Category Archives: Neurology

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

Alteplase for Acute Ischemic Stroke

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Introduction  

  1. Alteplase (rt-PA) has been used for acute ischemic stroke since its approval by the FDA in 1996 after publication of promising results of the NINDS trial 
  2. NINDS trial has been criticized for its strict inclusion criteria and all major clinical trials since have sought to show benefit in those patients excluded from the NINDS trial 
  3. Recent re-analysis of the ECASS III trial has been published using independent patient level data 

Pharmacology

MOA Initiates fibrinolysis by binding to fibrin in a thrombus and converts entrapped plasminogen to plasmin   
Dose Patient weight <100 kg: 0.09 mg/kg (10% of 0.9 mg/kg dose) as an IV bolus over 1 minute, followed by 0.81 mg/kg (90% of 0.9 mg/kg dose) as a continuous infusion over 60 minutes.      Patient weight ≥100 kg: 9 mg (10% of 90 mg) as an IV bolus over 1 minute, followed by 81 mg (90% of 90 mg) as a continuous infusion over 60 minutes.  
Administration 10% given as IV bolus over 1 minute; remainder infused over 1 hour  
PK/PD Duration: 1 hour after infusion terminated, bleeding risk can occur past 1 hour    Distribution: approximates plasma volume   Half-life elimination: 5 minutes    Excretion: hepatic and plasma clearance   
Adverse Effects Intracranial hemorrhage  Angioedema  GI/GU hemorrhage   
Drug Interactions and Warnings Tranexamic acid, avoid combination   Internal bleeding, thromboembolic events, cholesterol embolization   
Contraindications Active internal bleeding   
Ischemic stroke within 3 months except when within 4.5 hours
Severe uncontrolled hypertension   
Compatibility May be diluted in equal volume with:   0.9% sodium chloride   D5W   NOT compatible with lactated ringers  

Overview of the Evidence  

Trials that showed no benefit

 Design/sample sizeTime WindowPatient PopulationIntervention & ComparisonOutcomes
NINDS-1 (1995)PRCT (n=291)≤ 3 hours •            Mean 67 y •            Median NIHSS 14 •   TTT 0-90 m 47% •  TTT 91-180 m 53%•       0.9 mg/kg rt-PA (Max 90 mg) •       Placebo No difference in NIHSS score at 24 hours
ECASS II (1998)PRCT ( n=800) ≤ 6 hours •       Median 68 y •       Median NIHSS 11 •       TTT 0-3 h 19.8%  •       TTT 3-6 h 80.2%•       0.9 mg/kg rt-PA (Max 90 mg)  •       PlaceboNo difference in functional outcomes at 90 days No significant difference in morbidity, despite 2.5 fold ↑ SICH in rtPA group 
IST-3  (2012) PRCT (n =3035)≤ 6 hours  •       1407 patients >80 y • 201 patients >90 
y 
• TTT 4.2 h 		•       0.9 mg/kg t-PA (Max 90 mg) •       Placebo  No difference in functional outcomes
at 180 days   ↑ 7-day mortality in rt-PA group (11% vs.
7%) 
↑ SICH in rt-PA group 
(7% vs. 1%) 

Trials that showed benefit

 Design/sample sizeTime WindowPatient PopulationIntervention & ComparisonOutcomes
NINDS-2
(1995)		PRCT (n=333) ≤ 3 hours   • Mean 69 y 
• Median NIHSS
14 •  TTT 0-90 m 49% 
• TTT 91-180 m
51% 		• 0.9 mg/kg rt-PA (Max 90 mg) 
• Placebo 		• 
•  33% more patients treated with t-PA had mRS 0-1 at 90 days 
2.9% ↑ fatal ICH in tPA group 
ECASS III
(2008)		PRCT (n =821)3-4.5 hours• Mean 65 y 
• Median NIHSS 9 
• TTT 4 h 		• 0.9 mg/kg t-PA (Max 90 mg) 
• Placebo 		7% more patients treated with t-PA had mRS 0-1 at 90 days 
2.2% ↑ SICH in rt-PA group 
WAKE-UP 
(2018)		PRCT (n =503)≥ 4.5 hours since LKN• Mean 65 y 
• Median NIHSS 6 
• TTT 10 h 		• 0.9 mg/kg rt-PA (Max 90 mg) 
• Placebo 		11% more patients treated with t-PA had mRS 0-1 at 90 days  
8% increase in SICH 
EXTEND 
(2019)		PRCT (n =225)4.5-9 hours • Mean 73 y 
• Median NIHSS 12 
• TTT 7.5 hours 		• 0.9 mg/kg rt-PA (Max 90 mg) 
• Placebo 		Stopped early mRs
0-1 occurred in 35.4% of the tPa group and 29.5% of the placebo group (adjusted OR 1.44; 95%CI 1.01 – 2.06, p=0.04.  
o  In unadjusted
primary outcome
not  statistically 
significant
(OR 1.2, 95% 
CI 0.82 – 
1.76, p 
=0.35) 
More symptomatic intracranial hemorrhage in the tPa group (6.2% vs 
0.9%) 

Trials that showed harm

 Design/sample sizeTime WindowPatient PopulationIntervention & ComparisonOutcomes
ECASS-1
(1995)		PRCT (n=620)≤ 6 hours • Median 69 y 
• Median NIHSS 12 
• TTT 4.4 h 		• 1.1 mg/kg rt-PA (Max 100 mg) 
• Placebo 		• No difference in functional outcomes at 90 days 
• Significant ↑ 30-day mortality in T-PA group (22.4% vs. 
15.8%)  
ATLANTISB
(1999)		PRCT ( n =613)3-5 hours• Mean 65 y 
• Median NIHSS 10 
• TTT 4.5 h 		• 0.9 mg/kg rt-PA (Max 90 mg) 
• Placebo  		Stopped early   Trend towards ↑ mortality in rt-PA group (11% vs. 7%)
ATLANTIS-
A 
(2000)		PRCT (n =142)≤ 6 hours • Mean 67 y 
• Median NIHSS 10 
• TTT 4.5 h 		• 0.9 mg/kt t-PA (Max 90 mg) 
• Placebo  		• Stopped early  More
• 4-point improvement at 30 days with placebo than alteplase (75%
vs 60%) 
 
• Significant ↑ SICH w/in 10 days of rt-PA treatment (11% vs. 
0%) 
• Significant ↑ 90-day mortality in rt-PA group(23% vs. 7%)
Epithet (2008)PRCT (n =101)3-6 hours Mean 71 y 
Median NIHSS 13 		0.9 mg/kg t-PA (Max 90 mg) 
Placebo 		Non-significant difference in their primary outcome, which was a disease  oriented imaging outcome 
Non-significant difference in mortality (26% with alteplase vs 12% with placebo in patients with perfusion
mismatch 
TTT: Time-to-treatment; ITT: Intention-to-treat; PRCT: Prospective Randomized Controlled Trial;   

Revisiting the NINDS Study

Reason: the original authors of NINDS rt-PA stroke study (1995) performed further analysis after patients treated earlier did not seem to benefit compared to those treated later, contrary to an expected difference.  

However when the baseline NIHSS scores were shown by time-to-treatment instead of treatment group, baseline differences between the rt-PA and placebo groups became apparent.  

 Original Report (1995)  Re-analysis (2000)   
      
 Rt-PAPlacebo0-90 min 91-180 min 
   Rt-PAPlaceboRt-PAPlacebo
NIHSS, mean (SD); median 141415.2 (7.2); 1515.0 (6.7); 1413.5 (7.7); 1215.4 (6.9); 15
NIHSS, groups, percent       
0-5   8.36.2194.2
10-Jun  19.125.524.227.5
15-Nov  24.821.41721
16-20   25.525.521.619.8
>20   2230%21.418.327.5
The higher median NIHSS baseline scores in the placebo at 91-180 min group resulted in an overestimation of rt-PA’s efficacy in the original NINDS trial that even the original authors had to announce in their conclusions of their 2000 reanalysis.  

ECASS III Re-analysis 

  • Previously reported unadjusted analyses were based on modified NIHSS score. The secondary efficacy outcome was no longer significant using the original NIHSS score. 
  • In analyses adjusted for baseline imbalances, all efficacy outcomes were no longer significant. •     Increases in symptomatic intracranial hemorrhage remained significant in 5/6 analyses.  

 Conclusions  

  • Currently, the AHA recommends for eligible patients the benefit of alteplase therapy is time dependent, and treatment should be initiated as quickly as possible. 
  • Baseline imbalances favoring rt-PA in the NINDS trial and the ECASS III trial could be considered controversial, considering these trials were instrumental for drug approval and time window expansion. 
  • A re-analysis cannot overturn the original findings of a study, only increase or decrease the confidence in the findings it presented. 
  • The decision to use rt-PA for an acute ischemic stroke should continue to consider potential benefits with consideration for upfront risk of fatal ICH.   

References  

  1. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke a guideline for healthcare professionals from the American Heart Association/American Stroke A. Stroke. 2019;50(12):E344-E418. doi:10.1161/STR.0000000000000211 
  2. NINDS rt-PA Stroke Study Group. TISSUE PLASMINOGEN ACTIVATOR FOR ACUTE ISCHEMIC STROKE. N Engl J Med. 1995;333:1581-1587. 
  3. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet. 1998;352(9136):1245-1251. doi:10.1016/S01406736(98)08020-9 
  4. Sandercock P, Wardlaw JM, Lindley RI, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): A randomised controlled trial. Lancet. 2012;379(9834):2352-2363. doi:10.1016/S0140-6736(12)60768-5 
  5. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. N Engl J Med. 2008;359(13):1317-1329. doi:10.1056/nejmoa0804656 
  6. Thomalla G, Simonsen CZ, Boutitie F, et al. MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset. N Engl J Med. 2018;379(7):611-622. doi:10.1056/nejmoa1804355 
  7. Hacke W, kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA J Am Med Assoc. 1995;274(13):10171025. doi:10.1001/jama.274.13.1017 
  8. Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant Tissue-Type Plasminogen Activator (Alteplase) for Ischemic Stroke 3 to 5 Hours After Symptom Onset The ATLANTIS Study: A Randomized Controlled Trial. JAMA. 1999;282(21):2019-2026. 
  9. Clark WM, Albers GW, Madden KP, Hamilton S. The rtPA (Alteplase) 0-to 6-Hour Acute Stroke Trial, Part A (A0276g) Results of a Double-Blind, Placebo-Controlled, Multicenter Study. Stroke. 2000;31:811-816. 
  10. Davis SM, Rey G, Donnan A, et al. Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol. 2008;7:299-309. doi:10.1016/S1474 
  11. Ma H, Campbell BCV, Parsons MW, et al. Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke. N Engl J Med. 2019;380(19):1795-1803. doi:10.1056/nejmoa1813046 
  12. Marler JR, Tilley BC, Lu M, et al. Early stroke treatment associated with better outcome: The NINDS rt-PA Stroke Study. Neurology. 2000;55(11):1649-1655. doi:10.1212/WNL.55.11.1649 
  13. Alper BS, Foster G, Thabane L, Rae-Grant A, Malone-Moses M, Manheimer E. Thrombolysis with alteplase 3-4.5 hours after acute ischaemic stroke: Trial reanalysis adjusted for baseline imbalances. BMJ Evidence-Based Med. 2020;0(0):172-179. doi:10.1136/bmjebm-2020-111386 

Hypertonic Saline Versus Mannitol for ICP Reduction  

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Introduction  

  1. Elevated intracranial pressure (ICP) is caused by excess volume in the cerebral spaces, which causes a reduction in the cerebral perfusion pressure and affects blood flow and oxygenation to the brain.   
  2. Hyperosmolar agents (hypertonic saline and mannitol) are utilized to form a gradient across the blood-brain barrier to draw fluid from the cerebral space into the vasculature, thus reducing ICP  
  3. Mannitol was previously considered the gold standard of osmotic therapy, but hypertonic saline has proven to be at least as effective as mannitol at reducing ICP  

Pharmacology  

  Hypertonic Saline   Mannitol  
   Mechanism   Increases serum sodium levels, making it more hypertonic. Giving a bolus causes a gradient for   water to follow sodium extracellularly and move out   of the cerebral spaces into the vasculature, while a   continuous infusion aids in resuscitation   Osmotic diuretic by increasing the osmolality of the glomerular filtrate, thus blocking reabsorption of water and excretion of sodium. This leads to   movement of water to extracellular and vascular   spaces and reducing the ICP  
Dose  3 – 23.4% available      3%: optimal dose is unclear, reasonable to start with   300-500mL bolus or continuous infusion at 100mL/hr and titrate per response      23.4% : 0.43-0.5 mL/kg IV bolus, max 30mL/dose  5 – 25% solutions available (20% most common)      0.25 – 1g/kg/dose IV bolus q 6-8 hours (Usually 25-100g per dose)  
Administration  3% intermittent bolus or continuous infusion   *strong osmotic gradient not retained with continuous infusions      23.4% intermittent bolus over 15 minutes  Intermittent IV infusion over 30 minutes   
Adverse Effects  Hypervolemia,  respiratory distress, electrolyte imbalances (hypernatremia)  Hypotension, hypovolemia, AKI, electrolyte disturbances (specifically K+), extravasation  
Cautions/Pearls     Solutions > 3-5% require a central line      Requires in-line filter due to risk of crystallization Avoid in hypovolemia and anuria  
Patient population to consider use in  Hypovolemic, hypotensive, traumatic resuscitation   Euvolemia, hypertensive, fluid restrictions   
Monitoring  Serum sodium 145-155mEq/dL    Serum osmolality 300-320 mOsm/L Titrate based on ICP  Serum osmolality 300-320 mOsm/L  Titrated based on ICP  
Where to find in GHS  3% Sodium chloride – 500mL   EDZONE2, EDZONE3, ALL TRAUMA STATIONS  20% Mannitol – 500ML   EDZONE2, EDZONE3, TRAUMA-M, EDETENTION  

Considerations for Administration     

  3% Sodium Chloride  23.4% Sodium Chloride  20% Mannitol  
Vascular Access  Peripheral or central  Central ONLY  Peripheral or central  
Volume (per dose)  500mL +   ~30 mL  125 – 500 mL(20%)  
Equipment  Bolus: Infusion by gravity Continuous: IV infusion pump  Syringe pump preferred   IV infusion pump  

Overview of Evidence  

Author, year   Design/ sample   size  Intervention & Comparison  Outcome  
A. Kerwin, 2009  Retrospective analysis,  (22 patients)  HTS vs mannitol   mean ICP reduction in patients with TBI  HTS is as efficacious as mannitol, if not more so, and adds to the growing literature suggesting that HTS is an effective modality for the control of elevated ICP in patients with severe TBI  
M. Li, 2015  Meta-Analysis,    7 studies    (169 patients)  HTS vs mannitol in mean ICP reduction in patients with TBI  HTS reduces ICP more effectively than mannitol in the setting of TBI  
S. Burgess, 2016  Meta-Analysis,    7 trials    (191 patients)  HTS vs mannitol in mean ICP reduction, risk of ICP treatment  failure, mortality rates, and neurological outcomes  No statistical difference in mortality and neurological outcomes. No difference in mean reduced ICP; decreased risk of ICP treatment failure with HTS  
E. Berger- Pelleiter, 2016  Meta-Analysis,   11 studies   (1,820 patients)  HTS vs mannitol in reduction of mortality, ICP, and increasing functional outcomes  No significant reduction in mortality, no significant reduction in mean ICP, no significant difference in functional outcomes  
C.  Pasarikovski,  2017  Systematic   Review,   5 studies    (175 patients)  HTS vs mannitol in ICP reduction in aneurysmal subarachnoid hemorrhage  No difference between mannitol and 3% HTS in reducing ICP in patients with aneurysmal subarachnoid hemorrhage  
J. Gu, 2018  Mata-Analysis,   12 RCTs,    (438 patients)  HTS vs mannitol in ICP reduction, ICP control, changes in serum sodium and   osmolality, mortality,   neurological function  outcome  No difference in mean ICP reduction, neurological function, and mortality. HTS may be preferred in TBI patients with refractory intracranial hypertension  
It is essential to consider the adverse effects of each agent and the comorbidities for an individual patient rather than making a simple comparison in efficacy of hypertonic saline versus mannitol  

References

  • Burgess S, et al. Annals of pharmacotherapy. 2016;50(4):291-300.  
  • Li M, et al. Y, 2015. Medicine. 2015;9(4):17.  
  • Dastur C, et al. Stroke and vascular neurology. 2017;2:21-29.  
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Fosphenytoin vs Keppra for Status Epilepticus

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Introduction

  1. Status epilepticus is a neurological emergency that required urgent assessment and treatment with pharmacologic agents
  2. Lorazepam and diazepam are short-acting drugs that can produce immediate effects.
  3. Treatment with another long-acting anticonvulsant drug is necessary to prevent recurrent convulsions.
  4. Use of IV phenytoin (PHT) in the treatment of status epilepticus dates back to the 50s with fosphenytoin (FPHT) being the primary agent in some institutions.
  5. However, both PHT and FPHT can induce adverse reactions such as a reduction in blood pressure, arrhythmia, and allergic symptoms.

Pharmacology

Properties  Phenytoin/ Fosphenytoin  Levetiracetam  (Keppra)  
Dose   20 mg/kg/PE   (max 1500 mg)  1-4.5 g IV   (40-60 mg/kg)*  
Administration  Max IV fusion   
PHT 50 mg/min   
FPHT 150 mg/min  		1g IV Push ~2 min**  
1.5-2g IV over 7 min**  
(2-5 mg/kg/min)  
Formulation  IV/PO  IV/PO  
PK/PD  Onset: ~30 min***  
Half Life: 12-28 hr
Excreted:  >90%   in urine  		Onset: 30-45 min  
Half-life: 6-8 hr  
Excreted: 66% renal  
Adverse Effect  Phlebitis, hypotension, bradycardia & dysrhythmias  Abnormal behavior   
Dizziness   
Irritability  
Drug   Interactions and warnings  Major CYP3A4 Inducer (↓ drug levels)  —–  
Compatibility  PHT – only D5W  
FPHT- D5W or NS  		D5W or NS  
 
*GHS has utilized this administration based on clinical experience 
**PE= Phenytoin equivalents  
** Fosphenytoin takes 15 mins to be metabolized to active metabolite in addition to the infusion time

Overview of Evidence

   Author,  Year  Design/ sample   size  Dosing regimen   Outcome  
ESETT  RCT   N= >  VPA 30 mg/kg (max 3000 mg)          vs   LEV 60 mg/kg (max 4500mg)         vs   PHT 20 mg/kg (max 1500 mg)  Result expected 2020  
Nakamura, 2017  *Respective analysis/ n=63  LEV 1000 mg            vs   FPHT 22.5 mg/kg   No difference in control of seizure(81 vs 85.1%, p=0.69), adverse effects, or transition to PO antiepileptic drug   
Gujjar et al, 2017  *Prospective,   open-label   trial/   n=52  LEV 30 mg/kg            vs   PHT 20 mg/kg  LEV displayed no statistically significant difference than PHT in SE       Sequential use of these 92–97% of case controlled without anesthetic agents.  
Chakravarthi, 2017  *RCT n=44  LEV 20 mg/kg               vs   PHT 20 mg/kg  Both LEV and PHT were equally effective at termination of seizure activity within 30min and recurrence of seizures within 24 hours  
Mundlamuri,  2015  RCT/ n=150  VPA  30 mg/kg            vs   LEV 25 mg/kg           vs   PHT 20 mg/kg  No statistically significant difference in control of SE between VPA (68%), PHT (68 %,) and LEV (78%).   
Alvarez et al, 2011  Retrospective  analysis/ n=466  VPA  20 mg/kg   LEV 20 mg/kg   PHT 20 mg/kg  VPA controlled SE in 74.6%, PHT in 58.6% and LEV in 51.7% of episodes       LEV failed more often than VPA [odds ratio (OR) 2.69  
* Did not reach power according to sample size analysis or did not mention in methods

References  

  1. Phenytoin. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved November 12, 2018, from http://www.micromedexsolutions.com/  
  2. Levetiracetam. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved November 12, 2018, from http://www.micromedexsolutions.com/  
  3. Alvarez V. Second-line status epilepticus treatment: comparison of phenytoin, valproate, and levetiracetam. Epilepsia. 2011 Jul;52(7):1292-6.
  4. Chakravarthi S. Levetiracetam versus phenytoin in management of status epilepticus. J Clin Neurosci. 2015 Jun;22(6):959-63.  
  5. Mundlamuri RC. Management of generalised convulsive status epilepticus (SE): A prospective randomised controlled study of combined treatment with intravenous lorazepam with either phenytoin, sodium valproate or levetiracetam–Pilot study. Epilepsy Res. 2015 Aug;114:52-8.  
  6. Gujjar AR. Intravenous levetiracetam vs phenytoin for status epilepticus and cluster seizures: A prospective, randomized study. Seizure. 2017 Jul;49:8-12.  
  7. Nakamura K. Efficacy of levetiracetam versus fosphenytoin for the recurrence of seizures after status epilepticus. Medicine (Baltimore). 2017 Jun;96(25):e7206  
  8. Bleck T. The established status epilepticus trial 2013. Epilepsia. 2013 Sep;54 Suppl 6:89-92.