ED Muskoka Physicians - Living the Dream

EMRAP Club

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EMRAP Club

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IV vs PO antibiotics for SSTIs

This month I decided to do a bit of a lit review on a topic that’s been bugging me recently in our department. It’s not a new or landmark clinical trial, but a topic that I think deserves some attention and discussion! In our busy summer department, I’m often surprised at how many patients are brought back for standing orders for IV antibiotics (often Ceftriaxone!) for moderate cellulitis.  There is a lot of variability in who is given IV vs PO antibiotics, and for what indications, so I thought I would look at the evidence. 

TL:DR –  (“too long, didn’t read” for the non-millennials!)

  • In multiple (although small) studies, no difference in clinical resolution of cellulitis has been demonstrated between IV and oral antibiotics for simple/uncomplicated cellulitis
  • The IDSA recommendation that IV antibiotics for nonpurulent cellulitis be reserved for patients who are immunocompromised or have systemic signs of infection, hemodynamic instability, or altered mental status.  
  • Even one dose of IV antibiotics given in the ED can increase risk of antibiotic associated diarrhea and C.diff infection (25.7% vs 12.3% for PO Rx only)
  • PO availability of most common antibiotics is excellent – Keflex 90-100%, Clinda 90%
    • A RCT comparing resolution of cellulitis with PO Keflex vs IV Ancef + Probenecid showed NO benefit of IV therapy.
    • A previous RCT comparing IV Ceftriaxone to IV Ancef + Probenecid showed no superiority of Ceftriaxone over the Ancef… 
  • So… most of the time can we just go with Keflex?! Save the patient the time for the ER visit, the nursing time, the antibiotic use, the diarrhea risk, the risk of IV complications… and ensure appropriate outpatient follow-up in 72h.

Hey, this patient has cellulitis. Should I use Keflex or Ancef?

Study 1: Oral versus parenteral antimicrobials for the treatment of cellulitis: a randomized  non-inferiority trial 

Craig A. Aboltins, Anastasia F. Hutchinson, Rabindra N. Sinnappu, Damian Cresp, Chrissie Risteski, Rajasutharsan Kathirgamanathan, Mark A. Tacey, Herman Chiu, Kwang Lim, Oral versus parenteral antimicrobials for the treatment of cellulitis: a randomized non-inferiority trial. Journal of Antimicrobial Chemotherapy. Volume 70, Issue 2, February 2015, Pages 581–586, https://doi.org/10.1093/jac/dku397

This was a randomized trial done in 2015 in a single centre ED. Patients age 16+ were referred by the ED staff for treatment of cellulitis with IV antibiotics – i.e. staff thought the severity of cellulitis warranted IV therapy or that patient had failed outpatient treatment with PO antimicrobials. Cellulitis was defined by the presence of acute dermal/epidermal inflammation lasting <5 days and associated with pain, fever with a temperature of ≥37.8°C, tachycardia >90 beats/min, systemic symptoms or elevated inflammatory markers (pretty clinically clear definition, and probably includes the more severe end of the spectrum, people I would also automatically assume need IV therapy!) Patients were excluded for complicated cellulitis (defined as severe sepsis, extensive bullous skin changes or abscess formation), necrotizing fasciitis, periorbital cellulitis, cellulitis complicating trauma, immunosuppressed patients, mild cellulitis (defined as limited area and no systemic symptoms), vomiting precluding oral treatment, or prior treatment with oral antimicrobials for >48h or with IV for >12h. Patients were assigned to either Keflex 1g PO QID x 10 days (interestingly a higher dose than our usual 500mg PO QID), or Ancef 2g IV q12h x 10d, with a change to PO indicated when afebrile and area of cellulitis stopped progressing. The primary outcome was time until no advancement of the area of cellulitis. Secondary outcomes were failure of treatment, pain, complications of treatment and satisfaction with care. Only 47 patients were included in the trial, but it showed that PO therapy was non-inferior to IV therapy for uncomplicated cellulitis.

Study 2: Intravenous cefazolin plus oral probenecid versus oral cephalexin for the treatment of skin and soft tissue infections: a double-blind, non-inferiority, randomised controlled trial.

Dalen D, Fry A, Campbell SG, Eppler J, Zed PJ. Intravenous cefazolin plus oral probenecid versus oral cephalexin for the treatment of skin and soft tissue infections: a double-blind, non-inferiority, randomised controlled trial. Emerg Med J. 2018 Aug;35(8):492-498. doi: 10.1136/emermed-2017-207420. Epub 2018 Jun 18. 

This was a prospective multicentre RCT including 206 patients comparing IV Ancef + Probenecid vs PO Keflex for the treatment of uncomplicated cellulitis in two Canadian EDs. Patients age 19+ were included if they presented to the ED with a presumed diagnosis of mild-moderate cellulitis as assessed by the attending physician, were deemed well enough to have outpatient treatment, and could return to the ED daily for assessments. There were a bunch of relevant exclusion criteria: patients were excluded if oral antibiotic therapy was indicated but intravenous antibiotics were deemed to not be required by the emergency physician (ie, mild enough to be given oral therapy and sent home without follow-up in the ED). Patients with known chronic kidney disease (creatinine clearance <30 mL/min), known previous methicillin-resistant Staphylococcus aureus (MRSA) infection, use of antibiotics for >24 hours in the past seven days, wound/abscess requiring operative debridement or incision and drainage (either via clinical exam and/or ultrasound examination), suspected necrotising fasciitis, osteomyelitis or septic arthritis, febrile neutropenia, concomitant documented bacteraemia, two or more signs of systemic sepsis, infections at a site involving prosthetic materials, animal or human bite wound infections, postoperative wound infections, known peripheral vascular disease, superficial thrombophlebitis, pregnant/breast feeding, obesity (BMI>30 ) or a known allergy to study medication. Importantly, local antibiograms at both centres in the study reported MRSA rates <20%, similar to our centre.  Patients were randomized to receive either Keflex 500mg PO QID at home + Placebo pill + IV NS in the ED daily, or Ancef 2g IV + Probenecid 1g PO daily in the ED + PO Placebo QID at home. Primary outcome was treatment failure at 72h. Secondary outcomes were clinical cure at 7 days, admission to hospital and adverse events.  There were no significant differences in any outcomes. Failure rate at 72h was 4.2% (PO) vs 6.1% (IV). Conclusion: Cephalexin at appropriate doses appears to be a safe and effective alternative to outpatient parenteral cefazolin in the treatment of uncomplicated mild-moderate SSTIs who present to the ED.

But what if I really think this patient needs IV therapy? Should I just put them on Ceftriaxone?

Study 3: Once-Daily Intravenous Cefazolin Plus Oral Probenecid Is Equivalent to Once-Daily Intravenous Ceftriaxone Plus Oral Placebo for the Treatment of Moderate-to-Severe Cellulitis in Adults

M. Lindsay Grayson, Malcolm McDonald, Kimberley Gibson, Eugene Athan, Wendy J. Munckhof, Phillip Paull, Fran Chambers. Once-Daily Intravenous Cefazolin Plus Oral Probenecid Is Equivalent to Once-Daily Intravenous Ceftriaxone Plus Oral Placebo for the Treatment of Moderate-to-Severe Cellulitis in AdultsClinical Infectious Diseases. Volume 34, Issue 11, 1 June 2002, Pages 1440–1448, https://doi.org/10.1086/340056

This Australian study compared Ancef 2g IV + probenecid 1g PO daily to Ceftriaxone 1g IV daily + oral placebo in 132 ED patients treated for moderate-to-severe cellulitis in adults. These patients were slightly sicker than the previous studies mentioned: 41% had fever, 33% had lymphangitis, and 19% had ulceration. More than 50% of patients in each group had previously received ineffective antibiotic therapy. The duration of intravenous therapy was left to the discretion of the managing physician and outcomes were assessed at the end of therapy and at 1 month.  The duration of study therapy was similar for both groups (~6-7 days), and after they completed intravenous therapy, the vast majority of patients completed treatment with 7–10 days of oral antibiotic therapy (generally cephalexin or clindamycin). Cure rates at end of therapy were 86% vs 96% (no statistical difference). Cure rates at 1 month were also similar (82% vs 85%, no statistical difference). Nausea was more common in the Ancef-probenecid group, probably due to the probenecid. Conclusion: The once-daily regimen of cefazolin-probenecid is a cheap, practical, and effective treatment option for moderate-to-severe cellulitis, and it avoids the need to use third-generation cephalosporins in most patients.

What about just giving 1 dose of Ceftriaxone today, just to get them started, and then discharging with Keflex?

This has no evidence behind it. There is no support for the idea that a single dose of IV antibiotics results in better outcomes for any condition (even for pyelo/severe UTI! See this Cochrane study: Pohl A. Modes of administration of antibiotics for symptomatic severe urinary tract infections. Cochrane Database Syst Rev. 2007 Oct 17;2007(4)). It makes no sense to give a broad spectrum antibiotic and then step down to a narrow spectrum one, and in fact this might just increase antibiotic resistance. If we are using IV to PO stepdown strategy, we should be using a antibiotics with equivalent coverage – i.e. IV cipro to PO cipro, or IV Ancef to PO Keflex. However, even one dose of an IV antibiotic in the ED has been shown to increase the risk of antibiotic associated diarrhea and C.difficile infection from 12.3% for PO Abx Rx only to 25.7% for 1 dose IV followed by a PO Rx. (Haran JP, Hayward G, Skinner S. Factors influencing the development of antibiotic associated diarrhea in ED patients discharged home: risk of administering IV antibiotics. The American journal of emergency medicine. 2014; 32(10):1195-9.) 

Furthermore, the first line medications for cellulitis all have excellent bioavailability. Cephalexin is 90-100% bioavailable, clindamycin 90%, and doxycycline >90% when taken with food. (MacGregor 1997 – see table below for more detail). Really, theoretically, the only reason to use IV antibiotics (in the absence of sepsis or underlying immunocompromise) is if the patient isn’t able to tolerate/absorb PO.

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What if I think the patient has already failed oral/outpatient therapy for cellulitis?

As Dr. Helmen points out in his post in ACEP Now,  “One reason that IV antibiotics are overused is an incorrect diagnosis of “treatment failure.” All too often, patients with skin and soft tissue infections are deemed to have failed oral antibiotics after fewer than 48 hours of oral antibiotics. They then are needlessly switched to IV antibiotics. There is no evidence to support this practice. Treatment failure of simple cellulitis should only be entertained after a 48- to 72-hour trial of oral antibiotics. Even in many of these cases, switching classes of oral antibiotics is sufficient. IV antibiotics are not the automatic answer to ‘treatment failures.’”

Good reasons to admit patients to hospital might be more for wound care, or ensuring compliance with leg elevation, rather than simply the need for IV therapy. 

OK, but still, PO antibiotics can’t work for everyone, we see so many cases bounce back. What patient factors might make me choose IV therapy?

Yadav K, Suh KN, Eagles D, et al. Predictors of oral antibiotic treatment failure for nonpurulent skin and soft tissue infections in the emergency departmentAcad Emerg Med. 2019;26(1):51-59.

A 2019 retrospective chart review of 500 patients published in Academic Emergency Medicine looked at predictors of failure of PO antibiotics for nonpurulent SSTIs in adults. Independent predictors of oral antibiotic treatment failure (defined as hospitalization, change in class of oral antibiotic, or switch to IV therapy after 48 hours of oral therapy) included tachypnea at triage, the presence of chronic ulcers, history of MRSA colonization or infection, previous recent cellulitis (in the past year), chronic kidney disease, and diabetes.

What about guidelines?

I wish there were clearer guidelines about all of this. The 2014 Infectious Diseases Society of America does recommend that IV antibiotics for nonpurulent cellulitis be reserved for patients who are immunocompromised or have systemic signs of infection, hemodynamic instability, or altered mental status. “Systemic signs of infection” to me would mean fever, but remember that patients with fever were included in the studies above that showed no benefit of Ancef over Keflex.  While the studies on the subject are small, and guidelines are based on expert consensus, at this time it seems like perhaps the burden of proof should be laid on the IV therapy with current standard of care being PO antibiotics?!  Will this change your current practice? Who do you think we could safely try PO therapy for? The young healthy female with 24h lymphangitis? The non-diabetic with cellulitis and fever, but otherwise systemically well? If reassessing someone at 72h with no improvement in their forearm cellulitis, is looking for a foreign body or switching classes of antibiotic (i.e. to Septra for MRSA coverage) perhaps more appropriate than automatically giving them Ceftriaxone? I am interested in your thoughts!

Resources and further reading if you want a deep dive:

Ramakrishnan K, Salinas RC, Agudelo Higuita NI. Skin and Soft Tissue Infections. Am Fam Physician. 2015 Sep 15;92(6):474-83. 

Helman, Anton. IV vs. PO: Which Antibiotics Are Better for Common ED Infections? ACEP Now. Jan 21, 2020. https://www.acepnow.com/article/iv-vs-po-which-antibiotics-are-better-for-common-ed-infections/ Accessed July 15, 2021.

Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of AmericaClin Infect Dis. 2014;59(2):e10-52.

Low Risk Chest Pain

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Treatment of Corneal Abrasions

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January Virtual Journal Club

I’ll post a more “official” article and review later in the month but I came across this article about abscesses and thought it was interesting. Skin abscesses are not the sexiest topic but we treat them frequently so it would be worth considering a practice change if it improved patient comfort and/or outcome.

The SGEM post and podcast (link below) summarizes the article and does a critical appraisal. Original article is posted here: https://onlinelibrary.wiley.com/doi/full/10.1111/acem.14106

Essentially they looked at treatment failure as a primary outcome after treatment of skin abscesses with the loop technique versus standard packing with ribbon gauze. Secondary outcomes were ease of procedure, pain at the time of treatment, ease of care at 36 hours, and pain at 36 hours.

Study conclusion was:

“The LOOP and packing techniques had similar failure rates for treatment of subcutaneous abscesses in adults, but the LOOP technique had significantly fewer failures in children. Overall, pain and patient satisfaction were significantly better in patients treated using the LOOP technique.”

A few thoughts/questions:

What is everyone’s usual practice? Packing vs. no packing vs. leaving a small wick? Has anyone tried this loop technique?

Do we even stock vessel ties in the ER?

Given the questionable evidence regarding packing, wouldn’t it be easier to just not pack at all (ie. no loop or standard packing)?

Pediatric Sepsis

https://www.cps.ca/en/documents/position/diagnosis-and-management-of-sepsis-in-the-paediatric-patient

A review of the CPS Practice Point on Pediatric Sepsis (2020)

Fortunately, pediatric sepsis is relatively rare. We all treat adults with sepsis multiple times a month, but a child in septic shock is a rare, and terrifying, presentation in our community ER. However, sepsis is a major cause of morbidity and mortality in children, and requires prompt recognition and treatment. Just like in adults, sepsis care guidelines have focused on creating a systematic approach to these cases. This ‘practice point’ article put out by the CPS in 2020 uses 4 cases to succinctly review current global guidelines (including the Surviving Sepsis Campaign’s Pediatric Subgroup’s 2020 update). It’s worth a quick read. Not a classic journal club article as I’m not going through critical appraisal of the literature, but thought it was worth a quick review! Also, ties into the sim we ran this month – see below 🙂

We ran a simulated case this morning in Huntsville that highlighted a few practical points:

Case was a 7mo boy with ALL on chemo, presents with a fever, tachycardia, poor perfusion and altered mental status.


Key points : 

1. Early recognition of sepsis is key!  Worth regularly reviewing normal vitals in peds (chart in CPS article). Also we will be laminating a copy of a chart of normal pediatric vitals to hang on the side of the Peds crash carts (along with the NRP cards). Remember: a hypotensive septic kid is peri-arrest!

2. Practicalities of administering a fluid bolus in a baby – NEVER hang fluid by gravity (risk of too much or too little fluid) can put on pump or (preferably) do a push-pull method (draw off IV line with 60cc syringe, then push calculated amount over 5 minutes)   – R/A for response/fluid overload after each 20cc/kg bolus, aim for 60cc/kg in first hour of resuscitation and think about adding a vasopressor if not responding after 2nd bolus.

3. Vasopressors: 1st line is traditionally dopamine (which we have pre-mixed in crash cart) but this has changed officially in 2020  – Epinephrine (cold shock) or Norepinephrine (warm shock) is preferred, but these will need to be mixed up. (Look in dosing book on top of peds cart and be aware concentrations are vastly different from the way we mix it for adults!!)

4. Antibiotics – give early, give as IV push. Typically will be Ceftriaxone (100mg/kg) unless need broader coverage for risk MRSA/pseudomonas/immunosuppression etc.

5. Hydrocortisone – use more liberally in peds than adults, for fluid-refratory shock in sepsis, especially if history of steroid use (asthma/chemo etc). Dose = 2mg/kg IV push.

6. Hypoglycemia – more common in septic kids than adults. Remember D50 is caustic on veins, and not preferred in peds <2y. Can use D10W (1L bag kept1 in side of crash cart)  or dilute the D50 that is kept on the crash cart down to D25 with equal volume NS. Dose = 2.5-5mL/kg D10 IV push  OR 4ml/kg D25 IV


Great website for resources to review this topic including videos and a pdf algorithm which I’ve tried to attach:

https://trekk.ca/events/Sepsis-Announcement

What do you think the biggest barrier is in our department to providing excellent pediatric care? Do you have any suggestions for how we can improve?

Aerosol Generating Procedures

https://associationofanaesthetists-publications.onlinelibrary.wiley.com/doi/full/10.1111/anae.15292

Journal of anesthesia 

Purpose of the Study  – Quantify the amount of aerosolization during aerosol generating procedures to inform risk assessment

Study Design

-They monitored aerosolization with continuous sampling with an optical particle sizer, which allowed characterisation of aerosol generation within the zone between the patient and anaesthetist

-The extent to which COVID is transmitted as airborne is controversial 

Problems with the study

-Small sample size – used 4 ORs in the UK

-Only 19 intubations and 14 extubations 

-During intubation they use BVM and not RSI

Conclusion

– Tracheal intubation including facemask ventilation produced very low quantities of aerosolized particles – 500x less than a cough (actually state that “this study does not support the designation of elective tracheal intubation as aerosol generating”.

-Extubation, particularly when the patient coughed, produced a detectable aerosol, 15 folds greater than intubation but 35 folds less than a volatile cough .

Questions– They just say “facemask ventilation” – I think they need to be more specific.  What type of facemask did they use, what was the flow rate?

Take away –

(1)If a break in PPE then chance of acquiring COVID is probably minimal during intubation.

(2) patients coughing on us is more risk than intubation, therefore patient’s properly wearing masks can reduce this.

Development and Validation of a Penicillin Allergy Clinical Decision Rule
Trubiano et al. March 2020
JAMA Intern Med. 2020;180(5):745-752. doi:10.1001/ jamainternmed.2020.0403
Background
• Many patients self-report a penicillin allergy restricting antibiotic choice, and affecting antibiotic stewardship and local resistance patterns.
• Only 10% of self-reported penicillin allergies are confirmed.
• This prospective Australian study (n=622) sought to develop a point of
care clinical decision tool to identify the risk factors for a true penicillin
allergy
• Patients reporting a penicillin allergy underwent skin-prick testing,
intradermal testing, patch testing and/or an oral challenge (directly or
after skin testing).
• The prevalence of a positive penicillin allergy was 9.3%.
• The 4 factors associated with a positive result in the penicillin allergy test
are identified by the mnemonic PEN-FAST
• For patients reporting a PENicillin allergy:
• Five years or less since reaction (2 points)
• Anaphylaxis or angioedema OR
• Severe cutaneous adverse reaction (2 points)
• Treatment required for reaction (1 point)
0 points = Very low risk of positive penicillin allergy test <1% 1-2 points = Low risk of positive penicillin allergy test 5%
3 points = Moderate risk of positive penicillin allergy test 20% 4 points = High risk of positive penicillin allergy test 50%
• Using a cut-off of <3 gives a

• sensitivity of 70.7% • specificity of 78.5% • PPV of 25.3%
• NPV of 96.3%
• If a patient is low risk (ie <3), the study authors recommend an oral challenge in the ED prior to being sent home with a prescription.

https://edmuskoka.com/1849-2/

HALT IT – TXA for GI Bleeds

For this month’s physically distanced Journal Club – a review of the HALT IT trial looking at TXA for GI Bleeds.

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. The Lancet. 2020; 395(10241):1927-1936.  https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30848-5/fulltext

TL;DR:

  • Tranexemic acid (TXA) did NOT reduce 5-day mortality in upper and lower GI bleed patients.
  • It did show small increase risk of VTE.
  • Well designed, large trial. Best evidence to date for TXA in GI bleed.

Background:

  • GI bleeds have a high mortality rate (10%)
  • TXA is an antifibrinolytic agent that has been shown to be effective at preventing bleeding complications in a variety of settings (surgery, trauma, epistaxis)
    • We love it for its low cost, minimal SE profile, and numerous indications in the ER
  • A 2012 Cochrane Review for UGIB showed a reduction in all-cause mortality with TXA for GI bleeds
    • However, individual trials were small and prone to biases making it difficult to draw definitive conclusions… but was the best evidence we had until now

Clinical Question:

  • Does IV tranexamic acid reduce 5-day death due to bleeding?

Methods:

  • International, multi-centre, randomized, double-blind, placebo controlled trial (15 countries, 164 hospitals)
  • Intervention:
    • 1g TXA IV over 10 min the 125mg/hr x 24 hours (3g) vs. Placebo

Patients:

  • Adults (>16/18 yo depending on country)
  • With “significant” acute GI bleeding
    • Risk of bleeding to death:  
      • Hypotension
      • Tachycardia
      • Signs of shock
      • Likely to need transfusion, urgent endoscopy or surgery
  • Treating clinician had to be “substantially uncertain” about whether to use TXA

Outcome:

  • Primary outcome: death due to bleeding at 5 days
  • Secondary outcomes:
    • Death due to bleeding at 24 h and 28 d randomization
    • All cause and cause specific mortality at 28d
    • Rebleed (24h, 5d, 28d)
    • Blood product transfusion
    • MI/CVA
    • VTE (DVT/PE)
    • Seizures
    • Days in the ICU
    • Functional status in-hospital or at 28d
    • Other (cardiac events, sepsis, pneumonia, resp failure, renal failure, liver failure)

Results:

  • Patients:
    • 12 009 patients enrolled
    • 65% male, mean age 58
    • the mean time from bleeding onset to randomization was 22 hours
      • only 16% of patients presented within 3 hours
    • 89% had upper GI bleeding
    • 45% suspected to have variceal bleeds
    • 60% showed NO signs of shock at enrolment
  • NO BENEFIT
  • Primary outcome:
    • Death due to bleeding at 5 days = 3.7% (n=222) of TXA group and 3.8% (n=226) of placebo group (RR 0.99, 95% CI 0.82-1.18)
  • Secondary outcomes:
    • All cause mortality at 28 days (9.5% of TXA group and 9.2% of placebo group, RR 1.03, 95% CI 0.92-1.16)
    • No difference in rebleeding, surgery, endoscopy, need for transfusion, or total blood products transfused
    • RISKS – doubling of venous thromboembolic events (0.4% placebo and 0.8% TXA (RR 1.85, 95% CI 1.15-2.98)
    • NNH = 250

Limitations:

  • The authors changed the primary outcome from “all-cause mortality” to “death due to bleeding at 5d”
    • Not entirely sure why, as “all cause mortality” is clinically more relevant to us, “death” vs “death from bleeding” are one and the same when talking to family members
    • However, the change of this primary outcome forced the authors to increase their sample size by 4000, and still powered the study to detect a difference in the original outcome
  • The majority of patients in the trial had variceal bleeding due to liver disease and accounted for 75% of deaths, but also increased risk of VTE was more pronounced in patients with liver disease
  • Only 9% of patients were on anticoagulants, so unsure of applicability of data to that group

Thoughts:

  • Overall really well done study, very few protocol violations, excellent follow up
  • Time to randomization was high (mean ~ 22hrs)
    • Looking back at CRASH-2 showed mortality benefit (>20 000 pts, 4.9% vs 5.7% (p = 0.0077)) when 1g TXA given <3 hrs, but not after that.
    • Perhaps we would have been benefit it TXA was administered earlier in GI bleed patients
    • However, if these patients don’t present to us within that time frame, there is no point seeing if TXA works for GI bleeds if given in <3hrs
  • Since CRASH2 there has been lots of interest in TXA, but multiple studies since this positive publication have failed to show similar benefit from TXA
    • TICH -2 – no difference in mortality or neurological outcomes with TXA and ICH (Sprigg 2018)
    • WOMAN no difference in mortality or hysterectomy in PPH (WOMAN 2017) (*revised primary outcome, “death due to PPH” showed small benefit, NNT 267, but fragility index 0…, so overall not a resounding “positive study” in my opinion)
    • CRASH3 – no difference in mortality or neurologic outcomes in TBI (CRASH 2019)
    • Important to have these negative studies published given the well known publication bias of only positive studies
  • Not entirely clear why they had the inclusion criteria of “clinician substantially uncertain whether to use TXA”
    • How do we know if our gestalt is correct if we eliminated those patients from the trial?
    • Perhaps this is mostly to include obvious criteria such as allergy, or for ethical reasons for clinicians to be able to treat patients to the best of their ability, but it is hard to know how many patients were not included and if that would have had any effect on the outcome

Take Home Thoughts:

  • Despite some of the study weaknesses, this is a very well-designed, large trial, and a “negative” trial of this magnitude is clinically important.
  • Based on the current evidence, I will not be using TXA in the management of the GI bleed patients
  • What are you thoughts? Does this change your clinical practice?

References:

  1. Crash-2 Collaborators. (2011). The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. The Lancet377(9771), 1096-1101.
  2. Dewan, Y., Komolafe, E. O., Mejía-Mantilla, J. H., Perel, P., Roberts, I., & Shakur, H. (2012). CRASH-3-tranexamic acid for the treatment of significant traumatic brain injury: study protocol for an international randomized, double-blind, placebo-controlled trial. Trials13(1), 1-14.
  3. Gluud, L. L., Klingenberg, S. L., & Langholz, E. (2012). Tranexamic acid for upper gastrointestinal bleeding. Cochrane Database of Systematic Reviews, (1).
  4. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. The Lancet. 2020; 395(10241):1927-1936. 
  5. Justin Morgenstern, “TXA for GI bleeds”, First10EM blog, March 9, 2020. Available at: https://first10em.com/txa-for-gi-bleeds/.
  6. Roberts, I., Shakur-Still, H., Afolabi, A., Akere, A., Arribas, M., Brenner, A., … & Jairath, V. (2020). Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. The Lancet395(10241), 1927-1936.
  7. Salim Rezaie, “REBEL Cast Ep85: The HALT-IT Trial – TXA in Acute GI Bleeds”, REBEL EM blog, June 27, 2020. Available at: https://rebelem.com/rebel-cast-ep85-the-halt-it-trial-txa-in-acute-gi-bleeds/.
  8. Shakur, H., Elbourne, D., Gülmezoglu, M., Alfirevic, Z., Ronsmans, C., Allen, E., & Roberts, I. (2010). The WOMAN Trial (World Maternal Antifibrinolytic Trial): tranexamic acid for the treatment of postpartum haemorrhage: an international randomised, double blind placebo controlled trial. Trials11(1), 40.
  9. Sprigg, N., Flaherty, K., Appleton, J. P., Salman, R. A. S., Bereczki, D., Beridze, M., … & Dineen, R. A. (2018). Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial. The Lancet, 391(10135), 2107-2115.