the 48h study period. The primary outcome was the number of norepinephrine free days (NFD) at day 28. Propensity matching was utilized to account for confounders.

Results: 351 in the LOW group, 928 in the NORM group with 608 pairs in the propensity matched assessment.

  • Patients in the LOW group were
    • Older (65 v 61, p < 0.001)
    • More likely to have lower renal function (20% with CrCl < 20, 35% with CrCl 20-40) which corresponds to package insert dose reduction recommendations
    • Received lower doses of piperacillin/tazobactam (20.3 g v 30.4 g, < 0.001)
  • Norepinephrine free days were statistically significantly higher in the NORM dosing group when looking at all patients and the propensity score matched patients.
  • In-hospital mortality/hospice disposition was also lower in the NORM group (25.9% v 35.5%, p=0.014

Bottom Line: Dose reductions of piperacillin-tazobactam appears to be harmful early in the management of patients with septic shock.

 

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Question

Intraosseous (IO) administration uses bone marrow to deliver fluids and medications during cardiac resuscitation or other emergent situations where IV access cannot be established.

IV versus IO

  • No statistically significant difference between the pharmacokinetics!
  • Flow rates of IV cannula typically range from 20 to 200 mL/min versus IO ranging from 0.33 to >50 mL/min under pressure
    • Maximum rate of administration through IO is comparable to a 21G peripheral cannula.

Considerations When Using IO Access

  • Single line, ensure all drugs running through the IO are compatible with one another.
    • For example: plasmalyte is not compatible with most medications
  • If trying to quickly administer fluids utilize a pressure bag.
    • If medication administration (i.e. vasopressors) pump should be used
  • Contraindications to IO include:
    • Placement in fractured bone with vascular injury
    • Compartment syndrome
    • Cellulitis/burns at the site
    • Underlying bone disease
    • Soft tissue infection
    • Recent orthopedic surgery
  • Once a bone has been punctured by an IO attempt, it should not be used again for at least 48 hours. 
  • Intraosseous aspiration of blood is usable for lab tests, though accuracy has varied in studies. 

 

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