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Extracorporeal Treatment Options in Poisoned Patients

Background

Caring for a patient that is critically-ill secondary to a toxic ingestion is complicated and, in severe cases, extracorporeal treatments (ECTRs) may be considered. The most commonly used ECTRs are intermittent hemodialysis (iHD) and continuous renal replacement therapy (CRRT), but ECTRs also include exchange transfusion, hemoperfusion, liver dialysis, and therapeutic plasma exchange. Finding and evaluating the supporting literature for these treatment modalities in a timely manner is not feasible in most situations. In order to assist in this effort, the EXtracorporeal Treatments In Poisoning (EXTRIP) workgroup has reviewed and provided free, evidence-based recommendations regarding the use of ECTRs for many common toxins and toxicants [1]. These recommendations can be found in a summarized format on the EXTRIP website and the links to their comprehensive reviews are published on PubMed with direct links on their website. This international workgroup is made up of experts in toxicology, nephrology, emergency medicine, pediatrics, pharmacology, critical care, and more. An excellent example of this resource is their review and recommendations on ECTRs for poisoning secondary to beta-adrenergic antagonists (BAAs).

Evidence

The EXTRIP workgroup included 76 publications in this comprehensive review on the use of ECTRs in BAA poisoning [2]. They evaluated pharmacokinetic/toxicokinetic data for a total of 334 patients poisoned with various BAAs, of which ~90% of the data was published prior to 1990 and does not necessarily represent the improved clearance of these medications with modern ECTR modalities. Based on this evidence, they deemed atenolol, nadolol, and sotalol as dialyzable BAAs. They also reviewed case reports/series of 37 patients with BAA toxicity and made recommendations for those agents with sufficient evidence. Based on the above data, the EXTRIP group recommends iHD over CRRT in patients severely poisoned with atenolol or sotalol and kidney impairment. They make no recommendation for or against ECTR in patients severely poisoned with atenolol or sotalol with normal kidney function and they recommend against ECTR in patients severely poisoned with propranolol.

 Bottom Line

  • Some toxic ingestions may require invasive treatment strategies (e.g., ECTRs) but a comprehensive review of the literature may not be possible
  • The EXTRIP website is an excellent resource to assess if patients should receive emergent ECTRs due to specific toxins
  • Hemodialysis is recommended in severely symptomatic patients poisoned with atenolol or sotalol and with impaired kidney function

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. Ghannoum M, Nolin TD, Lavergne V, Hoffman RS, EXTRIP workgroup. Blood purification in toxicology: nephrology’s ugly duckling. Adv Chronic Kidney Dis. 2011;18(3):160-166. doi: 10.1053/j.ackd.2011.01.008. PMID: 21531321.
  2. Bouchard J, Shepherd G, Hoffman RS, et al. Extracorporeal treatment for poisoning to beta-adrenergic antagonists: systematic review and recommendations from the EXTRIP workgroup. Crit Care. 2021;25(1):201. doi: 10.1186/s13054-021-03585-7. PMID: 34112223.
By |2022-02-02T13:49:01-08:00Feb 5, 2022|EM Pharmacy Pearls, Tox & Medications|
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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 Interactions CYP3A4 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]
Dose 300 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
Notes Approved 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 Adjustments eGFR  ≥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 |2026-06-16T16:17:51-07:00Jan 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 |2026-06-16T16:17:47-07:00Jan 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 toxicity 0
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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ED Management of Cannabinoid Hyperemesis Syndrome: Breaking the Cycle

cannabis cannabinoid hyperemesis syndrome

What is cannabinoid hyperemesis syndrome?

Cannabinoid hyperemesis syndrome (CHS) is a condition in which patients who have been using cannabis or synthetic cannabinoids for a prolonged period of time develop a pattern of episodic, severe vomiting (usually accompanied by abdominal pain) interspersed with prolonged asymptomatic periods.

When should you consider cannabinoid hyperemesis syndrome as a diagnosis?

The diagnostic criteria for CHS require evidence of relief of symptoms with sustained cessation from cannabis, which makes them of limited utility in the Emergency Department (ED) [1]. However, a number of ED-based diagnostic criteria have been proposed with overlapping features [1,2]. There are 3 key components to assess for when making a presumed diagnosis:

  1. An episodic pattern of vomiting
    • Episodes of vomiting should last < 7 consecutive days
    • Asymptomatic periods often last > 1 month between episodes
  2. Prolonged cannabis use
    • Criteria vary: normally >1 time per week (often daily) for at least 1 year
    • Importantly, this is not an intoxication effect from a single large ingestion
  3. Exclusion of alternative diagnoses
    • Look for atypical features on history & exam including abnormal vital signs, diarrhea, focal abdominal pain, peritonitis, and jaundice
    • It is important to exclude pregnancy in all female patients
    • If a patient has never had an esophagogastroduodenoscopy (EGD), it is reasonable to refer newly diagnosed patients to gastroenterology for a non-emergent EGD to assess for a structural cause of the patient’s symptoms

What causes cannabinoid hyperemesis syndrome?

There is no singular theory that fully explains CHS. Importantly, the pattern of illness does not correlate well with the amount of cannabis consumed acutely, suggesting it is not related to a direct effect of the delta-9-tetrahydrocannabinol (THC) or a withdrawal effect. There are two prevailing theories related to changes in neuro-signaling and receptor expression with chronic THC exposure:

Theory #1: Downregulation of the cannabinoid receptor type 1 (CB-1) receptor which occurs with chronic THC use causing dysregulation of the hypothalamic-pituitary-adrenal stress axis. This theory supports why medications that have sedative or anxiolytic properties, such as haloperidol and benzodiazepines, have reported efficacy.

Theory #2: Changes in central nervous system dopamine signaling pathways with chronic THC exposure leading to a hypersensitive emesis response to dopamine. This theory is less well supported but has been used to explain the beneficial effects of dopamine antagonists such as haloperidol, droperidol, and olanzapine.

How should we treat cannabinoid hyperemesis syndrome in the ED?

Ondansetron, Metoclopramide, and Antihistamines

Traditional antiemetics have had low rates of success in treating CHS based on reported cases (ondansetron = 1.75%, metoclopramide = 4.35%) [3]. Antihistamines such as dimenhydrinate, diphenhydramine, and meclizine have no studies supporting their use, and the limited case reports available suggest they are ineffective [3]. While cases of treatment failure are more likely to be published which contributes to a reporting bias, clinical experience supports that CHS often does not respond well to these antiemetics. These medications may still have a role as an adjunct for patients who are refractory to other treatments, but given the evidence available supporting other agents, they can no longer be recommended as first-line therapy. Drawbacks to using a “traditional antiemetics first” strategies include a delay to effective treatment, prolonged ED length of stay, and prolongation of the QT interval.

Haloperidol

The HaVOC trial showed haloperidol was twice as effective as ondansetron at reducing nausea (change from baseline = -5.0 vs. -2.4) and abdominal pain (change from baseline = -4.3 vs. -2.1). Haloperidol also decreased rescue medication use (31% vs. 76%) and time from medication administration to ED discharge (3.1 hours vs. 5.6 hours) [4].

Lower doses of haloperidol were recommended (0.05 mg/kg) due to higher rates of adverse reactions with larger doses. Weight-band based dosing may be a more practical approach:

  • Haloperidol 2.5 mg IV for adults < 80 kg
  • Haloperidol 5 mg IV for adults > 80 kg

Olanzapine

There is very limited evidence supporting olanzapine specifically in CHS (6 reported cases) [3]. However, olanzapine has strong evidence supporting its antiemetic properties in oncology literature [5,6]. Unlike haloperidol, olanzapine does not prolong the QT interval and it has much lower rates of extrapyramidal side effects. Therefore, olanzapine may be a reasonable substitution for haloperidol in the following cases: documented allergy to haloperidol, prolonged QT interval, or previous extrapyramidal effects with haloperidol.

Capsaicin

While capsaicin is often discussed as a treatment [ALiEM trick of the trade], the evidence supporting its use is limited to a small case series and a small RCT with some significant limitations. The small RCT published in support of capsaicin had large baseline differences between the capsaicin and placebo groups. The placebo group was “more sick”, having higher baseline nausea which was not corrected for in the analysis [7].

The trial reported a significant reduction in nausea scores with capsaicin (60-minute nausea score: Placebo = 6.4 vs. Capsaicin = 3.2, p = 0.007) which looks impressive, but the change in nausea from baseline was much less substantial (change in nausea: Placebo = -2.1 vs. Capsaicin = -2.8). Overall, the evidence supporting capsaicin is limited, so its use should be a shared decision.

Benzodiazepines

Lorazepam has no studies assessing its utility in CHS, but a summary of case reports suggests an efficacy of 58.3% in 19 patients [3]. Despite the lack of evidence, clinical experience has led to lorazepam being recommended as an adjunct in recent cyclic vomiting syndrome guidelines for patients who have an anxiety component to their presentation [8]. Since 40-50% of traditional cyclic vomiting syndrome patients were chronic cannabis users, it is reasonable to extrapolate these guidelines to CHS until more specific literature is published.

Overall Approach to Treatment

Based on the currently available research outlined above and clinical experience, the following is a reasonable approach to acute symptomatic management of CHS in the ED:

What should we be considering at the time of discharge?

Like other chronic episodic illnesses (eg. migraines) the long-term management of CHS can be conceptualized to have three components: avoidance of triggers, management of acute episodes, and episode prevention (prophylaxis).

Avoidance of Triggers

  • The only cure for CHS is the prolonged cessation of cannabis. It is important to emphasize that it may take 6 months of cannabis cessation before symptoms improve, and to recognize that the challenges in stopping cannabis use are often underestimated. Professional addictions support is encouraged.

Management of Acute Episodes

  • Medications at home to abort acute episodes are a logical management strategy and may be a safe option to reduce recurrent ED visits in some patients. This will depend on which medications work for the patient, their comorbidities, and the patient’s access to reliable follow-up.
  • There is no current evidence to guide outpatient treatment. Traditionally, many gastroenterologists have used a combination of sublingual lorazepam and ondansetron which may be reasonable if a patient has responded to these medications in the ED.
  • The use of oral haloperidol at home is currently being studied, but there are no good protocols published to guide practice.

Episode Prevention

  • There have been no studies on using medications to reduce the frequency of CHS episodes. However, amitriptyline is recommended as a first-line prophylactic treatment for adults with cyclic vomiting syndrome as it reduces subjective symptoms scores, episode frequency, and ED utilization [9,10].
  • Using amitriptyline for CHS would be considered experimental and amitriptyline has several well-recognized side effects, requires slow up-titrated, and necessitates close follow-up. It may be reasonable for a patient to discuss with their primary care provider.

 

References

  1. Venkatesan T, Levinthal DJ, Li BUK, et al. Role of chronic cannabis use: cyclic vomiting syndrome vs cannabinoid hyperemesis syndrome. Neurogastroenterology & Motility. 2019 Jun;31(Suppl 2):e13606.
  2. Sorensen CJ, DeSanto K, Borgelt L, Phillips KT. Cannabinoid hyperemesis syndrome: diagnosis, pathophysiology, and treatment – a systematic review. Journal of Medical Toxicology. 2017;13:71-87.
  3. Richards JR, Gordon BK, Danielson AR, Moulin AK. Pharmacologic treatment of cannabinoid hyperemesis syndrome: a systematic review. Pharmacotherapy. 2017;37(6):725-34.
  4. Ruberto AJ, Sivilotti ML, Forrester S, et al. Intravenous haloperidol versus ondansetron for cannabis hyperemesis syndrome (HaVOC): a randomized, controlled trial. Annals of Emergency Medicine. 202 Nov;S0196-0644(20)30666-1.
  5. Hashimoto H, Abe M, Tokuyama O, Mizutani H, Uchitomi Y, Yamaguchi T, Hoshina Y, Sakata Y, Takahashi TY, Nakashima K, Nakao M, et al. Olanzapine 5 mg plus standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting (J-FORCE): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncology. 2020;21:242-49.
  6. Naravi RM, Qin R, Ruddy KJ, et al. Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. New England Journal of Medicine. 2016 Jul;375(2):134-42.
  7. Dean DJ, Sabagha N, Rose K, et al. A pilot trial of topical capsaicin cream for treatment of cannabinoid hyperemesis syndrome. Academic Emergency Medicine. 2020;27:1166-72.
  8. Venkatesan T, Levinthal DJ, Tarbell SE, et al. Guidelines on management of cyclic vomiting syndrome in adults by the American neurogastroenterology and motility society and the cyclic vomiting syndrome association. Neurogastroenterology & Motility. 2019;31(Supp 2):e13604.
  9. Hejazi RA, Reddymasu SC, Namin F, et al. Efficacy of tricyclic antidepressant therapy in adults with cyclic vomiting syndrome: a two year follow up study. Journal of Clinical Gastroenterology. 2010;44:18-21.
  10. Namin F, Patel J, Lin Z, et al. Clinical, psychiatric and manometric profile of cyclic vomiting syndrome in adults and response to tricyclic therapy. Neurogastroenterology & Motility. 2007;19:196-202.
By |2021-09-29T09:38:58-07:00Sep 27, 2021|Academic, Emergency Medicine, Tox & Medications|
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