Indications for use of Tranexamic Acid (TXA)

Indications for use of Tranexamic Acid (TXA)

Trauma

Trial Name: CRASH 2 (Positive trial)

Trial Type: Multicenter, double-blind RCT

Sample size: 20,211

Dose/Route of TXA: Loading dose 1g over 10 min, then infusion of 1g over 8hr

Primary outcome: All-cause mortality within 4 weeks of injury

Secondary outcome: Vascular occlusive events (AMI, stroke, PE, and DVT), surgical intervention, receipt of blood transfusion, and units of blood products transfused

Results:  Reduced All-cause mortality p 0.0035, death due to hemorrhage p 0.0077, no significant vascular occlusion p 0.96

Risk of thrombotic events: No increase in risk

Take home point: The use of TXA in trauma patients with “significant bleeding” reduces all-cause mortality without an increase in thromboembolic events.  This effect seems to be greatest in the subset of patients with severe shock (SBP ≤70mmHg) and when given ≤3 hours from time of injury 

Shakur H et al. Effects of Tranexamic Acid on Death, Vascular Occlusive Events, and Blood Transfusion in Trauma Patients with Significant Haemorrhage. Lancet 2010. PMID: 20554319

Trial Name: MATTERs (Positive trial)

Trial Type: Single center, retrospective, observational study

Sample size: 896

Dose/ route of TXA: 1 g initially, 2nd dose per MD discretion

Primary outcome: 24hr mortality, 48hr mortality, and 30-day mortality

Secondary outcome: Transfusion requirements and rate of thromboembolic complications.

Results: Not significantly decreased 24 hr p >0.05, Significantly decreased 48hrs p 0.004 and 30 day mortality p 0.03

Risk of thrombotic events: Increased overall VTE p 0.001 but patients who had a VTE also had higher burden of injury

Take home point:  Patients with penetrating injuries, requiring blood transfusions within 1hr of presentation the use of TXA reduced overall mortality

Morrison JJ et al. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg 2012. PMID: 22006852

ICH

Trial Name: Meta-Analysis of TXA for Traumatic Brain Injury- negative trial

Trial Type: Meta-analysis and systematic review of RCTs or quasi-RCTs 

Sample size:  510

Outcome: Mortality, neurological function, hematoma expansion

Results: statistically significant reduction in ICH progression with TXA non-statistically significant improvement of clinical outcomes in ED patients with TBI.

Risk of thrombotic events: No adverse effects reported

Take home point: Did not lead to a statistically significant mortality benefit or improved neurological functional status. Further evidence is required to support its routine use in patients with TBI.

Zehtabchi S et al. Tranexamic Acid for Traumatic Brain Injury: A Systematic Review and Meta-Analysis. Am J Emerg Med 2014. PMID: 25447601

Trial Name: Tranexamic Acid for Hyperacute Primary IntraCerebral Haemorrhage (TICH-2)- Negative

Trial Type: International, randomized, double-blind, placebo-controlled, parallel group

Sample size:  2325

Dose of TXA used: 1g IV TXA bolus followed by an 8hr infusion of 1g of TXA 

Outcome:  Functional Status at Day 90, Hematoma Expansion at Day 2, Mean Hematoma Volume Expansion from Baseline to 24hr, Death by Day 7, Death by Day 90

Results: No difference in neurological impairment (mean NIHSS score at day 7), 90-day functional outcomes, length of hospital stay, discharge disposition, venous thromboembolic events, or arterial occlusions

Risk of thrombotic events: None

Take home point: TXA was given >3hrs after stroke onset, patients had more severe strokes, and larger hematoma volumes (>60mLs) than prior studies. Possible benefit if given to a subset of patient within 3 hours with smaller strokes but cannot be recommended at this time in clinical practice for spontaneous ICH based on the results of these trials

Sprigg N et al. Tranexamic Acid for Hyperacute Primary IntraCerebral Haemorrhage (TICH-2): An International Randomised, Placebo-Controlled, Phase 3 Superiority Trial. Lancet 2018. PMID: 29778325

Post Partum Hemorrhage

Trial Name: WOMAN trial – Negative trial

Trial Type: Randomized, double-blind, placebo-controlled trial,

Sample size:  20,060 ≥16 years of age with post-partum hemorrhage after vaginal delivery or caesarean section 

Dose of TXA used: 1 g IV vs matching placebo, If bleeding continued after 30 minutes or stopped and restarted within 24hrs, a second dose of 1g of TXA or placebo was given

Outcome: Initial outcome of all-cause mortality and/or hysterectomy within 42 days of giving birth

Final Primary Outcome: Death from PPH

Results: No difference in all cause mortality or hysterctomy

Risk of thrombotic events:

Take home point: It is difficult to draw definitive conclusions from this trial as the NNT was still large (i.e. ≈250) and the study had a fragility index of 0. Data showed a consistent association of delayed administration of TXA with no benefit

WOMAN Trial Collaborators. Effect of Early Tranexamic Acid Administration on Mortality, Hysterectomy, and Other Morbidities in Women with Post-Partum Haemorrhage (WOMAN): An International, Randomised, Double-Blind, Placebo-Controlled Trial. Lancet 2017. PMID: 28456509

UGIB

Trial Name: Cochrane review

Trial Type: Systematic review and meta-analysis of 8 RCTs

Sample size:  1700

Dose of TXA used: Total daily dose of TXA ranged from 4 – 8g and ranged from 2 – 7 days with both PO and IV adminsteration

Outcome: Primary: all-cause mortality and adverse events

Secondary: Rebleeding and surgery

Results: All-Cause Mortality p 0.007, rebleeding P = 0.07

Risk of thrombotic events: No difference in thromboembolic events (only evaluated in 4 trials)

Take home point: May benefit in higher risk patients but better RCTs required to confirm or refute evidence. HALT IT trial underway currently with N of 12000

Bennett C et al. Tranexamic Acid for Upper Gastrointestinal Bleeding (Review). Cochrane Database Syst Rev 2014. PMID: 25414987

Epistaxis

Trial Name: Zahed et al 2017 – Positive study

Trial Type: Randomized, parallel group clinical trial

Sample size:  124 on antiplatelets

Dose of TXA used: topical TXA (500mg in 5mL) or anterior nasal packing.

Outcome: Primary outcome resolution at 10 minutes. Secondary outcomes were re-bleeding rate at 24hours and one week, ED length of stay, and patient satisfaction

Results: epistaxis treatment with topical application of TXA resulted in faster bleeding cessation (NNT 2) , less re-bleeding at 1-week, shorter ED LOS, and higher patient satisfaction as compared with anterior nasal packing.

Risk of thrombotic events: not evaluated

Take home point: Do it!

Zahed R et al. Topical Tranexamic Acid Compared With Anterior Nasal Packing or Treatment of Epistaxis in Patients Taking Antiplatelet Drugs: Randomized Controlled Trial. Acad Emerg Med 2017. PMID: 29125679

Post-Tonsillectomy Bleeding

Trial Name: Meta-Analysis 2012

Trial Type: Systematic review and meta-analysis

Sample size:  7 studies with 2,444 patients

Dose of TXA used: 250mg for children <25kg, 500mg for children >25kg

Outcome: mean volume of blood loss

Results: TXA led to a significant reduction of tonsillectomy blood loss volume but had no impact on the rate of patients with post-tonsillectomy hemorrhage.

Risk of thrombotic events: Not evaluated

Take home point:  In patients with minor post-tonsillectomy bleeding consider using nebulized TXA to reduce or stop bleeding.  

Chan CC et al. Systematic Review and Meta-Analysis of the Use of Tranexamic Acid in Tonsillectomy. Eur Arch Otorhinolaryngol 2013. PMID: 22996082

Heavy Menstrual Bleeding

Trial Name: Cochrane Review

Trial Type: Systematic review and metanalysis

Sample size:  1312 in 13 RCTs

Dose of TXA used: majority of studies used regular dose TXA (ranging from 3 g/day to 4 g/day), Four other studies used low‐dose TXA (ranging from 2 g/day to 2.4 g/day) 

Outcome: Volume of blood loss, Quality of life

Results:  Appears effective for treating HMB compared to placebo, NSAIDs, Oral luteal progestogens, ethamsylate or herbal remedies but less effective than levonorgestrel intrauterine system

Risk of thrombotic events: Not studied in most RCTs

Take Home point: Antifibrinolytic treatment (such as TXA) appears effective for treating HMB compared to placebo, NSAIDs, oral luteal progestogens, ethamsylate, or herbal remedies. There were too few data for most comparisons to determine whether antifibrinolytics were associated with increased risk of adverse events, and most studies did not specifically include thromboembolism as an outcome.

Bryant-Smith AC, Lethaby A, Farquhar C, Hickey M. Antifibrinolytics for heavy menstrual bleeding. Cochrane Database of Systematic Reviews 2018, Issue 4. Art. No.: CD000249. DOI: 10.1002/14651858.CD000249.pub2

Hemoptysis

Trial Name: Inhaled TXA RCT 2018

Trial Type: Prospective, double-blind, placebo-controlled randomized controlled trial 

Sample size:  47

Dose of TXA used: nebulized TXA (500mg/5mL

Primary outcome: rate of complete resolution of hemoptysis during first 5 days from admission, difference in daily volume of expectorated blood

Secondary outcome: rate of interventional bronchoscopy, rate of angiographic embolization, rate of surgery, mean hospital LOS

Results: Resolution of hemoptysis within 5 days of admission, NNT = 2, P<0.0005. Statistically shorter LOS, less invasive procedures

Risk of thrombotic events: not studied

Take home point: Although this was a small study, the advantages of inhaled TXA vs placebo in patients with non-massive hemoptysis included faster resolution of hemoptysis, shorter hospital LOS, fewer invasive procedures, and although not statistically significant, a trend toward improved 30d mortality.

Wand O et al. Inhaled Tranexamic Acid for Hemoptysis Treatment: A Randomized Controlled Trial. Chest 2018. PMID: 30321510

References:

See above

RebelEM

“Pressors” in Distributive Shock in Adults

“Pressors” in Distributive Shock in Adults

Thank you, Dr Dastmalchi, for requesting this POTD. I will review “pressors” for cardiogenic shock separately

• Vasopressors- Pure vasoconstriction without any inotropy eg Phenylephrine and Vasopressin

• Inotrope- Increase cardiac contractility à improving SV and cardiac output without any vasoconstriction eg Milrinone

• Inopressors - a combination of vasopressors and inotropes, because they lead to both increased cardiac contractility and increased peripheral vasoconstriction eg Norepinephrine, Epinephrine and Dopamine

Norepinephrine- Inopressor

• First line vasopressor in septic shock per Surviving Sepsis Guidelines

• Less arrhythmogenic than Epinephrine and Dopamine

Mechanism of action

• Stimulates alpha-1 and alpha-2 receptors

• Small amount of beta-1 agonist- modest inotropic effect

• Increased coronary blood flow and afterload

• Increases venous tone and return with resultant increased preload

Adverse effects

• Norepinephrine is considered safer than both Epinephrine and Dopamine.

• ARR of 11% compared to dopamine with NNT 9

• NE superior in improving CVP, urinary output, and arterial lactate levels compared to Epinephrine, Phenylephrine, and Vasopressin.

Indications

• First-line pressor choice in distributive shock, including both neurogenic and septic shock

• Norepinephrine as the only first-line pressor per SSC guidelines

Dosing

• Use weight-based dosing to avoid the adverse effects associated with norepinephrine use

• Weight-based dosing is based on GFR

• Norepinephrine has a rapid onset of action (minutes) and can be titrated every 2-5 minutes

Epinephrine- Inopressor

Mechanism of action

• Beta-1 and beta-2 receptors agonism à more inotropic effects than norepinephrine

• Epinephrine greatly increases chronotropy (heart rate) and thus stroke volume

• Some stimulatory effect on alpha-1 receptors

• Lower doses (1-10 mcg/min) à a beta-1 agonist

• Higher doses (greater than 10 mcg/min) à an alpha-1 agonist

Adverse effects

• Associated with an increased risk of tachycardia and lactic acidosis

• Hyperglycemia

• Increased incidence of arrhythmogenic events associated with epinephrine

• More difficult use lactate as a marker of the patient’s response to treatment

Indications

• SSC guidelines recommend epinephrine as a second-line agent, after norepinephrine

• “push-dose pressor”

• Due to beta-2 receptors agonism causing bronchodilation, epinephrine is first-line agent for anaphylactic shock

Dosing

• Guidelines for anaphylactic shock recommend an initial bolus of 0.1 mg (1:10,000) over 5 minutes, followed by an infusion of 2-15 mcg/min however associated with adverse cardiovascular events

• For septic shock start epinephrine at 0.05 mcg/kg/min (generally 3-5 mcg/min) and titrate by 0.05 to 0.2 mcg/kg/min every 10 minutes. maximum drip rate is 2 mcg/kg/min

Dopamine- Inopressor

• Fallen out of favor

• Associated with higher arrhythmogenic events

Mechanism of action

• Effects are dose-dependent

• Low doses à dopaminergic receptors à leads to renal vasodilation à increased renal blood flow and GFR although studies failed to demonstrate improved renal function with dopamine use clinically

• Moderate doses à beta-1 agonism à increased cardiac contractility and heart rate

• High doses à alpha-1 adrenergic effects à arterial vasoconstriction and increased blood pressure

Adverse Effects

• Several large, multi-center studies that demonstrate increased morbidity associated with its use

• Significantly higher rates of dysrhythmias à NNH 9

Indications

• Rescue medication when shock is refractory to other medications

Dosing

• Start at 2 mcg/kg/min and titrate to a maximum dose of 20 mcg/kg/min.

• Less than < 5 mcg/kg/min à vasodilation in the renal vasculature

• 5-10mcg/kg/min à beta-1 agonism

• 10 mcg/kg/min à alpha-1 adrenergic

Vasopressin- Vasopressor

• Add vasopressin (doses up to 0.04 units/min) to norepinephrine to help achieve MAP target or decrease norepinephrine dosage

• Restore catecholamine receptor responsiveness, particularly in cases of severe metabolic acidosis.

• pH independent

• Pure pressor à increase vasoconstriction with minimal effects on chronotropy or ionotropy

Mechanism of action

• At low doses (< 0.04 units/min) à increases vascular resistance (V1)

• No effect on heart rate and cardiac contractility

Adverse Effects

• Vasopressin has been shown to be as safe as norepinephrine at lower doses

• Increases SVR and afterload and decreases cardiac output although unclear if effect significant at lower doses

Indications

• Second line vasopressors per SSC guidelines for septic shock

• pH independent- Vasopressin in combination with epinephrine demonstrated improved ROSC in cardiac arrest patients with initial arterial pH <7.2 compared with epinephrine alone

Dosing

• Steady dose at 0.03-0.04 units/min

• Vasopressin is not titrated to clinical effect as are other vasopressors

• Think about it more as a replacement therapy and treatment of relative vasopressin deficiency

Phenylephrine- Vasopressor

• Pure pressor à increase vasoconstriction with minimal effects on chronotropy or ionotropy

• SSC guidelines does not make rated recommendations on Phenylephrine

• Limited clinical trial data

Mechanism of action

α1 agonism with peripheral vasoconstriction

Adverse Effects

• Bradycardia - decrease in heart rate mediated by the carotid baroreceptor reflex 2/2 increase in SVR

• Increases SVR and afterload and decreases cardiac output

Indications

• Patients that are susceptible to beta-adrenergic generated arrhythmia

• Push dose formulation

• Refractory shock

Dosing

0.1-2mcg/kg/min (onset: minutes, duration: up to ~20 minutes)

References:

Emdocs

LITFL

Pollard, Sacha, Stephanie B. Edwin, and Cesar Alaniz. "Vasopressor and inotropic management of patients with septic shock." Pharmacy and Therapeutics 40.7 (2015): 438.

Amlal, Hassane, Sulaiman Sheriff, and Manoocher Soleimani. "Upregulation of collecting duct aquaporin-2 by metabolic acidosis: role of vasopressin." American Journal of Physiology-Cell Physiology 286.5 (2004): C1019-C1030.

Khanna, Ashish, and Nicholas A. Peters. "The Vasopressor Toolbox for Defending Blood Pressure."

Turner, DeAnna W., Rebecca L. Attridge, and Darrel W. Hughes. "Vasopressin associated with an increase in return of spontaneous circulation in acidotic cardiopulmonary arrest patients." Annals of Pharmacotherapy 48.8 (2014): 986-991.

Targeted Temperature Management

Great job on resuscitating that V fib cardiac arrest and achieving sustained ROSC. 

Now what? Cool them!

Whether you cool them or not could determine whether your patient goes into multisystem organ failure in the ICU or walks out of the hospital few weeks later.

What:

Targeted temperature management (TTM) to improve survival and neurological outcomes among comatose survivors of patients with cardiac arrest

Who:

Adults with out-of-hospital cardiac arrest with an initial shockable rhythm and nonshockable rhythm

Inclusion criteria (must meet all criteria)

• Postcardiac arrest status (any rhythm as a cause of arrest is eligible)

• ROSC < 30 minutes from EMS/code team arrival

• Time at induction < 6 hours from ROSC

• Comatose status (patient does not follow commands)

• MAP ≥ 65 mm Hg (may include use of vasopressor drugs)

Exclusions may include

• DNR advanced directive, MOLST, poor baseline status, or terminal disease

• Traumatic etiology for the arrest

• Active bleeding or known intracranial bleeding (relative)

• Cryoglobulinemia (relative)

• Pregnancy (relative; consider obstetrician/gynecologist consultation)

• Recent major surgical procedure (relative)

• Severe sepsis/septic shock as cause of arrest (relative)

Why:

• Decreased fever-related tissue injury

• Reduction in ischemic-reperfusion injury

• Cerebral metabolic rate decreases by a 6-7% for every 1ºC drop in body temperature which reducing oxygen demand, preserving phosphate compounds and preventing lactate production and acidosis

• Bernard, et al (2002) found an Absolute Risk Reduction (ARR) for death or severe disability of 23%, NNT was 4.5

• The Hypothermia After Cardiac Arrest (HACA) Group (2002) found an ARR for unfavourable neurological outcome of 24%, and NNT of 4

How:

• IV cold saline 2-3 mL/kg

• Cooling vest and cooling machine- Arctic Sun

• If shivering does not occur, do not use neuromuscular blockade

• If paralysis employed, titrate to degree of shivering- do not need train-of-four monitoring

• Sedation of choice is institution dependent (MMC CICU uses Fentanyl and Midazolam)

When:

Initiation of TTM within122 minutesof hospital admission was associated with improved survival.
Most guidelines recommend initiation within6 hours

What temperature should be targeted:

This remains controversial, with guidelines accepting a range of temperature targets from 33-36C. Available evidence shows no benefit to hypothermia (33C) compared to normothermia (36C). In the absence of evidence, targeting 36C is prudent

• TTM36 is more hemodynamically stable than TTM33, which is relevant because these are often very unstable patients.

• TTM36 avoids electrolytic shifts associated with raising and lowering the temperature.

• Hypothermia at 33C suppresses immune function and associates with increased rates of pneumonia.

• TM33 will induce bradycardia, which is dangerous in patients with underlying torsades de pointes.

References

Bernard SA et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557-63. PMID 11856794

Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549-56. PMID 11856793

Nielsen N et al. Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest. N Engl J Med 2013; 369: 2197-206. PMID 24237006

Stanger, Dylan, et al. "Door‐to‐targeted temperature management initiation time and outcomes in out‐of‐hospital cardiac arrest: insights from the Continuous Chest Compressions Trial." Journal of the American Heart Association 8.9 (2019): e012001.

Donnino, Michael W., et al. "Temperature management after cardiac arrest: an advisory statement by the advanced life support task force of the international liaison committee on resuscitation and the American Heart Association emergency cardiovascular care committee and the council on cardiopulmonary, critical care, Perioperative and Resuscitation." Circulation 132.25 (2015): 2448-2456.

REBEL EM
LITFL
EB Medicine
Mayo Clinic Florida TTM Guideline