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Series Editor: Mike O’Brien, PharmD

Quick evidence-based pearls on all things pharmacology and pharmacy-related in Emergency Medicine

Oral Antivirals for Treatment of Mild-Moderate COVID-19 Infection

Background

Two new oral agents were given Emergency Use Authorization to be used in patients with mild-moderate COVID-19 at high risk of progression to severe infection, molnupiravir and nirmatrelvir/ritonavir (Paxlovid) [1,2]. Prior to this authorization, most evidence-based COVID therapies were parenteral and required significant healthcare resources to coordinate and administer.

Comparison

Nirmatrelvir/ritonavir [3]Molnupiravir [4]
Mechanism

Protease inhibitor leadings to interruption of viral replication

Ritonavir has no role in treating COVID-19, it is only included to boost levels of nirmatrelvir via CYP3A4 inhibition

Increased frequency of RNA mutations and impaired replication [5]
Efficacy vs Placebo (Hospitalization or Death)0.8% vs 6.3% (CI -7.21 to -4.03)6.8% vs 9.7% (CI -5.9 to -0.1)
Drug InteractionsCYP3A4 inducers, inhibitors, and substrates

May decrease efficacy of hormonal contraceptives, non-hormonal contraceptives should be considered

Contraindicated medications include: amiodarone, carbamazepine, clozapine, colchicine, dihydroergotamine, dronedarone, flecainide, lovastatin, ranolazine, sildenafil, simvastatin

Many other important interactions exist so care should be taken to assess all medication interactions

N/A
Cost*Patient: $0

US government: $530 [6]

Patient: $0

US Government: $700 [7]

Dose300 mg/100 mg BID for 5 days

Must be started within 5 days of symptom onset

800 mg BID for 5 days

Must be started within 5 days of symptom onset

NotesApproved for patients ≥ 12 years old AND ≥ 40 kg

Not approved for inpatient initiation

If patient is hospitalized, continuation is up to the discretion of the provider

Not used as pre-/post-exposure prophylaxis

Approved for patients ≥ 18 years

Not approved for inpatient initiation

If patient is hospitalized, continuation is up to the discretion of the provider

Not used as pre-/post-exposure prophylaxis

Renal/Hepatic Dose AdjustmentseGFR  ≥30 to <60 mL/min: 150 mg/100 mg BID

eGFR <30 mL/min: Not recommended

Child-Pugh class C: Not recommended

None

*Note: The US federal government has purchased 10 million doses of nirmatrelvir/ritonavir and 3 million doses of molnupiravir [8,9]. These supplies will be allocated to states and territories as needed and will be available to patients at no charge. 

Evidence:

Nirmatrelvir/ritonavir (Paxlovid)

Paxlovid was evaluated in the EPIC-HR trial, which is not fully published at this time [3]. This was a phase 2/3, double-blinded, randomized placebo controlled trial including nonhospitalized, unvaccinated patients adults with mild-moderate COVID-19 within 5 days of symptom onset with at least 1 risk factor† for development of severe illness from COVID-19. Exclusion criteria included patients with a history of COVID-19 infection or COVID vaccination. Patients were given Paxlovid 300 mg/100 mg or placebo BID for 5 days. The primary outcome was hospitalization or death at day 28. The modified intention-to-treat1 (mITT1) group excluded patients who did not receive nor were expected to receive COVID-19 mAb treatment. In the mITT1 group, the primary outcome occurred in 0.8% of patients receiving Paxlovid vs 6.3% of patients in the placebo group (8/1039 vs 66/1046, CI -7.21 to -4.03).

These results appear quite robust with a fragility index of 37. Additionally, in patients with detectable COVID antibodies there was less of an impact of the study medication. However, these patients still appeared to have some benefit (0.2% vs 1.5%, CI -2.45 to -0.23) which suggests that vaccinated patients may still benefit from Paxlovid.

†Risk factors for progression to severe disease: BMI >25, chronic lung disease, asthma, chronic kidney disease, current smoker, immunosuppressive disease or immunosuppressive treatment, cardiovascular disease, hypertension, sickle cell disease, neurodevelopmental disorders, active cancer, medically-related technological dependence, or age >60 years

Molnupiravir 

Molnupiravir was evaluated in the MOVe-OUT trial [10]. This was a phase 3, double-blinded, randomized, placebo controlled trial including nonhospitalized, unvaccinated adults with mild-moderate COVID-19 within 5 days of symptom onset with at least 1 risk factor‡ for development of severe illness from COVID-19. Exclusion criteria included anticipated hospitalization within 48 hours, eGFR <30 or dialysis dependent, pregnancy, and COVID vaccination. Patients were able to receive steroids but not monoclonal antibodies (mAbs) nor remdesivir. Patients were given molnupiravir 800 mg or placebo BID for 5 days. The primary outcome was hospitalization or death at 29 days. In the mITT population, the primary outcome occurred in 6.8% of patients in the study group vs 9.7% in the placebo group (48/709 vs 68/699, CI -5.9 to -0.1). Death occurred in 1 patient on molnupiravir and in 9 patients on placebo (0.1% vs 1.3%, RRR 89%, CI 14 to 99).

Despite the above results, this may not be the positive trial it initially appears. First of all, for the primary outcome, the fragility index is 0, meaning that if 1 more patient in the study group experienced the primary outcome then it would have changed the statistical significance. Additionally, when the mITT analysis was adjusted for sex, the absolute risk reduction remained 2.8% but the confidence interval was not significant (-5.7 to 0.1). Lastly, in the subgroup analysis, there was no benefit in patients that had positive COVID antibody tests and there was a slight preference towards placebo over molnupiravir (3.7% vs 1.4%, ARR 2.3, CI -1.7 to 7.1). This suggests that vaccinated patients may not benefit from this therapy as much (or at all) as compared to unvaccinated patients.

‡Risk factors for progression to severe disease: age >60 years, active cancer, chronic kidney disease, COPD, BMI ≥30, heart failure, coronary artery disease, cardiomyopathy, or diabetes mellitus

Note: Both the EPIC-HR and MOVe-OUT studies were funded by their respective pharmaceutical company.

Bottom Line:

  • Nirmatrelvir/ritonavir (Paxlovid) and molnupiravir are approved under FDA EUAs for patients with mild-moderate COVID infection at high risk of severe disease within 5 days of symptom onset
  • Both medications appear to reduce death or hospitalization within a month, with most benefit likely to be experienced by unvaccinated patients
  • Nirmatrelvir/ritonavir (Paxlovid) appears to be more effective but also has many more drug interactions and contraindications

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:

  1. O’Shaughenessy J. Food and Drug Administration. Molnupiravir Emergency Use Authorization 108. December 23, 2021. https://www.fda.gov/media/155053/download
  2. O’Shaughenessy J. Food and Drug Administration. Nirmatrelvir/ritonavir Emergency Use Authorization 105. December 22, 2021. https://www.fda.gov/media/155049/download
  3. Nirmatrelvir/ritonavir. Package insert. Pfizer, Inc. 2021. https://www.fda.gov/media/155050/download
  4. Molnupiravir. Package insert. Merck Sharp & Dohme Corp. 2021. https://www.merck.com/eua/molnupiravir-hcp-fact-sheet.pdf
  5. Kabinger F, Stiller C, Schmitzová J, et al. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nat Struct Mol Biol. 2021;28(9):740-746. doi: 10.1038/s41594-021-00651-0. PMID: 34381216.
  6. Mishra M. U.S. to buy 10 mln courses of Pfizer’s COVID-19 pill for $5.3 bln. Reuters. Accessed January 12, 2022. https://www.reuters.com/business/healthcare-pharmaceuticals/us-govt-buy-10-mln-courses-pfizers-covid-19-pill-529-bln-2021-11-18/
  7. Willyard C. How antiviral pill molnupiravir shot ahead in the COVID drug hunt. Nature. Published online October 8, 2021. doi: 10.1038/d41586-021-02783-1. PMID: 34625735.
  8. Paxlovid (nirmatrelvir/PF-07321332 and ritonavir). U.S. Department of Health & Human Services: Office of the Assistant Secretary of Preparedness and Response. Updated: January 12, 2022. Accessed January 12, 2022. https://www.phe.gov/emergency/events/COVID19/investigation-MCM/Paxlovid/Pages/default.aspx
  9. Molnupiravir (MK-4482). U.S. Department of Health & Human Services: Office of the Assistant Secretary of Preparedness and Response. Updated: January 12, 2022. Accessed January 12, 2022. https://www.phe.gov/emergency/events/COVID19/investigation-MCM/molnupiravir/Pages/default.aspx
  10. Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for oral treatment of covid-19 in nonhospitalized patients. N Engl J Med. Published online December 16, 2021. doi: 10.1056/NEJMoa2116044. PMID: 34914868.
By |2022-01-15T19:00:38-08:00Jan 15, 2022|EM Pharmacy Pearls, Infectious Disease, Tox & Medications|
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Balanced Fluids in Diabetic Ketoacidosis

Background

Many guidelines and treatment algorithms for diabetic ketoacidosis (DKA) recommend sodium chloride 0.9% as the replacement fluid of choice, though alternative fluids may be a better option [1-4]. Randomized trials, in adult and pediatric patients, demonstrate faster resolution of DKA when using balanced solutions (e.g., PlasmaLyte-A, lactated Ringer’s) compared to sodium chloride [5-7]. Dr. Josh Farkas provides further review of this topic in 3 excellent and detailed EMCrit posts [8-10].

Evidence

A phase-2 study published in 2021, SCOPE-DKA, randomized 93 patients with severe DKA (median venous pH 7.0) to receive PlasmaLyte-148 (PlasmaLyte-A) or sodium chloride 0.9% [11]. During the first 48 hours of treatment, patients received a average of ~6.5 L of fluid. At 24-hours, more patients in the PlasmaLyte group had resolution of DKA (defined as base excess ≥ -3 mEq/L) as compared to the sodium chloride group (69% vs 36%, p=0.002). However, by 48-hours, both groups had similar rates of DKA resolution (96% vs 86%, p=0.111). The study authors concluded that PlasmaLyte-148 may lead to faster resolution of metabolic acidosis in patients with DKA without an increase in ketosis, in line with findings from previous studies, but these results need to be confirmed in a larger, Phase 3 trial.

To further explore the nuances, strengths, and weaknesses of this study, please read the REBEL EM review by Dr. Mark Ramzy [13].

Bottom Line

  • The available data suggests that balanced fluids are beneficial in mild, moderate, and severe DKA.
  • PlasmaLyte-148 (PlasemaLyte A) may lead to faster resolution of metabolic acidosis than sodium chloride 0.9%. Though these findings need confirmation in a large, Phase 3 trial.
  • Generally, the composition of the initial liter is less important than prompt administration. However, for subsequent liters, a balance crystalloid (e.g., PlasmaLyte-148, or lactated Ringer’s) should be used instead of sodium chloride 0.9%.

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:

  1. Wolfsdorf J, Glaser N, Sperling MA, American Diabetes Association. Diabetic ketoacidosis in infants, children, and adolescents: A consensus statement from the American Diabetes Association. Diabetes Care. 2006;29(5):1150-1159. PMID: 16644656. doi: 10.2337/diacare.2951150.
  2. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32(7):1335-1343. PMID: 19564476. doi: 10.2337/dc09-9032.
  3. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee, Goguen J, Gilbert J. Hyperglycemic emergencies in adults. Can J Diabetes. 2013;37 Suppl 1:S72-76. PMID: 24070967. doi: 10.1016/j.jcjd.2013.01.023.
  4. Joint British Diabetes Societies Inpatient Care Group. The Management of Diabetic Ketoacidosis in Adults. 2021; online publication. Accessed January 3, 2022. https://abcd.care/sites/abcd.care/files/site_uploads/JBDS_02%20_DKA_Guideline_amended_v2_June_2021.pdf.
  5. Mahler SA, Conrad SA, Wang H, Arnold TC. Resuscitation with balanced electrolyte solution prevents hyperchloremic metabolic acidosis in patients with diabetic ketoacidosis. Am J Emerg Med. 2011;29(6):670-674. PMID: 20825879. doi: 10.1016/j.ajem.2010.02.004.
  6. Williams V, Jayashree M, Nallasamy K, Dayal D, Rawat A. 0.9% saline versus Plasma-Lyte as initial fluid in children with diabetic ketoacidosis (SPinK trial): a double-blind randomized controlled trial. Crit Care. 2020;24(1):1. PMID: 31898531. doi: 10.1186/s13054-019-2683-3.
  7. Self WH, Evans CS, Jenkins CA, et al. Clinical effects of balanced crystalloids vs saline in adults with diabetic ketoacidosis: a subgroup analysis of cluster randomized clinical trials. JAMA Netw Open. 2020;3(11):e2024596. PMID: 33196806. doi: 10.1001/jamanetworkopen.2020.24596.
  8. Farkas J. Four DKA Pearls. 2014. Accessed January 3, 2022. https://emcrit.org/pulmcrit/four-dka-pearls.
  9. Farkas J. Dominating the acidosis in DKA. 2016. Accessed January 3, 2022. https://emcrit.org/pulmcrit/bicarbonate-dka.
  10. Farkas J. IBCC – Diabetic Ketoacidosis (DKA). 2021. Accessed January 3, 2022. https://emcrit.org/ibcc/dka.
  11. Ramanan M, Attokaran A, Murray L, et al. Sodium chloride or Plasmalyte-148 evaluation in severe diabetic ketoacidosis (Scope-dka): a cluster, crossover, randomized, controlled trial. Intensive Care Med. 2021;47(11):1248-1257. PMID: 34609547. doi: 10.1007/s00134-021-06480-5.
  12. Ramzy M. SCOPE-DKA: Normal Saline vs Plasmalyte in Severe DKA. 2021. Accessed January 3, 2022. https://rebelem.com/scope-dka-normal-saline-vs-plasmalyte-in-severe-dka.
By |2022-01-03T10:16:35-08:00Jan 8, 2022|EM Pharmacy Pearls, Endocrine-Metabolic, Tox & Medications|
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Dose Order Matter? Which Antibiotic to Give First for a Bloodstream Infection

Background

Early antibiotics are recommended for treatment of many infections, including patients with sepsis or septic shock [1]. Critically-ill patients and those with a suspected infection at risk for severe illness are generally administered two (or more) empiric antibiotics in the emergency department (ED) which cover a wide range of potential pathogens. A typical approach includes utilizing a broad-spectrum antibiotic (frequently a beta-lactam such as cefepime or piperacillin-tazobactam) plus an anti-MRSA agent (typically vancomycin).

Early in the patient’s hospital stay they may have limited IV access, so the question often arises as to which antibiotic to give first, the broad-spectrum antimicrobial or the anti-MRSA agent. Additionally, though the overall risk of an allergic reaction is relatively low with most antimicrobials, when multiple agents are given simultaneously it can be difficult to ascertain which one may have caused a reaction and lead to incorrectly documented allergies, so it can be important to consider if the initial doses should be administered separately. However, there isn’t strong data to guide practice in terms of giving the initial antibiotics concurrently vs consecutively, from an allergy perspective. To further complicate the issue, patients may also develop delayed reactions so a strong causal relationship cannot always be determined. In practice, there are times (increasingly so with rising ED patient volumes) when we give antibiotics one at a time simply for logistical reasons. So that begs the question, which antibiotic should be given first?

Evidence

In patients with sepsis or septic shock, early antibiotics significantly decrease mortality [1]. This relationship is strongest for patients with septic shock, where the odds of in-hospital mortality was increased by 1.04-1.16 for each hour antibiotics were delayed [2-4]. Notably, broad spectrum antibiotics are deemed such as they cover both gram positive and gram negative pathogens, therefore the addition of an anti-MRSA agent contributes a relatively smaller amount of coverage and is primarily targeted at resistant gram-positive bacteria. Additionally, gram-negative pathogens tend to cause a higher degree of illness and mortality, so it would be reasonable to give the broad-spectrum antibiotic first [5-7]. As both cefepime and piperacillin-tazobactam are recommended to be infused over 30 minutes (though this can vary based on institutional policies) and vancomycin is typically infused over 1 hour for each gram, if vancomycin is administered first, patients may wait hours to receive a broad spectrum agent.

A recent study now supports this practice. This is an observational trial which evaluated 3,376 patients with a blood stream infection, 2,685 patients received a beta-lactam first and 691 patients received vancomycin first [8]. They found that patients who received a beta-lactam prior to vancomycin had significantly improved 48-hour and 7-day mortality. Further review of this article may be found on the JournalFeed blog post.

Bonus tip: Having antibiotics stocked on the unit reduces time to administration [9].

Bottom Line

  • Antibiotic delays lead to increased mortality, especially in patients with septic shock.
  • For patients with a suspected bloodstream infection, administering the broad-spectrum antibiotic first, instead of the anti-MRSA agent, has the potential to reduce mortality at 48 hours and 7 days. This should be the general approach for treatment of all infections when two or more antimicrobial agents are indicated.

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

  1. Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med. 2021;49(11):e1063-e1143. PMID: 34605781. doi: 10.1097/CCM.0000000000005337.
  2. Seymour CW, Gesten F, Prescott HC, et al. Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med. 2017;376(23):2235-2244. PMID: 28528569. doi: 10.1056/NEJMoa1703058.
  3. Liu VX, Fielding-Singh V, Greene JD, et al. The timing of early antibiotics and hospital mortality in sepsis. Am J Respir Crit Care Med. 2017;196(7):856-863. PMID: 28345952. doi: 10.1164/rccm.201609-1848OC.
  4. Peltan ID, Brown SM, Bledsoe JR, et al. Ed door-to-antibiotic time and long-term mortality in sepsis. Chest. 2019;155(5):938-946. PMID: 30779916. doi: 10.1016/j.chest.2019.02.008.
  5. Abe R, Oda S, Sadahiro T, et al. Gram-negative bacteremia induces greater magnitude of inflammatory response than Gram-positive bacteremia. Crit Care. 2010;14(2):R27. PMID: 20202204. doi: 10.1186/cc8898.
  6. Alexandraki I, Palacio C. Gram-negative versus Gram-positive bacteremia: what is more alarmin(G)? Crit Care. 2010;14(3):161. PMID: 20550728. doi: 10.1186/cc9013. 
  7. Morgan MP, Szakmany T, Power SG, et al. Sepsis patients with first and second-hit infections show different outcomes depending on the causative organism. Front Microbiol. 2016;7:207. PMID: 26955367. doi: 10.3389/fmicb.2016.00207.
  8. Amoah J, Klein EY, Chiotos K, Cosgrove SE, Tamma PD, CDC Prevention Epicenters Program. Administration of a β-lactam prior to vancomycin as the first dose of antibiotic therapy improves survival in patients with bloodstream infections. Clin Infect Dis. Published online October 4, 2021:ciab865. PMID: 34606585. doi: 10.1093/cid/ciab865.
  9. Lo A, Zhu JN, Richman M, Joo J, Chan P. Effect of adding piperacillin-tazobactam to automated dispensing cabinets on promptness of first-dose antibiotics in hospitalized patients. Am J Health Syst Pharm. 2014;71(19):1663-1667. PMID: 25225451. doi: 10.2146/ajhp130694.
By |2022-01-03T09:54:42-08:00Dec 4, 2021|EM Pharmacy Pearls, Infectious Disease|
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Simplified Dosing Scheme for DigiFab® in Acute Digoxin Poisoning

Simplified Dosing Scheme for DigiFab® in Acute Digoxin Poisoning

Background

Treatment of digoxin toxicity can be quite complex and generally involves the use of digoxin immune Fab (DigiFab®) for symptomatic patients. The dosing of DigiFab can vary depending on the amount ingested, serum concentration, and/or suspected chronicity of toxicity. Alternatively, for an acute ingested of an unknown amount where the serum concentration is not available, it is recommended that 10 vials of DigiFab be administered empirically. This antidote is expensive (~$5,000 per vial) and not always readily available in every hospital. Given the complicated dosing and cost, alternative dosing strategies are being explored.

Evidence

Researchers from Australia first proposed an initial 2-vial DigiFab dose for acute digoxin poisoning in a 2014 review article [1]. They followed this up with a pharmacokinetic study supporting the simplified dosing scheme [2]. Based on their early data, the Australian poison center recommendations were revised to instead use small doses of DigiFab (2 vials at a time) with repeat doses as needed to achieve clinical effect. This allowed them to prospectively study this new dosing strategy in 21 cases of digoxin toxicity [3]. Most patients required less than would have been administered following traditional dosing calculations. Patients receiving the lower-dosing scheme did have a rebound in free digoxin levels >2 ng/mL at a median time of 18 hours in patients with normal renal function and 103 hours in patients with an acute kidney injury. Most patients received 2 vials of DigiFab initially and a median of 4 vials total after receiving additional doses based on persistent or recurrent symptoms. Overall, patients required significantly less antidote with similar clinical outcomes. Importantly, there are limitations with the data to date, highlighted in a letter-to-the-editor with a subsequent response from the original authors [4, 5]. This titration approach should only be considered with input from a toxicologist and still requires the same level of monitoring.

Characteristics and Savings
Amount of digoxin ingested*13 mg (9.5-25 mg)
Initial potassium*5 mEq/L (4.5-5.4 mEq/L)
Fatalities due to digoxin toxicity0
Estimated vials saved^223-356 vials
Estimated cost savings^†$1.1-1.8 million
* Median (IQR)
^ Difference between titrated dosing scheme compared to doses based on ingested amount and serum concentration
† Based on cost of $5000 per vial

Pearls

Following administration of DigiFab, avoid measurement of the total digoxin concentration as this measures both free drug and drug bound to DigiFab, which will cause the result to be falsely elevated [6]. Additionally, extracorporeal treatments are not recommended for the removal of digoxin or the digoxin-Fab complex, regardless of the clinical context [7].

Bottom Line

  • In select cases of acute digoxin poisoning, patients may safely receive 2 vials of DigiFab with repeat doses as necessary based on symptoms. If considering this treatment approach, it is recommended to consult with a toxicologist and/or pharmacist.
  • Total serum digoxin levels can be falsely elevated following the administration of DigiFab.

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

  1. Chan BSH, Buckley NA. Digoxin-specific antibody fragments in the treatment of digoxin toxicity. Clin Toxicol (Phila). 2014;52(8):824-836. doi: 10.3109/15563650.2014.943907. PMID: 25089630.
  2. Bracken LM, Chan BSH, Buckley NA. Physiologically based pharmacokinetic modelling of acute digoxin toxicity and the effect of digoxin-specific antibody fragments. Clin Toxicol (Phila). 2019;57(2):117-124. doi: 10.1080/15563650.2018.1503288. PMID: 30306803.
  3. Chan BS, Isbister GK, Chiew A, Isoardi K, Buckley NA. Clinical experience with titrating doses of digoxin antibodies in acute digoxin poisoning. (ATOM-6). Clin Toxicol (Phila). Published online August 23, 2021:1-7. doi: 10.1080/15563650.2021.1968422. PMID: 34424803.
  4. Mahonski S, Howland MA, Su MK. Comment on: clinical experience with titrating doses of digoxin antibodies in acute digoxin poisoning. Clinical Toxicology. 2021;0(0):1-2. doi: 10.1080/15563650.2021.1994986. PMID: 34709957
  5. Chan BS, Buckle NA. Authors’ reply to comment on: clinical experience with titrating doses of digoxin antibodies in acute digoxin poisoning. Clin Toxicol (Phila). Published online December 14, 2021:1. doi: 10.1080/15563650.2021.2013497. PMID: 34904491.
  6. DigiFab®. Package insert. BTG International Inc; 2017.
  7. Mowry JB, Burdmann EA, Anseeuw K, et al. Extracorporeal treatment for digoxin poisoning: systematic review and recommendations from the EXTRIP Workgroup. Clin Toxicol (Phila). 2016;54(2):103-114. doi: 10.3109/15563650.2015.1118488. PMID: 26795743.
By |2021-12-16T04:46:32-08:00Oct 16, 2021|EM Pharmacy Pearls, Tox & Medications|
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Pre-Arrest Acidemia and the Effect of Sodium Bicarbonate on ROSC

Background

Sodium bicarbonate during a cardiac arrest is widely debated and used in many cases. In a 2018 PULMCrit post, Dr. Josh Farkas reviews much of the data and concludes that use of sodium bicarbonate is a “source of eternal disagreement.” A 2013 EMCrit article and podcast by Dr. Scott Weingart also details some of the controversy. The 2020 ACLS Guidelines state that routine use of sodium bicarbonate is not recommended in cardiac arrest [1]. Despite this recommendation, sodium bicarbonate is still often administered during resuscitations if a metabolic (or respiratory) acidosis is suspected or after a prolonged downtime. A recent study evaluated the effect of pre-arrest acid-base status on response to sodium bicarbonate and achievement of return of spontaneous circulation (ROSC) [2].

Evidence

This was a retrospective review of in-hospital cardiac arrests (IHCA) in patients with pre-arrest serum bicarbonate levels ≤21 mmol/L compared to >21 mmol/L. Pre-arrest bicarbonate levels were obtained <24 hours prior to the arrest. Similarly, post-arrest bicarb levels were obtained <24 hours following the arrest. Bicarbonate levels were recorded from basic chemistry panels rather than blood gases. All patients received a median sodium bicarbonate dose of 100 mEq. The groups were relatively well-matched, with the only major difference being the time to first bicarb administration was faster in the ‘acidotic’ group (6.9 vs. 9.2 minutes). Initial ECG rhythms were similar between the groups.

  • 102 patients in ‘acidotic’ group with a median pre-arrest bicarb level of 17 mmol/L
  • 123 patients in ‘non-acidotic’ group with a median pre-arrest bicarb level of 27 mmol/L
  • There was no difference in ROSC (53.9% vs 48.8%, p=0.44) or survival to discharge (8.8% vs 5.7%, p=0.36) between the acidotic group versus the nonacidotic group

Thoughts and Limitations

  • A meta-analysis found no difference in sustained ROSC or survival to discharge with sodium bicarbonate (Alshahrani 2021).
  • In the current study, prearrest bicarb levels could have resulted up to 24 hours prior to the arrest and the authors don’t comment on when exactly they were drawn. The timing limits the ability to know true acid-base status just prior to the arrest. And, that really limits applying this to out-of-hospital cardiac arrest where patients may have more significant acidemia if resuscitation is delayed.
  • A median bicarbonate concentration of 17 mmol/L isn’t really that low, relatively speaking, to indicate a potential impact from administering sodium bicarbonate.
  • Retrospective cardiac arrest studies are challenging. Many interventions happen around the same, making it impossible to connect any one of them with a specific outcome.
  • The study that would be more helpful is taking patients with metabolic/respiratory acidosis and giving have bicarb and the other placebo.

Bottom Line

  • In this cohort of IHCA patients, sodium bicarbonate administration did not improve the chances of ROSC or survival to hospital discharge, irrespective of pre-arrest acid-base status. In other words, attempting to correct ‘acidosis’ does not seem to change rate of ROSC.
  • Sodium bicarbonate use in cardiac arrest should be targeted (e.g., hyperkalemia with metabolic acidosis, sodium channel blockade secondary to an overdose).

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

  1. Panchal AR, Bartos JA, Cabañas JG, et al. Part 3: adult basic and advanced life support: 2020 american heart association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2020;142(16_suppl_2):S366-S468. doi: 10.1161/CIR.0000000000000916. PMID: 33081529.
  2. Mclean H, Wells L, Marler J. The effect of prearrest acid-base status on response to sodium bicarbonate and achievement of return of spontaneous circulation. Ann Pharmacother. Published online August 5, 2021:10600280211038392. doi: 10.1177/10600280211038393. PMID: 34353142.
By |2021-10-09T09:23:40-07:00Sep 18, 2021|Cardiovascular, Critical Care/ Resus, EM Pharmacy Pearls|
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INR reduction with FFP – How low can you go?

Background

Bleeding patients or those undergoing procedures that are at high risk of bleeding may require correction of their INR. Multiple products can be used to achieve this, including fresh frozen plasma (FFP). FFP contains many substances, including clotting factors, fibrinogen, plasma proteins, electrolytes, and anticoagulant factors. It is sometimes said that the intrinsic INR of FFP is approximately 1.6-1.7 and that it’s not possible to achieve a lower INR. This pearl will further explore these concerns.

Evidence

  • What is the INR of FFP?
    • The mean INR of FFP appears to be ~1.1 (0.9-1.3) [1,2].
    • Reports that the intrinsic INR of FFP is 1.6-1.7 may be based on the clinical experience of not being able to achieve an INR <1.6-1.7 with FFP.
  • Is it possible to “normalize” the INR with FFP alone?
    • Several studies have found that it’s difficult to achieve an INR <1.7 with only FFP [3,4]. However, other studies were able to achieve lower average INR values [2,5,6]. 
    • Overall, these studies found that there was a significantly greater decrease in INR when the pre-FFP INR was higher, but there was a much smaller decrease when the INR was closer to the normal range.
  • Why does FFP appear to have diminishing returns when the pre-FFP INR is lower?
    • The relationship between the INR and percentage of clotting factors present in the blood is not linear (see figure) [7].
    • For example: An increase of ~5% in clotting factors may decrease the INR from 3 to 2.5 but the same amount of FFP may only reduce an INR of 1.7 to 1.6.

Figure 1: Adapted from Dzik  2012 [7].

    • Additionally, the table below also demonstrates that small volumes of FFP result in large changes when the initial INR is elevated, but very large amounts of FFP are required to achieve an INR of 1.3 no matter the initial INR (see table).
Amount of FFP to Achieve a Target INR Based on Pre-FFP INR
Target INR
1.31.73.0
Initial INRVolume (L)Dose (mL/kg)Factor (%)Volume (L)Dose (mL/kg)Factor (%)Volume (L)Dose (mL/kg)Factor (%)
6.04.564452.536251.52115
5.04.361432.332231.01410
4.04.057402.029200.575
3.03.550351.52115–––
2.02.536250.575–––

Table 1: Adapted from Holland 2006 [3]. Note: 1 unit of FFP is ~200-250 mL

    • Given the above data, the issue preventing the achievement of an INR <1.7 appears to be the dose/volume of FFP required and not the intrinsic INR of FFP.
  • Does the INR need to be <1.7 to achieve hemostasis?
    • Since the INR only provides limited information regarding a single aspect of anticoagulation status, complete normalization for the INR to control bleeding is usually not necessary [6].
    • An INR elevation alone does not indicate a patient is coagulopathic or at an increased risk of bleeding [7]. Additionally, an INR elevation in patients with liver dysfunction likely reflects an overall state of decreased factor production, both procoagulant and anticoagulant factors [8].
    • The target INR varies depending on multiple patient factors and planned interventions, but an INR of 1.0 is likely not necessary to prevent bleeding or achieve hemostasis.

Bottom Line

  • A unit of FFP has an INR of ~1.1, but this doesn’t mean it can easily normalize the INR.
  • There is a non-linear relationship between percentage of clotting factors and the INR, resulting in diminishing returns from each unit of FFP as the INR decreases.
  • Very large doses of FFP may be required to fully correct an elevated INR, which frequently precludes its use.
  • Complete normalization of the INR is not required to achieve hemostasis or prevent bleeding from a procedure.

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

  1. Holland LL, Foster TM, Marlar RA, Brooks JP. Fresh frozen plasma is ineffective for correcting minimally elevated international normalized ratios. Transfusion. 2005;45(7):1234-1235. doi: 10.1111/j.1537-2995.2005.00184.x. PMID: 15987373.
  2. Only AJ, DeChristopher PJ, Iqal O, Fareed J. Restoration of normal prothrombin time/international normalized ratio with fresh frozen plasma in hypocoagulable patients. Clin Appl Thromb Hemost. 2016;22(1):85-91. doi: 10.1177/1076029614550819. PMID: 25294634.
  3. Holland LL, Brooks JP. Toward rational fresh frozen plasma transfusion: The effect of plasma transfusion on coagulation test results. Am J Clin Pathol. 2006;126(1):133-139. doi: 10.1309/NQXH-UG7H-ND78-LFFK. PMID: 16753596.
  4. Abdel-Wahab OI, Healy B, Dzik WH. Effect of fresh-frozen plasma transfusion on prothrombin time and bleeding in patients with mild coagulation abnormalities. Transfusion. 2006;46(8):1279-1285. doi: 10.1111/j.1537-2995.2006.00891.x. PMID: 16934060.
  5. Müller MCA, Straat M, Meijers JCM, et al. Fresh frozen plasma transfusion fails to influence the hemostatic balance in critically ill patients with a coagulopathy. J Thromb Haemost. 2015;13(6):989-997. doi: 10.1111/jth.12908. PMID: 25809519.
  6. McCully SP, Fabricant LJ, Kunio NR, et al. The International Normalized Ratio overestimates coagulopathy in stable trauma and surgical patients. J Trauma Acute Care Surg. 2013;75(6):947-953. doi: 10.1097/TA.0b013e3182a9676c. PMID: 24256665.
  7. Dzik W “Sunny.” Reversal of drug-induced anticoagulation: old solutions and new problems. Transfusion. 2012;52(s1):45S-55S. doi: 10.1111/j.1537-2995.2012.03690.x. PMID: 22578371.
  8. Harrison MF. The misunderstood coagulopathy of liver disease: a review for the acute setting. West J Emerg Med. 2018;19(5):863-871. doi: 10.5811/westjem.2018.7.37893. PMID: 30202500.
By |2021-08-28T10:03:39-07:00Aug 21, 2021|EM Pharmacy Pearls, Heme-Oncology|
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Succinylcholine and the Risk of Hyperkalemia

Succinylcholine and the Risk of Hyperkalemia

Background

Succinylcholine is frequently used in the ED to facilitate intubation, but it may be avoided in some cases due to the risk of hyperkalemia. The underlying physiology of this effect appears to be directly related to its therapeutic mechanism of action. When succinylcholine binds to and activates acetylcholine receptors, it leads to an influx of sodium and calcium and and an efflux of potassium into the extracellular space [1]. Additionally, when these acetylcholine receptors are immature or denervated, it seems that these channels may stay open significantly longer, allowing for an increased  amount of potassium to exit the cell, leading to an increased risk of hyperkalemia.

Evidence

Based on multiple studies that included patients with normal renal function, succinylcholine leads to a serum potassium increase of  ~0.5 mEq/L [2-4]. This is likely clinically insignificant in most patients. In fact, an ED-based study found a variable response with serum potassium increasing in 46 cases, decreasing in 46 cases, and not changing in 8 cases [3]. It seems that even patients on chronic dialysis are not at increased risk of developing clinically-significant hyperkalemia from succinylcholine [5].

So, when should succinylcholine potentially be avoided specifically due to hyperkalemia concerns [6]?

  • Hyperkalemia with ECG changes present prior to succinylcholine administration
  • Denervating, crush, or burn injuries after 72 hours
  • Rhabdomyolysis
  • Prolonged total body immobilization
  • Denervating diseases (e.g., multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS))
  • Inherited myopathies (e.g., Duchenne muscular dystrophy (DMD))

In patients for whom succinylcholine is determined to be not an option, non-depolarizing muscular blocking agents (NMBAs), such as rocuronium, are still safe and do not lead to hyperkalemia.

Bottom Line

  • Succinylcholine-induced hyperkalemia is more likely to occur in patients with predisposing conditions
  • Development of hyperkalemia following succinylcholine is variable and not always predictable
  • If succinylcholine is not an option due to potential risk of hyperkalemia, NBMAs (i.e., rocuronium) are still safe and effective

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

  1. Hovgaard HL, Juhl-Olsen P. Suxamethonium-induced hyperkalemia: a short review of causes and recommendations for clinical applications. Critical Care Research and Practice. 2021;2021:e6613118. doi: 10.1155/2021/6613118.
  2. Magee DA, Gallagher EG. “Self-taming” of suxamethonium and serum potassium concentration. Br J Anaesth. 1984;56(9):977-980. doi: 10.1093/bja/56.9.977. PMID: 6466531.
  3. Zink BJ, Snyder HS, Raccio-Robak N. Lack of a hyperkalemic response in emergency department patients receiving succinylcholine. Acad Emerg Med. 1995;2(11):974-978. doi: 10.1111/j.1553-2712.1995.tb03124.x. PMID: 8536123.
  4. Raman SK, San WM. Fasciculations, myalgia and biochemical changes following succinylcholine with atracurium and lidocaine pretreatment. Can J Anaesth. 1997;44(5 Pt 1):498-502. doi: 10.1007/BF03011938. PMID: 9161744.
  5. Thapa S, Brull SJ. Succinylcholine-induced hyperkalemia in patients with renal failure: an old question revisited. Anesth Analg. 2000;91(1):237-241. doi: 10.1097/00000539-200007000-00044 PMID: 10866919.
  6. Martyn JAJ, Richtsfeld M. Succinylcholine-induced hyperkalemia in acquired pathologic states: etiologic factors and molecular mechanisms. Anesthesiology. 2006;104(1):158-169. doi: 10.1097/00000542-200601000-00022. PMID: 16394702.
By |2021-07-23T11:02:43-07:00Jul 31, 2021|EM Pharmacy Pearls, Tox & Medications|
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