POTD: Tamiflu Tuesday

Respiratory season is here in Brooklyn, and with it comes the return of influenza. Just last week, we saw a significant increase (53%) in the number of positive influenza tests compared to the previous week. While the ED volume may make it seem like we’re at the peak, unfortunately, this graph from the New York State Department of Health suggests that we’re only just beginning. 

With the influx of influenza-positive patients into the ED, you may to wonder if there’s anything we can do for them. Tamiflu, also known as Oseltamivir, is a drug that can help alleviate the symptoms of influenza. This drug works by inhibiting the neuraminidase enzyme of the influenza virus, preventing its replication in the body. I personally like this graphic that perfectly summarizes the mechanism of action with a giant red X.

To Tamiflu or not to Tamiflu?

But of course, some things are simply too good to be true and the lore surrounding Tamiflu is rife with controversy.

To make a long story short, Tamiflu first entered the market in 1999 and received substantial support from the CDC and WHO. It even made it onto the World Health Organization’s List of Essential Medicines from 2009 to 2017. This support was based on multiple pharmaceutical-sponsored trials that showed a ~1.5-day reduction in influenza symptoms and a reduction in secondary complications, such as hospitalizations and pneumonia. However, in a shocking turn of events, the pharmaceutical companies (namely Roche) who sponsored these trials didn’t even provide the authors with access to the data but instead simply informed them of the data’s purported findings.

This discovery brought all the data into question. Since then, numerous studies have been conducted to assess the true efficacy of Tamiflu. I’ll list some of these studies below for your review, but the bottom line is that the data supporting Tamiflu’s benefits is, at best, lackluster.

Benefits of Tamiflu:

• Reduces the duration of symptoms by up to 36 hours (but more realistically around 17-24 hours) when started within 48 hours of symptom onset.

• Decreases the likelihood of contracting the flu by approximately 50-80% when used as a post-exposure prophylaxis medication within 48 hours of exposure.

Risks of Tamiflu:

• Nausea, vomiting, diarrhea, and/or headache occur in up to 17% of patients.

• Neuropsychiatric events (including confusion, delirium, hallucinations) have been reported.

• The cost of Tamiflu is around $60 for patients without insurance.

The saga and controversy of Tamiflu could go on much longer, but I’ll wrap it up here.

TLDR: The data for Tamiflu suggests a very modest reduction in the duration of symptoms (only about half to one full day) without a statistically significant reduction in complications such as hospitalizations or pneumonia. There are notable risks, including gastrointestinal distress and reports of neuropsychiatric events in children. Instead just get your flu shot.

Sources:

https://www.health.ny.gov/diseases/communicable/influenza/surveillance/2024-2025/flu_report_current_week.pdf

https://rebelem.com/the-alic4e-trial-oseltamivir-usual-care-vs-usual-care-alone/

https://www.bmj.com/tamiflu

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/215903

https://first10em.com/tamiflu-doesnt-work/

https://rebelem.com/the-tamiflu-debacle/

Tamiflu Trials:

Jefferson T et al. Oseltamivir for Influenza in Adults and Children: Systematic Review of Clinical Study Reports and Summary of Regulatory Comments. BMJ 2014. PMID: 24811411

Krumholz HM et al. Neuraminidase Inhibitors for Influenza: The Whole Truth and Nothing but the Truth. BMJ 2014. PMID: 24811413

Okoli GN et al. Use of Neuraminidase Inhibitors for Rapid Containment of Influenza: A Systematic Review and Meta-Analysis of Individual and Household Transmission Studies. PLOS One 2014.PMID: 25490762

Qiu S et al. Effectiveness and Safety of Oseltamivir for Treating Influenza: An Updated Meta-Analysis of Clinical Trials. Infectious Diseases 2015. PMID: 26173991

Heneghan CJ et al. Neuraminidase Inhibitors for Influenza: A Systematic Review and Meta-Analysis of Regulatory and Mortality Data. Health Technology Assessment 2016. PMID: 27246259

POTD: Flu-Like Symptoms

Today’s topic is inspired by the famous complaint of “flu-like symptoms.” More specifically, I’m covering the management of the common cold so you can effectively counsel your patients during discharge.

Setting expectations is crucial when treating patients with viral infections. Symptoms typically peak around days 2-4 of infection but can persist for up to two weeks. Unfortunately, there’s no magic cure; instead, the focus is on managing symptoms as the body fights off the virus. There are many over-the-counter medications available to alleviate these viral symptoms. Though admittedly the “cold and flu” isle is very colorful and rather intimidating, so let’s discuss some of the medications here.

Analgesics, particularly acetaminophen and NSAIDs, are the backbone of managing common cold symptoms. They effectively alleviate headaches, muscle aches, sore throat pain, and fevers. For specifically targeting throat pain, phenol oral anesthetic spray (Chloraseptic spray) or benzocaine-containing lozenges (Cepacol) are effective options.

Antihistamines are designed to treat allergic symptoms like itching, watery eyes, sneezing, coughing, and congestion. First-generation antihistamines, such as diphenhydramine (Benadryl), dimenhydrinate (Dramamine), doxylamine (NyQuil), brompheniramine (Dimetapp), and chlorpheniramine (Chlor-Trimeton) can cause sedation. Second-generation antihistamines, like cetirizine (Zyrtec), fexofenadine (Allegra), and loratadine (Claritin), don’t have this side effect. Antihistamines are commonly used by patients suffering from a cold; however, the data suggests that routine use of these medications doesn’t reduce the duration or severity of cold symptoms. 

Cough suppressants work by blocking the nerve impulses that trigger the coughing reflex. Dextromethorphan (Robitussin or Delsym) is a commonly used over-the-counter anti-tussive, while Benzonatate (Tessalon Pearles) acts similarly but requires a prescription. Studies suggest that both medications have some therapeutic effects, but their use should be balanced with their potential side effects. Dextromethorphan is a weak NMDA antagonist (similar to Ketamine) and is often abused for its hallucinogenic and dissociative properties. Benzonatate has a narrow therapeutic index, and overdose can lead to dysrhythmias and seizures, particularly in children.

Decongestants work by constricting nasal blood vessels to reduce swelling and decrease mucus production. Oxymetazoline spray (Afrin) is the most effective decongestant, but it’s important to advise patients not to use it for more than three days to prevent rebound congestion (aka rhinitis medicamentosa). Pseudoephedrine (Sudafed) is a decongestant pill that acts similarly and provides mild relief but it requires an ID to obtain due to its potential as an ingredient in meth. It’s important to distinguish pseudoephedrine (Sudafed) from phenylephrine (Sudafed PE). Phenylephrine is another common decongestant pill that is ineffective and the FDA has recommended it be removed. Vapoinhalers, which contain menthol and/or levmetamfetamine, are becoming increasingly popular as well. These inhalers cause local vasoconstriction in the nose when inhaled, which theoretically provides relief from nasal congestion, but the evidence supporting their effectiveness is limited.

Expectorants help thin and loosen mucus in the airways, making it easier to cough up phlegm. Guaifenesin (Mucinex) is a popular expectorant with questionable efficacy, performing only slightly better than a placebo in clinical studies. Instead, patients can try saline nasal sprays, simple oral hydration, humidifiers, or steam showers which can all moisten the airway to aid in mucus clearance. 

Homeopathic or herbal products, such as Oscillococcinum, Zicam, Echinacea, and Pelargonium sidoides, are touted as more “natural” remedies. These products contain botanical or animal derivatives but have no valid evidence supporting their use. (And while we’re on the topic, I’m sorry to say that vitamin C supplements also do not prevent or treat a cold. Unless you’re severely deficient in vitamin C and developing scurvy, most of that Airborne supplement is being peed out.)

Before we end I want to touch on two special topics…

Children are a unique consideration. The American Academy of Pediatrics recommends against giving any over-the-counter cough and cold medicines to children under the age of 6. Instead, they suggest acetaminophen, ibuprofen, and non-pharmacologic options such as nasal suctioning, saline nasal sprays, humidifiers, and steam showers. For children over one year old, honey may soothe the throat and calm a cough.

Combination medications, such as DayQuil, NyQuil, Theraflu, Tylenol Cold + Flu, and more, are found in most pharmacies’ cold and flu sections. These medications typically contain a combination of the aforementioned drugs. As per my best friend, who works in a retail pharmacy, these medications are kinda terrible and should generally be avoided. They are advertised well and commonly perceived as a “cure all” so people end up taking medications they don’t actually need. Instead, she recommends buying individual medications based on your specific symptoms.

And if you’re overwhelmed by what to grab at the pharmacy…

TLDR: Best OTC Cold and Flu Medications

Cough -> dextromethorphan (Delsym)

Congestion -> oxymetazoline spray (Afrin) or pseudoephedrine (Sudafed)

Sore throat -> phenol spray (Chloraseptic) or benzocaine lozenges (Cepacol)

Headache, myalgias, and/or fevers -> acetaminophen and ibuprofen

Sleep -> 3mg melatonin and diphenhydramine (Benadryl)

 Sources:

https://pmc.ncbi.nlm.nih.gov/articles/PMC9468790/#CD009345-sec-0103

https://pubmed.ncbi.nlm.nih.gov/36688284/

https://www.ncbi.nlm.nih.gov/books/NBK279544/

https://www.uptodate.com/contents/the-common-cold-in-adults-treatment-and-prevention?search=cough%20suppressant%20adult&source=search_result&selectedTitle=2%7E91&usage_type=default&display_rank=2#H67086900

https://pmc.ncbi.nlm.nih.gov/articles/PMC65295/#:~:text=Conclusion,and%20of%20doubtful%20clinical%20relevance

https://www.fda.gov/drugs/drug-safety-and-availability/fda-clarifies-results-recent-advisory-committee-meeting-oral-phenylephrine

https://www.ama-assn.org/delivering-care/population-care/what-doctors-wish-patients-knew-about-which-cold-medicines-work

POTD: EtomiDate or EtomiHate?

Hi everyone,

For a double dose of learning, today's extra POTD comes at the request of our wonderful PEM attending Dr. Hector Vazquez: should we be using etomidate in rapid sequence intubation (RSI) for septic pediatric patients?

Short answer? No. Long answer? It's complicated, but still no.

Etomidate's theorized effect on adrenal insufficiency = etomidate BAD

Etomidate is a bread-and-butter induction agent for us during intubation in the ED, often utilized for its hemodynamic stability and fast onset of action. However, the story started to really turn on etomidate in 2011 and 2012 when two systematic reviews and meta-analyses demonstrated that etomidate was associated with adrenal insufficiency and increased mortality in septic patients (Albert, Ariyan, & Rather, 2011; Chan, Mitchell, & Shorr, 2012). Why is this adrenal insufficiency thing such a big deal, anyways? It's because cortisol, our body's glucocorticoid that is produced by the adrenal gland, is absolutely vital during critical illness such as sepsis. Cortisol both helps maintain vascular responsiveness (good for blood pressure control in sepsis!) and has anti-inflammatory effects (good for fighting infection in sepsis!). The annoying part is that etomidate works through a cytochrome pathway that blocks conversion of cholesterol to cortisol. So more etomidate = less cortisol = adrenal insufficiency = not a good look.

Most of the adult literature on etomidate = etomidate EH BUT MOSTLY BAD

Honestly, like most of medicine, the data is controversial on the use of etomidate in sepsis in the adult literature. Even though the effect of etomidate on adrenal suppression is pretty well laid out, the question is if it is clinically significant and affects morbidity or mortality. A more recent systematic review and meta-analysis in 2021 reiterated the older meta-analyses findings, stating again an increase in adrenal suppression and mortality in septic patients (Albert & Sitaula, 2021). But, like most of medicine, many of the studies that were analyzed had some bias, some blinding blind spots, and varying definitions of all-cause mortality. A more recent RCT in 2023 even showed that there was no mortality difference between septic patients intubated with a single dose of etomidate vs. ketamine (Srivilaithon et al., 2023). All to say, the data isn't doing etomidate any favors when it comes to its use in septic adults, but it's not straight forward either. It's mostly bad, but we need better data, too. Journey with etomidate at your own risk.

Pediatric Sepsis Guidelines 2020 = etomidate BAD

Which brings us to peds patients. And make no mistake, the pediatric providers are stating it nice and clear for us: do not use etomidate in pediatric septic patients. In 2020, an expert panel released the holy grail for pediatric sepsis management, titled "Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis- Associated Organ Dysfunction in Children." Included in these guidelines are 77 evidence-based statements made up of 6 strong recommendations, 52 weak recommendations, and 9 best-practice statements. 

And here's their recommendation regarding etomidate: We suggest not to use etomidate when intubating children with septic shock or other sepsis-associated organ dysfunction (weak recommendation, low quality of evidence). So no etomidate, but a weak recommendation... why do we even trust that? Well, pediatric patients just simply don't get the same research funding and consideration that adult patients get. A lot of the recommendations thus are based off of scant data, poor data, or adult data. And with such low quality of evidence overall, they only can claim to have weak recommendations. With regards to this recommendation in particular, as of 2020, no RCTs exist in critically ill children comparing etomidate to another sedation agent. But the recommendation is going off of two observational studies that included children in their patient population and four adult RCTs. Is it the cleanest recommendation? Definitely not. But they made an educated decision and pediatric septic patients should not be getting etomidate for RSI based on this recommendation. Maybe try ketamine instead.

So what were the 6 strong recommendations then?

1. In children with septic shock, we recommend starting antimicrobial therapy as soon as possible, within 1 hour of recognition (strong recommendation, very low quality of evidence)

2. We recommend removal of intravascular access devices that are confirmed to be the source of sepsis or septic shock after other vascular access has been established and depending on the pathogen and the risks/benefits of a surgical procedure (strong recommendation, low quality of evidence)

3. In healthcare systems with no availability of intensive care and in the absence of hypotension, we recommend against bolus fluid administration while starting maintenance fluids (strong recommendation, high quality of evidence)

4. We recommend against using starches in the acute resuscitation of children with septic shock or other sepsis-associated organ dysfunction (strong recommendation, moderate quality of evidence)

5. We recommend against the routine use of inhaled nitrous oxide (iNO) in all children with sepsis-induced PARDS (strong recommendation, low quality of evidence)

6. We recommend against insulin therapy to maintain glucose target at or below 140mg/dL (7.8 mmol/L) (strong recommendation, moderate quality of evidence)

To me, it wasn't so interesting to see what was included as strong recommendations, but more to see what was not included. If it's not listed here, but is typically something you would expect to be doing for a septic patient, it is likely listed as a weak recommendation or a best-practice statement. Meaning, lots of things we don't have all the evidence for but we have all collectively decided to do them anyway.

Happy intubating,

Kelsey

Resources:

1) https://pubmed.ncbi.nlm.nih.gov/21373823/

2) https://pubmed.ncbi.nlm.nih.gov/22971586/

3) https://jtd.amegroups.org/article/view/5542/5525#B19

4) https://pubmed.ncbi.nlm.nih.gov/32912050/

5) https://www.acepnow.com/article/should-you-etomidate-me/2/

6) https://www.nature.com/articles/s41598-023-33679-x

7) https://pubmed.ncbi.nlm.nih.gov/32032273/