Category Archives: Pharmacy Friday Pearls

Concomitant Parenteral Benzodiazepines and Olanzapine





Clinical Content
5 min read
March 30, 2023

Concomitant Parenteral Benzodiazepines and Olanzapine

J

Jimmy

PharmD





Clinical Content
4 min read
March 30, 2023

Concomitant Parenteral Benzodiazepines and Olanzapine

J

Jimmy

PharmD

Download Handout

Introduction

  1. Intramuscular olanzapine and parenteral benzodiazepines are commonly used agents in the ED for acute agitation.
  2. An FDA warning states that potentially fatal respiratory depression can occur when olanzapine and parenteral benzodiazepines are administered concomitantly stating “concomitant administration of intramuscular olanzapine and parenteral benzodiazepine has not been studied and is therefore not recommended.”
  3. This warning initially stemmed from post-marketing adverse event monitoring data, but the clinical significance of this warning is questionable

Pharmacology

  Olanzapine Lorazepam Midazolam
Dose 5-10 mg w/ maximum of 30 mg/day 1-4 mg PRN until adequately sedated 2.5-5mg PRN until adequately sedated
Administration IM: Reconstitute 10 mg vial with 2.1 mL SWFI. Resulting solution is ~5 mg/mL. Use within 1 hour following reconstitution IM: administer undiluted IV: dilute IV dose prior to use with an equal volume of compatible diluent IM: administer undiluted IV: can administered undiluted or dilute with compatible diluent
PK/PD Onset: within 15 minutes Duration: at least 2 hours Metabolism: glucuronidation and CYP450 (1A2 and 2D6) Half-life: 30 hours in adults; ~1.5x greater in elderly Excretion: urine (57%) and feces (30%) Onset: 15-30 minutes Duration: 6-8 hours Metabolism: hepatic Half-life: 13-18 hours Excretion: urine (88%) and feces (7%) Onset: 15 minutes Duration: 2-6 hours Metabolism: hepatic CYP3A4 Half-life: 2-6 hours Excretion: urine (90%)
Adverse Effects Orthostatic hypotension, dizziness, and drowsiness Drowsiness and sedated state Drowsiness and sedated state
Drug Interactions and warnings Patients should remain recumbent if drowsy/dizzy until hypotension, bradycardia, and/or hypoventilation have been ruled out Have been associated with anterograde amnesia, cardiorespiratory effects, CNS depression, hypotension, and paradoxical reaction. Use with opioid agonists and other CNS depressants should be avoided when possible. Have been associated with anterograde amnesia, cardiorespiratory effects, CNS depression, hypotension, and paradoxical reaction. Use with opioid agonists and other CNS depressants should be avoided when possible.
Compatibility SWFI D5W, NS, SWFI D5W, NS

Overview of Evidence

Author, year Design/ sample size Intervention & Comparison Outcome
Klein 2018 Prospective observational study (n=737) Intramuscular haloperidol 5 mg, ziprasidone 20 mg, olanzapine 10 mg, midazolam 5 mg, and haloperidol 10 mg were administered for treatment of agitation in the ED. At 15 minutes, participants having received midazolam were most likely to be adequately sedated (71% vs 40-61%).Olanzapine resulted in more participants being adequately sedated compared to haloperidol 5 mg, haloperidol 10 mg, or ziprasidone 20 mg (61% vs 40-52%).Adverse events were uncommon and were not statistically different between groups.
Marder 2010 Overview of Post-Marketing Adverse Event Case Reports (n=160) 539,000 patients received IM olanzapine in a period of 21 months: -Adverse events: 160 (0.03%) -Serious AEs: 83 (0.01%) -Fatalities: 29 (0.0053%) Of the fatalities, olanzapine and benzodiazepines were given concomitantly 66% of the time while 76% also received other concomitant antipsychotics.Of the fatalities, 76% of the patients had comorbid conditions or clinically significant risk factors for the AE that occurred.12 cases of death occurred >24 hours up to 12 days following the injections.
Wilson 2010 Retrospective chart review (n=25) Patients receiving IM olanzapine for agitation in the ED with vital signs documented both before and after (w/in 4 hours) administration 10/25 (40%) received concomitant olanzapine + benzo.Decreased oxygen saturations were seen in patients who had ingested significant amounts of alcohol (irrespective of benzo use).Of the patients that received olanzapine + benzo, only those with significant alcohol use had decreased oxygen saturations.
Chan 2012 Randomized placebo-controlled trial (n=336) Agitated adult patients in the ED were randomized to saline, droperidol 5mg, or olanzapine 5mg. All patients then received midazolam 2.5-5mg until adequately sedated Differences in time to sedation from placebo for droperidol and olanzapine were 4 and 5 mins, respectively.Patients receiving olanzapine or droperidol were 1.6x more likely to achieve adequate sedation.Low rates of AEs were seen and were comparable in all groups (e.g., O2 de-saturation: 7.8% control; 8% droperidol; 4.6% olanzapine.
Williams 2018 Medication use evaluation (n=91) Patients receiving IM olanzapine and IM lorazepam within a 24-hour period Concomitant administration within 60 mins occurred in 41 patients.No instances of hypotension, bradycardia, bradypnea, or oxygen desaturation occurred following administration.

Conclusions

1. The concomitant administration of IM olanzapine and IM/IV benzodiazepines is likely not as clinically risky as was initially thought.

2. Careful consideration should be used when recommending agents for the management of acute agitation to ensure the agent and dose is appropriate. Additionally, patient-specific factors, particularly the use/presence of additional CNS depressants (e.g., alcohol) should be considered.

References

  1. Olanzapine. Lexicomp [online database]. Hudson, OH. Woltes Kluwer Clinical Drug Information, Inc. Accessed 2021, December 20.
  2. Lorazepam. Lexicomp [online database]. Hudson, OH. Woltes Kluwer Clinical Drug Information, Inc. Accessed 2021, December 20.
  3. Midazolam. Lexicomp [online database]. Hudson, OH. Woltes Kluwer Clinical Drug Information, Inc. Accessed 2021, December 20.
  4. Klein LR. Ann Emerg Med. 2018;72(4):374-385. doi:10.1016/j.annemergmed.2018.04.027
  5. Chan EW,  Ann Emerg Med. 2013;61(1):72-81. doi:10.1016/j.annemergmed.2012.07.118
  6. Marder SR. J Clin Psychiatry. 2010;71(4):433-441. doi:10.4088/JCP.08m04411gry
  7. Olanzapine. Package insert. Eli Lilly and Company; 2009
  8. Williams AM. Ment Health Clin. 2018;8(5):208-213. Published 2018 Aug 30. doi:10.9740/mhc.2018.09.208
  9. Wilson MP. J Emerg Med. 2012;43(5):889-896. doi:10.1016/j.jemermed.2010.04.012

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Alteplase for Acute Ischemic Stroke





Clinical Content
10 min read
March 24, 2023

Alteplase for Acute Ischemic Stroke

J

Jimmy

PharmD





Clinical Content
8 min read
March 24, 2023

Alteplase for Acute Ischemic Stroke

J

Jimmy

PharmD

Download Handout

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 size Time Window Patient Population Intervention & Comparison Outcomes
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)  •       Placebo No 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 size Time Window Patient Population Intervention & Comparison Outcomes
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 size Time Window Patient Population Intervention & Comparison Outcomes
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-PA Placebo 0-90 min   91-180 min  
      Rt-PA Placebo Rt-PA Placebo
NIHSS, mean (SD); median  14 14 15.2 (7.2); 15 15.0 (6.7); 14 13.5 (7.7); 12 15.4 (6.9); 15
NIHSS, groups, percent             
0-5      8.3 6.2 19 4.2
10-Jun     19.1 25.5 24.2 27.5
15-Nov     24.8 21.4 17 21
16-20      25.5 25.5 21.6 19.8
>20      2230% 21.4 18.3 27.5
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 

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Hypertonic Saline Versus Mannitol for ICP Reduction  





Clinical Content
4 min read
March 17, 2023

Hypertonic Saline Versus Mannitol for ICP Reduction  

J

Jimmy

PharmD

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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.  
  • Kerwin A, et al. J Trauma. 2009;67:277-282.  
  • Pasarikovski C, et al. World Neurosurg. 2017;105:1-6.  
  • Gu J, et al. Neurosurg Rev. 2018;42:499.  
  • Berger-Pelleiter E, et al. CJEM. 2016;18:112–120.  
  • Farrokh S, et al. Curr opin crit care. 20119; 25:105-109.  
  • Witherspoon B, et al. Nurs Clin N Am. 2017;52:249-60.   
  • Micromedex [Electronic].Greenwood Village, CO: Truven Health Analytics. Retrieved August 12, 2019 from http://www.micromedexsolutions.com

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Fosphenytoin vs Keppra for Status Epilepticus





Clinical Content
5 min read
March 10, 2023

Fosphenytoin vs Keppra for Status Epilepticus

J

Jimmy

PharmD





Clinical Content
3 min read
March 10, 2023

Fosphenytoin vs Keppra for Status Epilepticus

J

Jimmy

PharmD

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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.  

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Management of Hypertensive Emergency





Clinical Content
7 min read
February 23, 2023

Management of Hypertensive Emergency

J

Jimmy

PharmD





Clinical Content
5 min read
February 23, 2023

Management of Hypertensive Emergency

J

Jimmy

PharmD

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Introduction

  1. Hypertensive emergency is characterized by systolic blood pressure (SBP) > 180 mmHg or diastolic blood pressure (DBP) > 120 mmHg with evidence of target organ damage. 
  2. Rapid blood pressure lowering with intravenous antihypertensives is warranted to prevent further organ damage. 
  3. Patients presenting with intracranial hemorrhage, aortic dissection, preeclampsia, or pheochromocytoma crisis should achieve target blood pressure within one hour of presentation. 
  4. Current literature lacks evidence of mortality benefit with any one antihypertensive drug. Selection of a medication should consider target organ(s) affected, underlying disease states, and time to target blood pressure. 

Treatment in Selected Co-Morbidities

Condition BP Goal Preferred Agents
Acute aortic dissection   SBP < 120 mmHg within 20 min Esmolol Labetalol Nicardipine Nitroprusside
Eclampsia or Preeclampsia   SBP < 140 mmHg  within 1 hour Nicardipine Labetalol Hydralazine
Pheochromocytoma (catecholamine excess)   SBP < 140 mmHg  within 1 hour Nicardipine Phentolamine*
Intracranial hemorrhage SBP < 160 mmHg within 6 hours Nicardipine Labetalol
Acute ischemic stroke Pre-alteplase: < 185/110 mmHg Post-alteplase: < 180/105 for 24 hours No thrombolytic: SBP reduced 15% in 24 hours**                                                                        Nicardipine Labetalol
*Phentolamine currently unavailable due to nationwide shortage
**Permissive hypertension may be reasonable; maintain SBP < 220 mmHg or DBP < 120 mmHg

Pharmacology: Intravenous Antihypertensives

 First-line Agents  
Medication Class Onset Duration Dosing Clinical Pearls
Nicardipine     Ca channel blocker  IV: 5-10 min IV: 2-6 hours Initial: 5 mg/hr  Titration: 2.5 mg/hr every 15 min  Maximum: 15 mg/hr  No dose adjustments in elderly patients 
Esmolol             Beta-blocker  IV: 1-2 min IV: 10-20 min Bolus: 500-1,000 mcg/kg Initial: 50 mcg/kg/min  Titration: repeat bolus dose, then increase by 50 mcg/kg/ min every 10 min Maximum: 200 mcg/kg/min  Contraindications:  Bradycardia Decompensated HF 
Labetalol     Beta-blocker  Alpha-1 antagonist IV: 2-5 min Peak: 5-15 min IV: 2-6 hours Peak: 18 hours Bolus: 10-20 mg IV push every 10 min IV infusion: 0.5 – 10 mg/min titrated 1-2 mg/min every 2 hours Maximum: 300 mg total  Precaution: Second-/thirddegree heart block Bradycardia Heart failure
 
Second-line Agents		  
Phentolamine* Non-selective alpha antagonist IV: Seconds IV: 15 min   Initial: 5 mg IV push  May repeat every 10 min PRN   Useful in catecholamine excess and clonidine withdrawal 
  Nitroglycerin         NOdependent vasodilator IV: 2-5 min IV: 5-10 min ACS: Initial: 5 mcg/min  Titration: 5 mcg/ min every 3-5 min Maximum: 20 mcg/min  Pulmonary edema: Initial: 100-200 mcg/min Titration: 50 mcg/min every 3-5 min Maximum: 400 mcg/min Indicated in ACS or pulmonary edema  Use caution in volume-depleted patients 
Sodium nitroprusside     NOdependent vasodilator IV: Seconds IV: 1-2 min Initial: 0.3-0.5 mcg/kg/min  Titration: 0.5 mcg/kg/min every 1 min Maximum: 10 mcg/kg/min  Requires intra-arterial BP monitoring   Tachyphylaxis and cyanide toxicity with prolonged use – Limit treatment duration
Hydralazine   Direct vasodilator IV: 10 min IM: 20 min IV: 1-4 hours IM: 2-6 hours Initial: 10-20 mg IV push  Repeat every 4-6 hours PRN  Not available as an IV infusion 
Enalaprilat         ACE inhibitor IV: 15-30 min IV: 12-24 hours Initial: 1.25 mg IV over 5 min  Titration: increase by 5 mg every 6 hours as needed  Slow onset (~15 min)  Contraindications:  Pregnancy MI Bilateral renal stenosis 
*Phentolamine currently unavailable due to nationwide shortage

Overview of Evidence

Author (Title), Year  Design Purpose Outcome
Anderson (INTERACT), 2008 RCT (N=404) Comparison of BP goals  (SBP < 140 vs SBP < 180)  in patients with acute ICH Mean hematoma expansion was smaller in the intensive group (13.7% vs 36.3%) No difference in death or disability at 3 months (48% vs 49%) Limitation: included patients with SBP > 150 mmHg, over 30% of patients were treated with oral antihypertensive therapy
Quereshi (ATACH-2), 2016 RCT (N=1,000) Comparison of BP goals  (SBP 110-139 vs SBP 179-140)  in patients with acute ICH All patients received nicardipine infusion No difference between death or disability at 3 months (38.7% vs 37.7%) Increased renal adverse events within 24 hours in the intensive group (9.0% vs 4.0%) Limitation: mean SBP differed by only 10 mmHg between groups 2 hours post-randomization (129 mmHg vs 141 mmHg)
Peacock (CLUE), 2011 RCT (N=226) Nicardipine IV infusion versus labetalol IV bolus for management of hypertensive emergency Patients receiving nicardipine were more likely to reach target BP within 30 min (91.7% vs 82.5%) Rescue antihypertensive use did not differ significantly between groups within first 6 hours Limitation: only 63.3% of patients had evidence of target organ damage at randomization
Yang, 2004 Prospective cohort (N=40) Nitroprusside IV versus nicardipine IV for hypertensive emergency with pulmonary edema No significant difference between blood pressure readings across groups at any time point No adverse events reported in either group Limitation: nicardipine dosing started at 3 mcg/kg/min (12.5 mg/hr in a 70 kg patient)

Conclusions

  1. Selection of a first-line antihypertensive should consider compelling indications and acute blood pressure goals, as robust literature comparing long-term outcomes across drug classes is lacking for most indications.
  2. Nicardipine may provide more consistent blood pressure control than labetalol. This is particularly important in patients with acute stroke, as large fluctuations in blood pressure are believed to negatively impact cerebral perfusion.
  3. Aggressive lowering of SBP less than 140 mmHg in patients with acute ICH has not been shown to improve long-term outcomes and may negatively impact renal perfusion. 
  4. Nicardipine has been shown to provide similar blood pressure control to nitroprusside. In patients with acute ICH, nitroprusside use within 24-hours of presentation was associated with higher in-hospital mortality. 

References

  1. Whelton, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. J Amer Heart Assoc 2018;71(6):e13-e115. 
  2. Benken ST. Hypertensive emergencies. CCSAP 2018;1:7-30.
  3. Anderson, et al. Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial. Lancet Neurol 2008;7:391-9. 
  4. Quereshi, et al. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage. New Engl J Med 2016;375(11):1033-43. 
  5. Peacock WF, et al. CLUE: a randomized comparative effectiveness trial of IV nicardipine versus labetalol use in the emergency department. Critical Care 2011;15(R157):1-8. 
  6. Yang HJ, Kim JG, Lim YS, et al. Nicardipine versus nitroprusside infusion as antihypertensive therapy in hypertensive emergencies. J Int Med Res 2004;32:118-23. 

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Fibrinolytics for STEMI





Clinical Content
6 min read
February 16, 2023

Fibrinolytics for STEMI

J

Jimmy

PharmD


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Introduction

  1. Percutaneous coronary intervention (PCI) is the preferred reperfusion strategy during a cardiac arrest; thrombolytic therapy is an option without PCI capability, followed by transfer to a PCI capable center.
  2. Thrombolytic therapy is most effective when administered within 30 minutes of first medical contact, however, may be considered within 12–24 hours of symptom onset and ongoing ischemia or extensive ST elevation.
  3. During ACS-Induced Cardiac Arrest, the goal for fibrinolysis is 30 minutes and reperfusion with PCI is preferred, however, if PCI is delayed, fibrinolytics therapy could be considered.

Pharmacology

Alteplase Tenecteplase
MOA Initiates fibrinolysis by binding to fibrin in a thrombus and converts entrapped plasminogen to plasmin. Promotes initiation of fibrinolysis by binding to fibrin and converting plasminogen to plasmin; similar to alteplase but more fibrin specific.
Dose Weight based:
>67kg: infuse 15mg IV bolus over 1–2 min, followed by 50mg infusion over 30 min, then 35mg over 1 hour (max 100mg)
≤67kg: infuse 15mg IV bolus over 1–2 min, followed by 0.75mg/kg infusion over 30 min, then 0.5mg/kg over 1 hour (max 100mg) 		Weight based:
<60kg: 30mg
≥60 to <70kg: 35mg
≥70 to <80kg: 40mg
≥80 to <90kg: 45mg
≥90kg: 50mg
Administration Bolus administered over 1 minute followed by infusion. Single bolus over 5 seconds.
PK/PD Duration: 1 hour after infusion terminated
Distribution: approximates plasma volume
Half-life elimination: 5 minutes
Excretion: hepatic and plasma clearance 		Distribution: weight related
Metabolism: hepatic
Half-life elimination: biphasic; initial 20–24 min, terminal 90–130 min
Excretion: plasma clearance
Adverse Effects Intracranial hemorrhage, ecchymosis, GI/GU hemorrhage, sepsis, cerebrovascular accident. Hemorrhage and hematoma, cerebrovascular accident.
Drug Interactions & Warnings Tranexamic acid — avoid combination. Internal bleeding, thromboembolic events, cholesterol embolization. Tranexamic acid — avoid combination. Internal bleeding, thromboembolic events, arrhythmias.
Contraindications Active internal bleeding; ischemic stroke within 3 months (except when within 4.5 hours); severe uncontrolled hypertension. Active internal bleeding; severe uncontrolled hypertension; recent intracranial/intraspinal surgery; ischemic stroke within 3 months.
Compatibility May be diluted in equal volume with 0.9% sodium chloride or D5W. Incompatible with dextrose.

Overview of Evidence

Author, Year Design / Sample Size Intervention & Comparison Outcome
Guillermin 2016a Meta-analysis of RCT (n=18,208) Tenecteplase 30–50mg vs alteplase 80–100mg Bleeding 4.8% in tenecteplase vs 5.8% alteplase (p=0.0002). No difference in mortality at 30 days.
Llevadot 2001 Retrospective review (38 studies) Reteplase, anoteplase, tenecteplase Tenecteplase and reteplase associated with accelerated infusion and more convenient bolus administration. Less fibrin-specific agents may cause greater systemic coagulopathy with potential for more bleeding.
Boersma 1996 Retrospective review (n=50,246) Fibrinolytic therapy vs placebo Mortality reduction in patients treated within 2 hours compared to later (p=0.001).
GUSTO 1993 Randomized, controlled trial (n=41,021) Streptokinase + SQ heparin; streptokinase + IV heparin; alteplase + IV heparin; alteplase + streptokinase + IV heparin Alteplase administered over 1.5 hours with IV heparin provided survival benefit over standard therapy. Thrombolytic therapy administered within 24–48 hours of admission.
Armstrong 2013b Randomized controlled trial (n=1,892) PCI vs bolus tenecteplase, clopidogrel, and enoxaparin Tenecteplase prehospital resulted in effective reperfusion when PCI was not completed within 1 hour. Fibrinolytic therapy associated with increased risk of intracranial bleeding.
Cardiac Arrest Data
Bottiger 2001 Prospective cohort (n=40) Alteplase 50mg bolus, repeat 50mg in 30 min vs placebo Increase in ROSC (68% vs 44%) and ICU admission compared to placebo.
Schreiber 2002 Retrospective chart review (n=157) Alteplase 15mg bolus followed by 50mg infusion over 30 min and 35mg over 60 min Thrombolytic therapy achieved better functional neurological recovery more frequently (p=0.03).
Lederer 2004 Retrospective chart review (n=108) Alteplase 100mg (15mg followed by 85mg over 90 min) 81% of patients discharged without neurological deficit. 67% of patients still alive 5–10 years after the event.
Li 2006 Meta-analysis Alteplase 15mg bolus followed by 50mg infusion over 30 min and 35mg over 60 min Thrombolytic therapy improved the rate of ROSC (p<0.01). 48% of patients had acute coronary artery obstruction.
Bottiger 2008 Randomized, double-blind, multicenter trial (n=1,050) Tenecteplase 30mg if <60kg
Tenecteplase 35mg if 60–69kg
Tenecteplase 40mg if 70–79kg
Tenecteplase 45mg if 80–89kg
Tenecteplase 50mg if >90kg
vs placebo 		No difference between tenecteplase and placebo in 30-day survival, ROSC, or neurologic outcomes. Increased intracranial hemorrhages in tenecteplase patients.
RuizBailen 2001 Retrospective cohort (n=303) Streptokinase; alteplase accelerated regimen; alteplase double bolus Systemic thrombolysis patients had lower mortality, less mechanical ventilation, fewer CPR attempts (p<0.0001). No fatal hemorrhagic complications.

a Administered as tenecteplase 30–50mg bolus and alteplase 15mg bolus followed by 0.75mg/kg infusion over 30 min.
b Half-dose tenecteplase administered in patients ≥75 years old.
c Reteplase administered as two boluses of 10 million units given 30 minutes apart.

Conclusions

  1. Evidence supports PCI is the first-line option for management of patients requiring reperfusion during cardiac arrest when a STEMI is suspected.
  2. Available evidence suggests tenecteplase and alteplase are appropriate fibrinolytic therapies when PCI is unavailable.
  3. Tenecteplase is an alternative fibrinolytic therapy and has been evaluated as safe and efficacious as a bolus dose of 30–50mg.
  4. When alteplase is the only fibrinolytic therapy available, there is data to support bolus therapy +/- a weight-based infusion during cardiac arrest.
  5. Thrombolytic agents administered during CPR can improve the rate of survival but are associated with a risk of severe bleeding.

References

  1. Lexicomp [Electronic version]. Macedonia, OH: Truven Wolters Kluwer Health. Retrieved January 26, 2021, from https://online.lexi.com/lco/action/login.
  2. Guillermin A, Yan D, Perrier A, Marti C. Safety and efficacy of tenecteplase versus alteplase in acute coronary syndrome: a systematic review and meta-analysis of randomized trials. Arch Med Sci 2016; 12(6):1181–1187.
  3. Llevadot J, Giugliano R, Antman E. Bolus fibrinolytic therapy in acute myocardial infarction. JAMA. 2001;286(4):442–449.
  4. Boersma E, Maas A, Deckers J, Simoons M. Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet. 1996;348:771–775.
  5. GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. NEJM. 1993;329(10):673–682.
  6. Armstrong P, Gershlick A, Goldstein P, et al. Fibrinolysis or primary PCI in ST-segment elevation myocardial infarction. NEJM. 2013;268(15):1379–1387.
  7. Wilcox R. Randomized, double-blind comparison of reteplase double-bolus administration with streptokinase in acute myocardial infarction (INJECT). Lancet. 1995;346(8971):329–336.
  8. Van de Werf F, Cannon CP, Luyten A, et al. Safety assessment of single-bolus administration of TNK tissue-plasminogen activator in acute myocardial infarction: the ASSENT-1 trial. Am Heart J. 1999;137(5):786–791.
  9. Lederer W, Lichtenberger C, Pechlaner C, et al. Recombinant tissue plasminogen activator during cardiopulmonary resuscitation in 108 patients with out-of-hospital cardiac arrest. Resuscitation. 2001;50(1):71–76.
  10. Schreiber W, Gabriel D, Sterz F, et al. Thrombolytic therapy after cardiac arrest and its effect on neurological outcome. Resuscitation. 2002;52(1):63–69.
  11. Lederer W, Lichtenberger C, Pechlaner C, et al. Long-term survival and neurological outcome of patients who received recombinant tissue plasminogen activator during out-of-hospital cardiac arrest. Resuscitation. 2004;61(2):123–129.
  12. Li X, Fu QL, Jing XL, et al. A meta-analysis of cardiopulmonary resuscitation with and without the administration of thrombolytic agents. Resuscitation. 2006;70(1):31–36.
  13. Bottiger BW, Arntz HR, Chamberlain DA, et al. Thrombolysis during resuscitation for out-of-hospital cardiac arrest. NEJM. 2008;359(25):2651–2662.
  14. Kurkciyan I, Meron G, Sterz F, et al. Major bleeding complications after cardiopulmonary resuscitation: impact of thrombolytic treatment. J Intern Med. 2003;253(2):128–135.
  15. Ruiz-Bailén M, Aguayo de Hoyos E, Serrano-Córcoles M, et al. Efficacy of thrombolysis in patients with acute myocardial infarction requiring cardiopulmonary resuscitation. Intensive Care Med. 2001;27(6):1050–1057.
  16. Richling N, Herkner H, Holzer M, et al. Thrombolytic therapy vs primary percutaneous intervention after ventricular fibrillation cardiac arrest due to acute ST-segment elevation myocardial infarction. Am J Emerg Med. 2007;25(5):545–550.
  17. Böttiger B, Bode C, Kern S, et al. Efficacy and safety of thrombolytic therapy after initially unsuccessful cardiopulmonary resuscitation: a prospective clinical trial. Lancet. 2001;357(9268):1583–1585.

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Procainamide for Wide Complex Tachycardia





Clinical Content
5 min read
February 9, 2023

Procainamide for Wide Complex Tachycardia

J

Jimmy

PharmD





Clinical Content
4 min read
February 9, 2023

Procainamide for Wide Complex Tachycardia

J

Jimmy

PharmD

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Introduction

  1. Ventricular tachycardia (VT) is an uncommon but dangerous medical condition, with an extremely variable clinical presentation.
  2. Intravenous procainamide is guideline recommended and is the drug of choice for the treatment of hemodynamically stable VT with a class IIa recommendation.
  3. Procainamide is an old drug with new evidence that supports it’s use but dosing strategies and administration techniques makes it difficult to use at the bedside.

Pharmacology

  Procainamide
Dose and administration
  • Bolus Dosing
    • 10-17 mg/kg over 20-60 minutes (Max dose suggest 1g and max rate of 20-50 mg/min)                   
    • alternative Dosing: 100 mg every 5 minutes at max rate of 50 mg/min to max dose 1g 
  • Renal Adjustments
    • eCrCl 10-50 ml/min: Reduce initial dosing by 25-50 %
    • eCrCL < 10 ml/min: Reduce initial dosing by 50-75%  
  • Maintenance Infusion Dosing 1-6 mg/min 
Mechanism of Action  •      Class 1A anti-arrhythmic that binds to fast sodium channels inhibiting recovery after repolarization. It also prolongs the action potential and reduces the speed of impulse conduction
PK/PD
  • Onset: IV <2 minutes; IM 10-30 minutes
  • Time to Peak: IV 25-60 minute; IM 15-60 minutes
  • Duration: IV/IM: 3-4 hours
  • Metabolism: Converted by the liver to N-acetylprocainamide (NAPA), an active compound
  • Half-life: 2.5– 4.7 hr (NAPA— 7 hr); increased in renal impairment
  • Excretion: 40– 70% excreted unchanged by the kidneys
Adverse Effects Hypotension Hepatotoxicity Positive ANA titer Lupus-like syndrome Anaphylaxis caused by sulfite salt Myasthenia gravis exacerbation  Angioedema
Drug Interactions and warnings         •      Interacts with diazepam, diltiazem, milrinone, phenytoin, and hydralazine
Compatibility Compatible in  o                0.9 % Sodium Chloride and 0.45% sodium chloride,  Incompatible with  o        D5 (depending on procainamide concentration), LR, and D5NS 
Comments •      Define hospital’s dosing and administration policy as there is a risk for adverse event’s due to multiple dosing strategies in the literature

Overview of Evidence

Author, year  Design/ sample size Intervention & Comparison Outcome
Ortiz,2017 Randomized controlled trial   n= 62 IV procainamide 10 mg/kg over 20 min IV amiodarone 5mg/kg over 20 min Major cardiac adverse occurred in 3 of 33 (9%) procainamide and 12 of 29 (41%) amiodarone patients.   Tachycardia terminated within 40 min in 22 (67%) procainamide and 11 (38%) amiodarone patients. 
Maril,2010 Multicenter cohort study    n= 187 IV Amiodarone 2 mg/kg infusion at a rate of at least 10 mg⁄ min   IV Procainamide 10 mg/kg infusion at a rate of at least 15 mg⁄ min •      The rates of VT termination were 25% (13 ⁄ 53) and 30% (9 ⁄ 30) for amiodarone and procainamide, respectively.
Komura,2010 Retrospective analysis   n= 90 IV Procainamide 100 mg over 1–2 min   IV Lidocaine bolus of 50 mg •      Procainamide and lidocaine terminated VTs in 53/70 (75.7%) and in 7/20 (35.0%) respectively.
Maril,2006 Retrospective case series   n= 33 IV Amiodarone 150 mg over 15 minutes Amiodarone rate of successful ventricular tachycardia termination was 8 of 28 (29%).   Two of 33 patients (6%) required direct current cardioversion for presyncope or hypotension temporally associated with amiodarone treatment.
Gorgels,1996 Randomized parallel study   n= 79 IV Procainamide 10 mg/kg   IV Lidocaine 1.5 mg/kg Lidocaine terminated 6 of 31 VTs and procainamide 38 of 48 (p <0.001).    A comparison of the QRS width and QT interval before and at the end of the injection revealed significant lengthening of these values after procainamide but no change after lidocaine.
Callans,1992 Observational study   n= 15 IV Procainamide rate of 50 mg/min until the arrhythmia terminated or a total dose of 15 mg/kg  •      Procainamide was well tolerated and resulted in termination of ventricular tachycardia in 93% of patients after administration of 100 to 1,080 mg (median dose 600 mg).

References

  1. Procainamide. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved July 6, 2020, from http://www.micromedexsolutions.com/
  2. Long B, Koyfman A. Best Clinical Practice: Emergency Medicine Management of Stable Monomorphic Ventricular Tachycardia. J Emerg Med 2017;52:484-492.
  3. Ortiz M, Martín A, Arribas F, et al. Randomized comparison of intravenous procainamide vs. intravenous amiodarone for the acute treatment of tolerated wide QRS tachycardia: the PROCAMIO study. Eur Heart J. 2017;38(17):1329-1335. doi:10.1093/eurheartj/ehw230
  4. Marill KA, deSouza IS, Nishijima DK, et al. Amiodarone or procainamide for the termination of sustained stable ventricular tachycardia: an historical multicenter comparison. Acad Emerg Med. 2010;17(3):297-306. doi:10.1111/j.1553-2712.2010.00680.x
  5. Komura S, Chinushi M, Furushima H, et al. Efficacy of procainamide and lidocaine in terminating sustained monomorphic ventricular tachycardia. Circ J. 2010;74(5):864-869. doi:10.1253/circj.cj-09-0932
  6. Marill KA, deSouza IS, Nishijima DK, Stair TO, Setnik GS, Ruskin JN. Amiodarone is poorly effective for the acute termination of ventricular tachycardia. Ann Emerg Med. 2006;47(3):217-224. doi:10.1016/j.annemergmed.2005.08.022
  7. Gorgels AP, van den Dool A, Hofs A, et al. Comparison of procainamide and lidocaine in terminating sustained monomorphic ventricular tachycardia. Am J Cardiol. 1996;78(1):43-46. doi:10.1016/s0002-9149(96)00224-x
  8. Callans DJ, Marchlinski FE. Dissociation of termination and prevention of inducibility of sustained ventricular tachycardia with infusion of procainamide: evidence for distinct mechanisms. J Am Coll Cardiol. 1992;19(1):111-117. doi:10.1016/0735-1097(92)90060-z
  9. Wellens HJ, Bär FW, Lie KI, Düren DR, Dohmen HJ. Effect of procainamide, propranolol and verapamil on mechanism of tachycardia in patients with chronic recurrent ventricular tachycardia. Am J Cardiol. 1977;40(4):579-585. doi:10.1016/0002-9149(77)90074-1

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Digoxin Poisoning Management





Clinical Content
4 min read
February 3, 2023

Digoxin Poisoning Management

J

Jimmy

PharmD





Clinical Content
2 min read
February 3, 2023

Digoxin Poisoning Management

J

Jimmy

PharmD

Digoxin Poisoning Management

Pharmacy Friday Pearl – Pharmacy & Acute Care University



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Introduction

  • Digoxin treats atrial flutter, atrial fibrillation, and heart failure.
  • Toxicity occurs when Na+/K+-ATPase inhibition raises intracellular Na+/Ca2+, triggering dysrhythmias.
  • EKG red flags: PVCs, biphasic T waves, shortened QT interval, variable AV block.
  • Therapeutic range 0.8 – 2.0 ng/mL; toxicity often begins > 2 ng/mL.

Digoxin Immune Fab (DigiFab / DigiBind)

Parameter Key Details
Dose 1 vial = 40 mg (binds 0.5 mg digoxin).
Unknown ingestion → 10-vial empiric dose.
Alternative: vials = 2 × total body load (mg).
Chronic unknown: adults 3 – 6 vials; children 1 – 2 vials.
Administration IV infusion over 30 min (rapid bolus if arrest imminent).
Onset / Duration Onset 20 – 90 min • Duration 15 – 20 h.
Adverse Effects Orthostatic hypotension, ventricular tachycardia, hypokalemia.
Mechanism Fab fragments swiftly bind circulating digoxin, neutralising toxicity.
Compatibility Compatible only with 0.9 % sodium chloride.

Clinical pearl: monitor serum K+ closely—intracellular shifts often trigger hypokalemia post-Fab.

Overview of Key Evidence

Author / Year Design (n) Key Findings
Wei 2021 Case series (121) FAERS: DigiBind serious AEs 87 % vs DigiFab 63 %; hypotension, cardiac arrest, death most frequent.
Ward 2000 Observational (16) Both Fab products reduced free digoxin below assay limits; total digoxin ↑ ≈10-fold (binding confirmed).
Renard 1997 Observational (16) Fab clearance declined linearly with renal impairment & age; t½ 11 – 34 h; all patients recovered without AEs.
Antman 1990 Open-label (150) 90 % toxicity resolved/improved; median dose 5 vials (200 mg); maximum 40 vials.
Roberts 2016 Systematic review Fab therapy remains first-line; hyperkalemia & ventricular arrhythmias are key toxicity predictors.
Ujhelyi 1995 PK review Fab exhibits two-compartment kinetics; repeat dosing may be needed in large body-load poisonings.

Clinical Conclusions

  • Digoxin toxicity is life-threatening but rapidly reversible with Digoxin Immune Fab.
  • If the ingested amount is unknown, administer an empiric 10-vial dose.
  • Do not delay Fab therapy for age- or renal-based calculations.

Full Reference List

  1. Bismuth C, Gaultier M, Conso F, Efthymiou ML. Hyperkalemia in acute digitalis poisoning. Clin Toxicol. 1973;6(2):153-162.
  2. David MNV, Shetty M. Digoxin. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022.
  3. Lexicomp Online, Lexi-Drugs Online. Waltham, MA: UpToDate, Inc. January 2023.
  4. Antman EM et al. Treatment of life-threatening digitalis intoxication with digoxin-specific Fab fragments. Circulation. 1990;81(6):1744-1752.
  5. Renard C et al. Pharmacokinetics of digoxin-specific Fab: effects of renal function & age. Br J Clin Pharmacol. 1997;44(2):135-138.
  6. Roberts DM et al. Pharmacological treatment of cardiac glycoside poisoning. Br J Clin Pharmacol. 2016;81(3):488-495.
  7. Ujhelyi MR, Robert S. Pharmacokinetic aspects of digoxin-specific Fab therapy. Clin Pharmacokinet. 1995;28(6):483-493.
  8. Wei S et al. Adverse events with digoxin Immune Fab in FAERS 1986-2019. Drugs – Real World Outcomes. 2021;8:253-262.
  9. Ward SB et al. Pharmacokinetics & bioaffinity of DigiTAb vs Digibind. Ther Drug Monit. 2000;22(5):599-607.

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Push Dose Vasopressors





Clinical Content
5 min read
January 27, 2023

Push Dose Vasopressors

J

Jimmy

PharmD





Clinical Content
4 min read
January 27, 2023

Push Dose Vasopressors

J

Jimmy

PharmD

Download PDF

Patient Case  

  • The team gets a call that there is a 75 year old male that triggered a sepsis alert in route with EMS and is currently desaturating on 15 L of oxygen with decision made to intubate this patient  
  • Prior to intubation, the patient hasn’t responded to  a NS bolus infusion these are the patient’s vitals: 
  • Knowing that pre-intubation hypotension has been associated with peri-intubation cardiac arrest, which agent do you order? If it is not commercially available, how do you make it?  

Pharmacology  

  Phenylephrine (PE)   Epinephrine (EPI)  
Properties   A1 ++++   ↑ BP   B1  ±        ↔HR   B2  ±      A1 +++      ↑ BP   B1 +++++   ↑ HR   B2 +++++  
Dose   100-200 mcg PRN Q 1-5 minute   10- 20 mcg PRN Q 1-5 minute  
Formulation   Premixed Syringe- 1000 mcg/10 ml   Not commercially available  
PK/PD   Onset: 1 minute   Duration: ~10-20 minutes   Onset: 1 minute   Duration: ~5-10 minutes  
Adverse Effects   Reflex bradycardia Hypertension   Tachycardia   Hypertension  
 Precautions   Bradycardia, heart block, heart failure, angina, acute MI   Tachycardia  
Compatibility   Compatible with NS, LR, D5   Compatible with NS, LR, D5  
Location in GHS   CPR, Trauma, Zone 2+3 Pyxis   1 mg/ml: CPR, Trauma, Zone 2+3 Pyxis  
Comments   Administer through a large bore peripheral IV; Low extravasation risk   Administer through a large bore peripheral IV; Low extravasation risk   
Making Epinephrine and Phenylephrine the “EASY WAY” Supplies: 10 ml of NS, Insulin syringe, epinephrine or phenylephrine vial, tape, pen Instructions:    Take an insulin syringe and draw up 0.1 ml of epinephrine 1 mg/ml or phenylephrine 10 mg/ml, dilute in 10 ml of NS, label epinephrine 10 mcg/ml (100 mcg total) or phenylephrine 100 mcg/ml (1000 mcg total) 
Making Epinephrine and Phenylephrine the Alternative Way   Epinephrine    Draw up 9 mL of normal saline into a 10 mL syringe (DO NOT use 10ml IV line “flush” syringes)  Into this syringe, draw up 1 mL of EPINEPHphrine 0.1 mg/mL (1 mg/10ml) from a cardiac syringe   Label syringe epinephrine 10 mcg/ml      Phenylephrine o Draw up 1 mL of phenylephrine from a 10 mg/mL vial into a 3 mL syringe o Inject this into a 100 mL bag of normal saline. Label bag; safely discard when finished  o Draw up 10 mL into a 10 mL syringe o Label syringe phenylephrine 100 mcg/ml         

Overview of Evidence  

Author, year    Design/ sample size   Intervention & Comparison   Outcome  
Rotando, 2019   Observational   ED/ICU   N=146   PE 100 mcg/ mL   or   Ephedrine 50 mg/10 mL   Most common indication = peri-intubation hypotension   Both agents associated with:   ↑ SBP by 26 mmHg   ↑ SBP by 26 mmHg   ↓ HR by 6 beats per minute   
Schwartz, 2016   Observational   ED   N=76   PE 100 mcg/ mL     (pre-filled syringe)      46.5%  patients were initiated on vasopressor drip ≤ 30 minutes;   mean MAP ↑ from 56.5 to 79.3 mmHg most common dose 100 mcg most common indication = peri-intubation hypotension  
Panchal, 2015   Observational   ED   N=119   PE 100 mcg/1 mL     PE given during the peri-intubation period: ↑ SBP by 20 mmHg, ↑ DBP by 10 mmHg, HR unchanged  
Doherty, 2012   RCT   OR   N=60   PE  IV push 120 mcg    (pre-filled syringe)   Vs    PE infusion @ 120 mcg/min   The infusion used more drug ( 1740 v 964  mcg)      Push dose pressor  had favorable impact of MAP compared to infusion   

References

  1. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved March 18, 2019, from http://www.micromedexsolutions.com/ 
  2. Scott Weingart. EMCrit Podcast 205 – Push-Dose Pressors Update. EMCrit Blog. Published on August 7, 2017. Accessed on March 19th 2019. Available at [https://emcrit.org/emcrit/push-dose-pressor-update/ ] 
  3. Holden D. Ann Emerg Med. 2018 Jan;71(1):83-92. 
  4. Panchal AR. J Emerg Med. 2015 Oct;49(4):488-94. 
  5. Rotando A. Am J Emerg Med. 2019 Mar;37(3):494-498. 
  6. Doherty A. Anesth Analg. 2012 Dec;115(6):1343-50. 
  7. Schwartz MB. Am J Emerg Med. 2016 Dec;34(12):2419-2422 

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Sodium Bicarbonate in Cardiac Arrest





Clinical Content
5 min read
January 26, 2023

Sodium Bicarbonate in Cardiac Arrest

J

Jimmy

PharmD





Clinical Content
3 min read
January 26, 2023

Sodium Bicarbonate in Cardiac Arrest

J

Jimmy

PharmD

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Introduction

  1. Out-of-hospital cardiac arrest (OHCA) remains a leading cause of mortality and a substantial issue of public health concern worldwide.
  2. Sodium bicarbonate (SB) administration has been considered an important part of treatment for severe metabolic acidosis in cardiac arrest, because based on pathophysiologic considerations, normalization of extracellular and intracellular pH was considered a meaningful endpoint of resuscitation.
  3. Correction of metabolic acidosis with SB was recommended by early advanced cardiac life support (ACLS) guidelines published in 1973, and SB was the medication most frequently used during cardiac arrest until mid-1980s
  4. The 2010 ACLS Guidelines for adults published by the American Heart Association (AHA) state that “Routine use of sodium bicarbonate is not recommended for patients in cardiac arrest” (class lll recommendation, based on level of evidence (LOE) B)

Pharmacology

Dose   0.5-1 meq/kg/dose •     Repeat doses should be guided by arterial blood gases
Administration   IV injection during cardiac arrest
PK/PD   Onset Iv: Rapid Duration IV: 8-10mins Excretion: Urine (<1%)
Adverse Effects   Hypocalcemia Intracellular acidosis (without adequate ventilation) HYPERNATREMIA Hyperosmosis Shift O2 release by hemoglobin
Compatibility   Sodium bicarbonate solution may inactivate catecholamines such as epinephrine
  • May decrease of the biological effect of epinephrine to 77- 82 % of nonalkaline solution  
  • not powered

Overview of Evidence

Author, Year   Design/ sample size   NaHCO3 regimen    Outcome  
Chen YC, 2018   Observational/ n=5589    Not reported   Sodium bicarbonate during ED resuscitation was significantly associated with an increased rate of survival to hospital admission.  
Kawano T, 2017   Prospective observational/ n=13,865   Not reported    In OHCA patients, prehospital SB administration was associated with worse survival rate and neurological outcomes to hospital discharge.  
Ahn S, 2017   RCT/ n=50   50 mEq/L vs Placebo   No difference in sustained ROSC  (4% vs 16%) or good neurological outcome (0% vs 4% , p=.1)      SB had significant effect on pH (6.99 vs.   6.90, P=0.038) and bicarbonate levels   (21.0 vs. 8.0 mEq/L)  
Wang CH, 2016   Retrospective observational study/ n=109   Not Reported   SB was positively associated with sustained ROSC when serum potassium   level was <7.9 mEq in IHCA      Calcium and SB was positively associated with sustained ROSC when serum potassium level <9.4 mEq/L IHCA  
Vukmir RB, 2005   RCT/ n=792   1 mEq/kg NaHCO3   Overall survival rate was 13.9%      No difference in survival in those who   received bicarbonate      2-fold increase in survival in arrest >15 min (32.8 vs 15.4)*  
Bishop RL, 1976   Animal+human   case studies/ n=6   1 mEq/kg of 7.5% sodium bicarbonate in dogs      0.5-0.9 mEg/kg in humans   Animal 1 mEq/Kg   SB resulted in increases in the Pco2 (27→49),  pH (7.38 →7.56) and   the serum osmolality (309→349)      Man 0.5-0.9 mEq/Kg    SB resulted in increases in the Pco2 (24.5→38.8),  pH (7.23 →7.48) and the serum osmolality (308→343)  

References

  1. Sodium bicarbonate. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved October 11, 2018, from http://www.micromedexsolutions.com/ 
  2. Bishop RL, et al. Sodium bicarbonate administration during cardiac arrest. Effect on arterial pH PCO2, and osmolality. JAMA. 1976 Feb 2;235(5):506-9.
  3. Vukmir RB, et al. Sodium bicarbonate in cardiac arrest: a reappraisal. Am J Emerg Med. 1996 Mar;14(2):192206. 
  4. Vukmir RB, et al. Sodium bicarbonate improves outcome in prolonged prehospital cardiac arrest. Am J Emerg Med. 2006 Mar;24(2):156-61. 
  5. Wang CH,et al. The effects of calcium and sodium bicarbonate on severe hyperkalaemia during cardiopulmonary resuscitation: A retrospective cohort study of adult in-hospital cardiac arrest. Resuscitation. 2016 Jan;98:105-11. 
  6. Ahn S, et al. Sodium bicarbonate on severe metabolic acidosis during prolonged cardiopulmonary resuscitation: a double-blind, randomized, placebo-controlled pilot study. J Thorac Dis. 2018 Apr;10(4):22952302 
  7. Kawano T, et al. Prehospital sodium bicarbonate use could worsen long term survival with favorable neurological recovery among patients with out-of-hospital cardiac arrest. Resuscitation. 2017 Oct;119:63-69. 
  8. Chen YC, et al. The association of emergency department administration of sodium bicarbonate after out of hospital cardiac arrest with outcomes.  Am J Emerg Med. 2018 Mar 5. pii: S0735-6757(18)30187-6. 

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