Tag Archives: Jordan Spurling

Tranexamic Acid in Trauma by Jordan Spurling

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Introduction

  1. Trauma is the leading cause of death in individuals up to 45 years old and the fourth leading cause of death overall for all ages.1
  2. Uncontrolled hemorrhage is the leading cause of early mortality in major trauma.2
  3. Trauma-associated hemorrhagic death occurs as an effect of uncontrolled bleeding and trauma-induced coagulopathy.3
  4. Tranexamic acid is an antifibrinolytic medication that works by forming a reversible complex that displaces plasminogen from fibrin resulting in inhibition of fibrinolysis.4
  5. Tranexamic acid is readily available, simple to administer, relatively inexpensive, with minimal side effects.

Pharmacology

 Tranexamic Acid
DoseLoading dose: 1 g over 10 minutes started within 3 hours of injury2 gram via slow IV Push*   Maintenance: 1 g over the next 8 hours as a continuous infusion
AdministrationLoading dose:  administer undiluted   Max rate:100 mg/minute   For continuous IV infusions: dilute with compatible solutions and administer at a rate not to exceed 100 mg/minute
PK/PDDistribution: Vd: IV: 9 to 12 L   Protein binding: ~3%, primarily to plasminogen   Half-life elimination: ~2 hours   Excretion: Urine (>95% as unchanged drug)
Adverse EffectsHypersensitivity reactions, ocular effects, seizures and myoclonus, thromboembolic effects, abdominal pain, headache, back pain
*Emerging data from prehospital and military data use

Overview of Evidence

Author, year Design/ sample sizeIntervention & ComparisonOutcome
Morrison, 2012○ Observational (n=896)○ TXA 1g bolus + repeat prn vs placebo.All-cause mortality overall within 48 hours and in hospital mortality significantly reduced with TXA
Roberts, 2013○ Randomized placebo-controlled (n = 20,2011)○ TXA 1g bolus + 1g over 8 hours vs placebo○ All-cause mortality at 28 days was significantly reduced by TXA ○ Treatment within 1 hour and 1-3 hours from injury significantly reduced the risk of death due to bleeding
Sprigg, 2018○ Randomized placebo-controlled (n= 2325)○ TXA 1 g bolus + 1g over 8 h infusion vs placebo○ Patients in the tranexamic acid group experienced a reduction in early deaths and serious adverse events, but not long term functional status
Roberts, 2019○ Randomized, placebo-controlled (n=12737)○ TXA 1 g bolus + 1g over 8 hours vs placebo○ Treatment within 3 h of injury reduced head injury-related death.
Rowell, 2020○ Double-blinded, randomized ( n= 966)● TXA 1 g bolus + 1 g 8-hour infusion vs 2 g bolus bolus + placebo infusion vs placebo bolus + placebo infusion○ No statistically significant difference in 28-day mortality, favorable neurologic function, 6 month disability rating score, or progression of intracranial hemorrhage
Roberts, 2020○ Randomized placebo-controlled (n = 12,009)○ TXA 1 g + 3g infusion vs placebo○ No significant difference in death due to bleeding within 5 days
Bossers, 2021● Prospective observational cohort (n = 1827)○ Pre-hospital TXA vs no TXA patients with TBI○ No association between TXA and mortality was found at 30 days ○ TXA was associated with increased mortality in patients with isolated TBI
Guyette, 2021○ Double-blind, placebo-controlled, randomized ( n= 927)○ TXA 1 g bolus only vs TXA 1g  + 1 g infusion vs TXA 1g bolus + 1g bolus + 1g infusion vs placebo bolus + placebo infusion○ Prehospital administration of tranexamic acid compared with placebo did not result in a lower rate of 30-day mortality in this population. ○ No differences were found in 24-hour mortality or in-hospital mortality
Mahmood, 2021○ Randomized placebo-controlled (n = 1767)○ TXA 1 g bolus + 1 vs placebo○ No evidence that TXA prevents IPH expansion
Gruen, 2023○ Double-blind, randomized, placebo-controlled  (n = 1310)○ TXA 1 g bolus prior + infusion vs matched placebo○              No difference in survival with a favorable functional outcome at 6 months ○              No difference in 6 months mortality

Conclusions

  • Tranexamic acid has been studied in pre-hospital, hospital, and combat setting in patients who have sustained a traumatic injury
  • Efficacy of tranexamic acid was demonstrated in some studies above, while other studies failed to show a significant difference in outcomes
  • Dosing of tranexamic acid varied significantly in the above studies, however one dosing regimen has been widely adopted
  • Tranexamic acid has minimal adverse effects, is relatively inexpensive, and readily available in many settings

References

  1. Rhee P, Joseph B, Pandit V, et al. Increasing trauma deaths in the United States. Ann Surg. 2014;260(1):13-21. doi:10.1097/SLA.0000000000000600
  2. Callcut RA, Kornblith LZ, Conroy AS, et al. The why and how our trauma patients die: A prospective Multicenter Western Trauma Association study. J Trauma Acute Care Surg. 2019;86(5):864-870. doi:10.1097/TA.0000000000002205
  3. Latif RK, Clifford SP, Baker JA, et al. Traumatic hemorrhage and chain of survival. Scand J Trauma Resusc Emerg Med. 2023;31(1):25. Published 2023 May 24. doi:10.1186/s13049-023-01088-8
  4. Hijazi N, Abu Fanne R, Abramovitch R, et al. Endogenous plasminogen activators mediate progressive intracerebral hemorrhage after traumatic brain injury in mice. Blood. 2015;125(16):2558-2567. doi:10.1182/blood-2014-08-588442
  5. Cai J, Ribkoff J, Olson S, et al. The many roles of tranexamic acid: An overview of the clinical indications for TXA in medical and surgical patients. Eur J Haematol. 2020;104(2):79-87. doi:10.1111/ejh.13348
  6. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg. 2012;147(2):113-119. doi:10.1001/archsurg.2011.287
  7. Roberts I, Shakur H, Coats T, et al. The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients. Health Technol Assess. 2013;17(10):1-79. doi:10.3310/hta17100
  8. Sprigg N, Flaherty K, Appleton JP, et al. Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial. Lancet. 2018;391(10135):2107-2115. doi:10.1016/S0140-6736(18)31033-X
  9. CRASH-3 trial collaborators. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury
  10. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved January 17, 2021, from http://www.micromedexsolutions.com/

Seizure Prophylaxis in Traumatic Brain Injury by Jordan Spurling

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Introduction

  1. Traumatic brain injury (TBI) is a leading cause of death and disability in the United States.
  2. The Brain Trauma Foundation updated its guidelines for the management of severe TBI in 2016; however, there remains a lack of randomized clinical trials addressing many aspects of care in TBI patient.
  3. The incidence of early post-traumatic seizures may be as high as 30 percent in patients with severe TBI
  4. Antiseizure medications in acute management of TBI has been shown to reduce incidence of early seizures but has not been shown to prevent later development of epilepsy
  5. Prevention of early seizures is beneficial in order to prevent status epilepticus, further aggravating systemic injury.
  6. The Brain Trauma Foundation guidelines recommend phenytoin for early post-traumatic seizures for 7 days following injury, however levetiracetam is commonly used in this setting.

Pharmacology

 PhenytoinValproic AcidLevetiracetamLacosamide
DoseLoading dose: 17 to 20 mg/kg IV (max dose 2 g)   Maintenance dose: 100 mg every 8 hours or 5 mg/kg/day divided q8h (individual doses not to exceed 400 mg) Duration not to exceed 7 days10 – 15 mg/kg/dayLoading dose: 20 mg/kg IV infused over 5-20 min   Maintenance dose: 1 g IV over 15 min every 12 hours for 7 days (may be increased to 1.5 g q12)50 – 100 mg IV twice daily   May give loading dose of 200 mg
Administration IV piggyback rate of ≤50 mg/minuteIV piggyback over 60 minutes at a rate ≤20 mg/minuteIV push or piggyback over 5-20 minBolus: May be administered undiluted at ≤80 mg/minute   Infusion: over 30 to 60 minutes
PK/PDOnset: 30 min – 1 hour   Half-life:10 to 12 hours.Peak: <1 hour   Half-life:9 to 19 hoursPeak: 5-30 minutes   Half-life: 6-8 hoursPeak: < 1 hour   Half-life: ~13 hours
Adverse EffectsHematologic effects, cardiovascular effects, CNS effects, gingival hyperplasia, hepatotoxicityCNS effects, hematologic effects, hepatotoxicity, encephalopathy, pancreatitisCNS depression, hypersensitivity reactions, psychiatric and behavioral abnormalities, increased blood pressure, astheniaCardiac arrhythmias including bradycardia, AV block, CNS effects
WarningsVesicant, acute toxicityNot recommended for post-traumatic seizure prophylaxis in patients with acute head traumaCaution in renal impairment.Administer loading doses under medical supervision due to increased incidence of CNS adverse reactions

Guideline Recommendation

JournalRecommendations
Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition – 2017Phenytoin is recommended to decrease the incidence of early PTS (within 7 d of injury), when the overall benefit is thought to outweigh the complications associated with treatment. There is insufficient evidence to recommend levetiracetam compared with phenytoin regarding efficacy in preventing early post-traumatic seizures and toxicity.

Overview of Evidence

Author, yearDesign/ sample sizeIntervention & ComparisonOutcome
Temkin, 1990A randomized, double-blind study   N = 404Phenytoin vs PlaceboWithin the first week 3.6% of phenytoin patients experienced seizure compared to 14.2% (p<0.001)   Between day 8-1 year 21.5% of patients in phenytoin group experienced seizure compared to 15.7% in placebo group   Phenytoin is effective in reducing seizures within the first 7 days after severe head injury
Young, 2004Randomized, Double-Blinded, Placebo- Controlled Trial in pediatric patients (age < 16 yo)

N = 102		Phenytoin vs Placebo for prevention of early posttraumatic seizuresDuring the 48-hour observation period, 3 of 46 (7%) patients in the phenytoin group and 3 of 56 (5%) patients in the placebo group experienced a posttraumatic seizure. No significant difference in survival or neurologic outcome between the two groups. Phenytoin did not significantly reduce the rate of posttraumatic seizures at 48 hours, neurologic outcomes, or overall survival at 30 days.
Jones, 2008Prospective, single-center trial   N = 32Phenytoin vs Levetiracetam in patients with severe TBI (GCS 3-8)Patients treated with levetiracetam and phenytoin had equivalent incidence of seizure activity (p = 0.556)   Patients receiving levetiracetam had a higher incidence of abnormal EEG findings (p = 0.003).   Levetiracetam is as effective as phenytoin in preventing early posttraumatic seizures but is associated with an increased seizure tendency on EEG
Temkin, 1990A randomized, double-blind study N = 404Phenytoin vs PlaceboWithin the first week 3.6% of phenytoin patients experienced seizure compared to 14.2% (p<0.001)   Between day 8-1 year 21.5% of patients in phenytoin group experienced seizure compared to 15.7% in placebo group   Phenytoin is effective in reducing seizures within the first 7 days after severe head injury
Szaflarski, 2009Prospective, single-center, randomized, single-blinded comparative trial N = 52Levetiracetam vs Phenytoin in patients with severe traumatic brain injury (sTBI) or subarachnoid hemorrhageLevetiracetam patients experienced better long-term outcomes than those on phenytoin.   No differences between groups in seizure occurrence during cEEG (levetiracetam 5/34 vs. phenytoin 3/18; P = 1.0) or at 6 months (levetiracetam 1/20 vs. phenytoin 0/14; P = 1.0), or mortality (levetiracetam 14/34 vs. phenytoin 4/18; P = 0.227).   Lower frequency of worsened neurological status (P = 0.024), and gastrointestinal problems (P = 0.043) in levetiracetam group   Levetiracetam improved long-term outcomes of compared to phenytoin with less ADRs and may be an alternative.
Chi-yuan, 2010Retrospective, cohort study   N = 171Sodium Valproate vs Placebo in early posttraumatic seizures in traumatic brain injury (TBI) patients.  No patients who received sodium valproate treatment experienced seizures; however, this was not statistically significant.   Sodium valproate is effective in decreasing the risk of early posttraumatic seizures in severe TBI patients
Inaba, 2012Prospective, comparative study   N = 1,191Levetiracetam vs Phenytoin for prevention of early post-traumatic seizuresNo difference in seizure rate (1.5% vs.1.5%, p = 0.997)   No difference between levetiracetam and phenytoin in the prevention of early post traumatic seizures, mortality or ADRs in patients following TBI.
Caballero, 2013Multicenter retrospective analysis   N = 90Phenytoin vs Levetiracetam in TBI with at least one day of EEG monitoringPrevalence of EEG-confirmed seizure activity was similar between the levetiracetam and phenytoin groups (28% vs 29%; p = .99).   The median daily cost of levetiracetam therapy was $43 compared to $55 for phenytoin therapy and monitoring (p = .08).   Levetiracetam may be an alternative treatment option for seizure prevention inTBI patients in the ICU while also providing lower costs for drug therapy and monitoring.  
  Kruer, 2013Retrospective observational study   N = 109Phenytoin vs Levetiracetam in patients with a TBI and GCS < 8.79 out of 81 (98%) patients admitted between 2000 and 2007 received PHT, whereas 18 of 28 (64%) patients admitted between 2008 and 2010 received LEV. 1 patient out of 89 receiving phenytoin had a posttraumatic seizure and 1 patient out of 20 recieving levetiracetam experiences a posttraumatic seizure   Only 2 patients experienced posttraumatic seizure after receiving AED, indicating low incidence of posttraumatic seizures.
Gabriel, 2014Single-center, prospective cohort analysis   N = 19Phenytoin vs Levetiracetam after severe TBINo difference in  Glasgow Outcome Scale–Extended score assessed ≥6 months after injury   No difference in early seizures (p = 0.53) or late seizures (p = 0.53)   Higher days with fever experienced in the hospital in the phenytoin group.   Long-term functional outcome in patients who experienced a TBI was not affected by treatment with PHT or LEV.
Khan, 2016Randomized controlled trial N = 154Phenytoin vs Levetiracetam in patients with moderate to severe head traumaPhenytoin was effective in preventing early post traumatic seizures in 73 of 77 patients (94.8%)   Levetiracetam effectively controlled seizures in 70 of 77 patients (90.95%) cases   No statistically significant difference in the efficacy of Phenytoin and Levetiracetam in prophylaxis of early post-traumatic seizures in moderate to severe traumatic brain injury.

Conclusions

  • The Brain Trauma Foundation guidelines recommend phenytoin for early post-traumatic seizures for 7 days following injury, however levetiracetam is commonly used in this setting.
  • In recent studies, lacosamide and levetiracetam showed no difference compared to phenytoin in prevention of early post-traumatic seizures following TBI
  • Less side effects were associated with levetiracetam and lacosamide compared to phenytoin when used in seizure prophylaxis in TBI.

References

  1. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved October  17, 2023, from http://www.micromedexsolutions.com/
  2. Carney N, Totten AM, O’Reilly C, et al. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery. 2017;80(1):6-15. doi:10.1227/NEU.0000000000001432
  3. Frey LC. Epidemiology of Posttraumatic Epilepsy: A critical review. Epilepsia. 2003;44(s10):11-17. doi:10.1046/j.1528-1157.44.s10.4.x
  4. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved October 13, 2023, from http://www.micromedexsolutions.com/
  5. Temkin NR, Dikmen SS, Wilensky AJ, Keihm J, Chabal S, Winn HR. A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med. 1990;323(8):497-502. doi:10.1056/NEJM199008233230801
  6. Young KD, Okada PJ, Sokolove PE, et al. A randomized, double-blinded, placebo-controlled trial of phenytoin for the prevention of early posttraumatic seizures in children with moderate to severe blunt head injury. Annals of Emergency Medicine. 2004;43(4):435-446. doi:10.1016/j.annemergmed.2003.09.016
  7. Jones KE, Puccio AM, Harshman KJ, et al. Levetiracetam versus phenytoin for seizure prophylaxis in severe traumatic brain injury. Neurosurg Focus. 2008;25(4):E3. doi:10.3171/FOC.2008.25.10.E3
  8. Szaflarski JP, Lindsell CJ, Zakaria T, Banks C, Privitera MD. Seizure control in patients with idiopathic generalized epilepsies: EEG determinants of medication response. Epilepsy Behav. 2010;17(4):525-530. doi:10.1016/j.yebeh.2010.02.005
  9. Ma CY, Xue YJ, Li M, Zhang Y, Li GZ. Sodium valproate for prevention of early posttraumatic seizures. Chin J Traumatol. 2010;13(5):293-296.
  10. Inaba K, Menaker J, Branco BC, et al. A prospective multicenter comparison of levetiracetam versus phenytoin for early posttraumatic seizure prophylaxis. J Trauma Acute Care Surg. 2013;74(3):766-773. doi:10.1097/TA.0b013e3182826e84
  11. Caballero GC, Hughes DW, Maxwell PR, Green K, Gamboa CD, Barthol CA. Retrospective analysis of levetiracetam compared to phenytoin for seizure prophylaxis in adults with traumatic brain injury. Hosp Pharm. 2013;48(9):757-761. doi:10.1310/hpj4809-757
  12. Kruer RM, Harris LH, Goodwin H, et al. Changing trends in the use of seizure prophylaxis after traumatic brain injury: A shift from phenytoin to Levetiracetam. Journal of Critical Care. 2013;28(5). doi:10.1016/j.jcrc.2012.11.020
  13. Gabriel WM, Rowe AS. Long-term comparison of GOS-E scores in patients treated with phenytoin or levetiracetam for posttraumatic seizure prophylaxis after traumatic brain injury. Ann Pharmacother. 2014;48(11):1440-1444. doi:10.1177/1060028014549013
  14. Khan SA, Bhatti SN, Khan AA, et al. Comparison Of Efficacy Of Phenytoin And Levetiracetam For Prevention Of Early Post Traumatic Seizures. J Ayub Med Coll Abbottabad. 2016;28(3):455-460.
  15. Kwon YH, Wang H, Denou E, et al. Modulation of Gut Microbiota Composition by Serotonin Signaling Influences Intestinal Immune Response and Susceptibility to Colitis. Cell Mol Gastroenterol Hepatol. 2019;7(4):709-728. doi:10.1016/j.jcmgh.2019.01.004