ED Muskoka Physicians - Living the Dream

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.

travel

Hey gang,

Anyone travel within the last 14 days out of country….the new isolation guidelines that came out today do apply…

give me a call or text if you have and I will walk you through it!

!

conference call

call in number for conference calls – for ED group

always the same 705-704-9984

PIN 0001255

communication

Hi all, good group chat this am. Sorry if you couldn’t make it.

If you have questions please ask one of us that was on the call (Evan, Kelly, Deb, Emma, Adam, Heather, Nelson, Jeff, Mike, Kirsten, Stacey) as we can share group brain with you.

Tuesday – heads up – a patient with COVID intubation sim – Dr Jewell and Dr Smith…!! Great SIM . Thank you both in advance.

Allyson Snelling just resent the simcoe muskoka update and the MAHC community test site info about again this am to the emails she has for all Md’s. If you didn’t; get from her please contact with what email you want on these…then you should get all future updates.

Just spoke to Allyson some are easy fixes and some are not.

MD conference call

COVID CHAT for MAHC ED docs tomorrow at 8:30 am.

call 705-704-9984

pin:0001255

Intention is to discuss our updated local plan, answer questions of each other about the covid 8 update from MAHC and community test sites info just sent out. Most of us are Type A ( hint , hint) and no one has all the answers or do we need to micro manage others but lets brainstorm, feel we are all on the same page, and support each other and our care of our community and our nurses/teams, etc. Max time 30 mins.

Update

So – although I am signed out as director the next 9 days I just cancelled our family trip to the USA. Bummer. I know a couple of you who have done the same.

So many of us will be around when we weren’t gonna be before.

Hard times for us all. But safety is likely in numbers for our groups as some of us may get sick and not be able to work. Hopefully not…but likely. And if we aren’t leaving the country then no automatic quarantine or risk of being caught in another country.

Please is you feel sick consider calling me ( or the acting director) to plan what to do with some support. Please be ready as the back up doctor . Also if we are dropping like flies I will be reaching out to community MD’s to back up us and the hospital.

We need to be healthy as a team and help each other ( insert group hug here with a one meter distance between each of us for social isolation)!

I propose we start having “opt in” conference calls as a way to ask questions of each other as MD’s and see what is happening on the front line ( practical stuff ). More info to come.

Hep A

Final update on Hep A issue in Muskoka as public health information I circulated and Liz sent out to all Muskoka Md’s…

If you have questions about a patient in front of you around this issue and need help Angela Hollingshead is happy o help. She has had lots of discussions with public health around this…

ED MAHC COVID 19

Just thought I would send out a couple practical things…

  1. keep reading updates from MAHC , OMA, latest in NEJM, etc as you feel you can to keep up to date with COVID 19 – the media is over the top in lots of ways so just be careful your sources. Some restrictions of public events may be driven by political or “non – science” reasons.
  2. MAHC is gonna try and focus future communications on operational/MAHC and community based efforts as I have asked for more practical frontline guidelines and aid as this is what we need.
  3. limit visitors in ER – this should be enforced at all times
  4. hospital entry screening – starting – as in communication today
  5. If patient being sent to the ER for swab by public health this doesn’t mean they need to be seen by a doctor. If nursing worried about patient then we should see them. I also suggest we offer to see the patient and nursing ask the patient that and chart it…. So far my N of 5 have all declined.
  6. community test sites on the horizon – I’m told – they are awaiting “approval my public health” and then this will be communicated out.
  7. testing at MD discretion …hard to know who to test – travel history and illness is recommended but if was at a conference? or an NBA game this week? Just keep in mind we have limited tests in Ontario and we are still waiting pandemic planning guidance…hopefully this is coming soon.
  8. Donning and doffing update /refresher by Angela Hollingshead (occupational health) at anytime…just give her a call. You could even mock up an intubation scenario with RT/Angela and others if you want to do! If you want me to organize let me know.

COVID 19

I thought this might be a good time to review COVID 19 and coronaviruses.

Intro:

Coronaviruses (CoV) are a large family of viruses that cause illness ranging from the common cold to more severe diseases such as Middle East Respiratory Syndrome (MERS-CoV) and Severe Acute Respiratory Syndrome (SARS-CoV)A novel coronavirus (nCoV) is a new strain that has not been previously identified in humans.  

Coronaviruses are zoonotic, meaning they are transmitted between animals and people.   SARS-CoV was transmitted from civet cats to humans and MERS-CoV from dromedary camels to humans. Several known coronaviruses are circulating in animals that have not yet infected humans. 

Best preventative strategies are: WASH YOUR HANDS; stay 1-3m away from people in social situations; cover your mouth with your elbow if you cough or sneeze; avoid touching your face,nose or eyes. Avoid close contact with people who are sick; stay home when you are sick; and clean and disinfect frequently touched objects and surfaces. Coronavirus is spread by DROPLET transmission and these steps above minimize exposure to droplets.

What about masks?

  • If you are healthy, you only need to wear a mask if you are taking care of a person with suspected 2019-nCoV infection.
  • Wear a mask if you are coughing or sneezing.
  • Masks are effective only when used in combination with frequent hand-cleaning with alcohol-based hand rub or soap and water.

What about Canada? To date there are 77 confirmed cases in Canada, 34 in Ontario. That number will go up.

How infectious is COVID 19?

It looks like it is more infectious that influenza. The R0 is a measure of how readily a virus is transmitted. The R0 for influenza ia 1-2-1.4 and the estimates for COVID 19 are around 3. This means for every one person infected they will pass it along to three other people.

What is the case fatality rate of COVID 19?

This is a moving target. Early in the outbreak when only the sickest patients were being identified, the case fatality rate (CFR) was over 10%. That number is steadily decreasing as more cases are being diagnosed and more testing is being done. The denominator now will include the MANY people who have mild symptoms. Still, the most current estimates have the CFR at 2-3%. A study in the NEJM had the mortality rate estimated at 1.4%. Some areas are reporting mortality rates of less than 1%. We won’t know for a while longer the best estimate for mortality rate but for now it looks to be more serious than seasonal influenza. On average seasonal influenza has a mortality rate of about 0.1%.

Your age matters when estimating mortality rate!

Under the age of 40, the death rate so far is only 0.2%; 0.4% for ages 40-49; 1.3% for 50-59, 3.6% for 60-69; 8% for 70-79 and 15% for 80-89.

Comorbidities Matter:

Death rate higher if you have cardiovascular disease (10.5%), respiratory disease (6.3%) , diabetes (7.3%), hypertension (6%) or cancer (5.6%). The death rate fwith no known conditions is aorund 0.9% currently.

What is the clinical spectrum of the disease?

So far, it seems that fever, dry cough and dyspnea are the commonest symptoms. However, influenza-type symptoms including sore throat, headache and myalgia have also been described in some). So far, about 80% of cases have been classified as mild, 14% severe (dyspnea, pneumonia) and 5% critical (respiratory failure, septic shock, and/or multiple organ dysfunction/failure). Sympotms can atake up to 14 days after exposure to develop.

What should you do if you see a patient with severe acute respiratory illness (SARI) and possible exposure to COVID 19?

Take precautions mentioned previously. Mask on patient. Mask on providers. Gown and eye protection on provider.

Early supportive therapy and monitoring. Give supplemental oxygen therapy immediately to patients with SARI and respiratory distress, hypoxia, or shock.

Use contact precautions when handling contaminated oxygen interfaces of patients with nCoV infection.

Use conservative fluid management in patients with SARI when there is no evidence of shock. Remarks: Patients with SARI should be treated cautiously with intravenous fluids, because aggressive fluid resuscitation may worsen oxygenation, especially in settings where there is limited availability of mechanical ventilation.

Give empiric antimicrobials to treat all likely pathogens causing SARI. Give antimicrobials within one hour of initial patient assessment for patients with sepsis. Although the patient may be suspected to have nCoV, administer appropriate empiric antimicrobials within ONE hour of identification of sepsis. Empiric antibiotic treatment should be based on the clinical diagnosis (community-acquired pneumonia, health care-associated pneumonia [if infection was acquired in healthcare setting], or sepsis), local epidemiology and susceptibility data, and treatment guidelines. Empiric therapy should be de-escalated on the basis of microbiology results and clinical judgment.

Do not routinely give systemic corticosteroids for treatment of viral pneumonia or ARDS outside of clinical trials unless they are indicated for another reason. A systematic review of observational studies of corticosteroids administered to patients with SARS reported no survival benefit and possible harms (avascular necrosis, psychosis, diabetes, and delayed viral clearance). A systematic review of observational studies in influenza found a higher risk of mortality and secondary infections with corticosteroids; the evidence was judged as very low to low quality due to confounding by indication. A subsequent study that addressed this limitation by adjusting for time-varying confounders found no effect on mortality. Finally, a recent study of patients receiving corticosteroids for MERS used a similar statistical approach and found no effect of corticosteroids on mortality but delayed lower respiratory Clinical management of severe acute respiratory infection when Novel coronavirus (2019-nCoV) infection is suspected:

Application of timely, effective, and safe supportive therapies is the cornerstone of therapy for patients that develop severe manifestations of 2019-nCoV. Understand the patient’s co-morbid condition(s) to tailor the management of critical illness and appreciate the prognosis. Communicate early with patient and family.

References

1. Rosjo H, Varpula M, Hagve TA, et al. Circulating high sensitivity troponin T in severe sepsis and septic shock: distribution, associated factors, and relation to outcome. Intensive Care Med 2011;37:77-85. 2. Pocket book of hospital care for children: Guidelines for the management of common childhood illnesses

. 2nd ed. Geneva: WHO; 2013. 3. Gunnerson KJ, Shaw AD, Chawla LS, et al. TIMP2*IGFBP7 biomarker panel accurately predicts acute kidney injury in high-risk surgical patients. J Trauma Acute Care Surg 2016;80:243-9. 4. Oxygen therapy for children: a manual for health workers [http://www.who.int/maternal_child_adolescent/documents/child-oxygen-therapy/en/]. Geneva: WHO; 2016. 5. Global Epidemiological Surveillance Standards for Influenza [http://www.who.int/influenza/resources/documents/influenza_surveillance_manual/en/]. Geneva: WHO; 2014. 6. Shalhoub S, Farahat F, Al-Jiffri A, et al. IFN-alpha2a or IFN-beta1a in combination with ribavirin to treat Middle East respiratory syndrome coronavirus pneumonia: a retrospective study. J Antimicrob Chemother 2015;70:2129-32. 7. ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012;307:2526-33. 8. Riviello ED, Kiviri W, Twagirumugabe T, et al. Hospital Incidence and Outcomes of the Acute Respiratory Distress Syndrome Using the Kigali Modification of the Berlin Definition. Am J Respir Crit Care Med 2016;193:52-9. 9. Khemani RG, Smith LS, Zimmerman JJ, Erickson S, Pediatric Acute Lung Injury Consensus Conference Group. Pediatric acute respiratory distress syndrome: definition, incidence, and epidemiology: proceedings from the Pediatric Acute Lung Injury Consensus Conference. Pediatr Crit Care Med 2015;16:S23-40. 10. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016;315:801-10. 11. Goldstein B, Giroir B, Randolph A, International Consensus Conference on Pediatric Sepsis. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005;6:2-8. 12. Davis AL, Carcillo JA, Aneja RK, et al. American College of Critical Care Medicine Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock. Crit Care Med 2017;45:1061-93. 13. Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996;22:707-10. 14. Infection prevention and control of epidemic-and pandemic prone acute respiratory infections in health care

. Geneva: WHO; 2014. 15. Infection prevention and control during health care for probable or confirmed cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection: Interim guidance. Geneva: WHO; 2015. 16. Schultz MJ, Dunser MW, Dondorp AM, et al. Current challenges in the management of sepsis in ICUs in resource-poor settings and suggestions for the future. Intensive Care Med 2017;43:612-24. 17. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med 2017;43:304-77. 18. Clinical management of human infection with pandemic (H1N1) 2009: revised guidance

. Geneva: WHO; 2009. 19. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med 2006;3:e343. 20. Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam J, Lim WS. Corticosteroids as adjunctive therapy in the treatment of influenza. Cochrane Database Syst Rev 2016;3:CD010406. 21. Delaney JW, Pinto R, Long J, et al. The influence of corticosteroid treatment on the outcome of influenza A(H1N1pdm09)-related critical illness. Crit Care 2016;20:75. 22. Arabi YM, Mandourah Y, Al-Hameed F, et al. Corticosteroid Therapy for Critically Ill Patients with Middle East Respiratory Syndrome. Am J Respir Crit Care Med 2018;197:757-67. 23. Laboratory testing for Middle East Respiratory Syndrome Coronavirus: Interim guidance [http://www.who.int/csr/disease/coronavirus_infections/merslaboratory-testing/en/]. Geneva: WHO; 2018. 24. Ou X, Hua Y, Liu J, Gong C, Zhao W. Effect of high-flow nasal cannula oxygen therapy in adults with acute hypoxemic respiratory failure: a metaanalysis of randomized controlled trials. CMAJ 2017;189:E260-E7. 25. Lee MK, Choi J, Park B, et al. High flow nasal cannulae oxygen therapy in acute-moderate hypercapnic respiratory failure. Clin Respir J 2018;12:2046-56. 26. Luo Y, Ou R, Ling Y, Qin T. The therapeutic effect of high flow nasal cannula oxygen therapy for the first imported case of Middle East respiratory syndrome to China [Chinese]. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2015;27:841-4. Clinical management of severe acute respiratory infection when Novel coronavirus (2019-nCoV) infection is suspected: Interim Guidance 10 27. Rochwerg B, Brochard L, Elliott MW, et al. Official ERS/ATS clinical practice guidelines: noninvasive ventilation for acute respiratory failure. Eur Respir J 2017;50. 28. Arabi YM, Arifi AA, Balkhy HH, et al. Clinical course and outcomes of critically ill patients with Middle East respiratory syndrome coronavirus infection. Ann Intern Med 2014;160:389-97. 29. Leung CCH, Joynt GM, Gomersall CD, et al. Comparison of high-flow nasal cannula versus oxygen face mask for environmental bacterial contamination in critically ill pneumonia patients: a randomized controlled crossover trial. J Hosp Infect 2019;101:84-7. 30. Hui DS, Chow BK, Lo T, et al. Exhaled air dispersion during high-flow nasal cannula therapy versus CPAP via different masks. Eur Respir J 2019;53. 31. Hui DS, Chow BK, Lo T, et al. Exhaled air dispersion during noninvasive ventilation via helmets and a total facemask. Chest 2015;147:1336-43. 32. Detsky ME, Jivraj N, Adhikari NK, et al. Will This Patient Be Difficult to Intubate?: The Rational Clinical Examination Systematic Review. JAMA 2019;321:493-503. 33. Fan E, Del Sorbo L, Goligher EC, et al. An Official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guideline: Mechanical Ventilation in Adult Patients with Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med 2017;195:1253-63. 34. Rimensberger PC, Cheifetz IM, Pediatric Acute Lung Injury Consensus Conference G. Ventilatory support in children with pediatric acute respiratory distress syndrome: proceedings from the Pediatric Acute Lung Injury Consensus Conference. Pediatr Crit Care Med 2015;16:S51-60. 35. ARDS Network Tools. 2014. (Accessed 25 July, 2018, at http://www.ardsnet.org/tools.shtml.) 36. Amato MB, Meade MO, Slutsky AS, et al. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med 2015;372:747-55. 37. Messerole E, Peine P, Wittkopp S, Marini JJ, Albert RK. The pragmatics of prone positioning. Am J Respir Crit Care Med 2002;165:1359-63. 38. Guerin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 2013;368:2159-68. 39. National Heart L, and Blood Institute Acute Respiratory Distress Syndrome Clinical Trials Network,, Wiedemann HP, Wheeler AP, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006;354:2564-75. 40. Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA 2010;303:865-73. 41. Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial Investigators, Cavalcanti AB, Suzumura EA, et al. Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA 2017;318:1335-45. 42. Goligher EC, Kavanagh BP, Rubenfeld GD, et al. Oxygenation response to positive end-expiratory pressure predicts mortality in acute respiratory distress syndrome. A secondary analysis of the LOVS and ExPress trials. Am J Respir Crit Care Med 2014;190:70-6. 43. Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010;363:1107-16. 44. National Heart L, Blood Institute PCTN, Moss M, et al. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Engl J Med 2019;380:1997-2008. 45. Combes A, Hajage D, Capellier G, et al. Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome. N Engl J Med 2018;378:1965-75. 46. Goligher EC, Tomlinson G, Hajage D, et al. Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome and Posterior Probability of Mortality Benefit in a Post Hoc Bayesian Analysis of a Randomized Clinical Trial. JAMA 2018;320:2251-9. 47. Alshahrani MS, Sindi A, Alshamsi F, et al. Extracorporeal membrane oxygenation for severe Middle East respiratory syndrome coronavirus. Ann Intensive Care 2018;8:3. 48. Combes A, Brodie D, Bartlett R, et al. Position paper for the organization of extracorporeal membrane oxygenation programs for acute respiratory failure in adult patients. Am J Respir Crit Care Med 2014;190:488-96. 49. Levy MM, Evans LE, Rhodes A. The Surviving Sepsis Campaign Bundle: 2018 update. Intensive Care Med 2018;44:925-8. 50. Lamontagne F, Meade MO, Hebert PC, et al. Higher versus lower blood pressure targets for vasopressor therapy in shock: a multicentre pilot randomized controlled trial. Intensive Care Med 2016;42:542-50. 51. Rochwerg B, Alhazzani W, Gibson A, et al. Fluid type and the use of renal replacement therapy in sepsis: a systematic review and network metaanalysis. Intensive Care Med 2015;41:1561-71. 52. Rochwerg B, Alhazzani W, Sindi A, et al. Fluid resuscitation in sepsis: a systematic review and network meta-analysis. Ann Intern Med 2014;161:347-55. 53. Loubani OM, Green RS. A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters. J Crit Care 2015;30:653 e9-17. 54. Schmidt GA, Girard TD, Kress JP, et al. Official Executive Summary of an American Thoracic Society/American College of Chest Physicians Clinical Practice Guideline: Liberation from Mechanical Ventilation in Critically Ill Adults. Am J Respir Crit Care Med 2017;195:115-9. 55. Muscedere J, Dodek P, Keenan S, et al. Comprehensive evidence-based clinical practice guidelines for ventilator-associated pneumonia: prevention. J Crit Care 2008;23:126-37. 56. Klompas M, Branson R, Eichenwald EC, et al. Strategies to prevent ventilator-associated pneumonia in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol 2014;35:915-36. 57. Marschall J, Mermel LA, Fakih M, et al. Strategies to prevent central line-associated bloodstream infections in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol 2014;35:753-71. © World Health Organization 2020. All rights reserved. This is a draft. The content of this document is not final, and the text may be subject to revisions before publication. The document may not


Hypertension in the Emergency Department

Sorry, but you do not have permission to view this content.