What evidence is available on the safety and efficacy of IV push valproic acid?

Comment by InpharmD Researcher

Limited observational data suggest that IV push valproic acid may be as effective and safe as IV piggyback valproic acid. Available findings suggest that IVP administration may be feasible, with low rates of adverse events; however, further research is needed to determine the optimal administration strategy for IV push valproic acid in treating status epilepticus specifically.

Background

A recent review article on intravenous push (IVP) administration of antiseizure medications emphasizes the growing use of this approach in emergency departments. IVP offers a significant advantage by eliminating the need for pharmacy compounding and preparation, as well as the setup of infusion materials, tubing, and pumps, allowing for faster drug administration. Regarding the intravenous push of valproic acid (VPA), the authors highlight that this method could reduce delays associated with traditional infusion techniques, offering the potential for quicker intervention. Current dosing guidelines for VPA suggest a range of 15 to 45 mg/kg, with infusion times of 2.5 to 7.5 minutes. Limited research indicates that IVP administration at a rate of 6 mg/kg/min may be feasible, with low rates of adverse events, such as dizziness, thrombocytopenia, and mild hypotension, none of which were related to the infusion rate. Given the promising data from studies on undiluted rapid VPA administration, further research into IVP administration for the treatment of status epilepticus is warranted. Additionally, VPA has demonstrated efficacy in terminating benzodiazepine-resistant status epilepticus when compared to other antiseizure medications, further supporting the potential benefits of IVP administration in emergency settings. [1]

A 2024 retrospective study investigated the safety of IVP valproate sodium versus intravenous piggyback (IVPB) for various indications. The study was conducted at a women’s hospital in adult patients and utilized a pre-post analysis between March and May 2022 (IVPB) and June and August 2022 (IVP). Overall, there were low rates of peripheral infusion site reactions. Two phlebitis events occurred in the IVPB group (0.2%), while 4 occurred in the IVP administration group (0.9%; p= 0.10). Two infiltration events occurred in the IVPB group (0.2%), while 8 occurred in the IVP administration group (1.8%; p= 0.01). Similar safety profiles were observed for valproate-associated bradycardia, hypotension, and sedation events, and all events were classified as possible or doubtful by the Naranjo algorithm. Time from pharmacist order to verification and administration was also significantly faster for IVP compared to IVPB. These findings suggest that IVP is safe, but also provides more optimal operational outcomes and clinical benefits in the acute care setting. [2]

A 2007 study investigated the protein binding parameters of undiluted valproic acid (VPA) sodium administered as a rapid intravenous infusion in epilepsy patients from the Limdi et al. study (See Table 1). A total of 40 epileptic patients were administered 20 or 30 mg/kg loading dose at a rate of 6 or 10 mg/kg/min. Aside from the indication of VPA, patients were relatively healthy. Using the one-binding site model, the data suggests that VPA 30 mg/kg loading dose produced higher total and unbound concentrations versus 20 mg/kg. However, the estimated dissociation constant of 9.3 mg/L was found to be within the therapeutic range of unbound VPA concentrations among healthy historical controls (5-15 mg/mL). [3]

References:

[1] Aljadeed R, Gilbert BW, Karaze T, Rech MA. Intravenous push administration of anti-seizure medications. Front Neurol. 2025;15:1503025. doi:10.3389/fneur.2024.1503025
[2] Wang FY, McLaughlin KC, Schontz MJ, DeGrado JR, Dannemiller RE. Safety of Intravenous Push Valproate Compared with Intravenous Piggyback at a Tertiary Academic Medical Center. Clin Drug Investig. 2024;44(3):175-181. doi:10.1007/s40261-024-01349-z
[3] Dutta S, Faught E, Limdi NA. Valproate protein binding following rapid intravenous administration of high doses of valproic acid in patients with epilepsy. J Clin Pharm Ther. 2007;32(4):365-371. doi:10.1111/j.1365-2710.2007.00831.x
Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

What evidence is available on the safety and efficacy of IV push valproic acid?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Table 1 for your response.

 

Safety of Rapid Intravenous Loading of Valproate

Design

Open-label, prospective trial

N= 40

Objective

 To evaluate the safety of administration of undiluted valproic acid (VPA) sodium (20 or 30 mg/kg/min) administered intravenously at rates of 6 or 10 mg/kg/min

Study Groups

20 mg/kg (n= 20)

30 mg/kg (n= 20)

Inclusion Criteria

 Age 19 years or older, taking VPA to control seizures or epilepsy indication for use

Exclusion Criteria

 Allergy to VPA, liver disease, status epileptics, concurrent high-dose lamotrigine therapy

Methods

VPA sodium was prepared from 5 mL vials (equivalent to 100 mg valproic acid) as an undiluted solution to be infused via peripheral access by manual injection, using a stopwatch to monitor administration rate. IV access was confirmed with a saline flush before and after dosing. Patients were divided to receive 20 mg/kg or 30 mg/kg as loading dose, with each cohort group further divided to be infused at a rate of 6 mg/kg/min or 10 mg/kg/min.

6 mg/kg/min = 3.3 min administration time for a 20 mg/kg dose and 5 min for a 30 mg/kg dose

10 mg/kg/min = 2 min administration time for a 20 mg/kg dose and 3 min for a 30 mg/kg dose

Duration

 Up to 24 hours monitoring

Outcome Measures

 Local tolerance graded on a 1-10 scale (0= none, 10= worst), heart rate (HR), mean arterial pressure (MAP), changes in vital signs and level of consciousness

Baseline Characteristics

  

All patients (N= 40)

  

Age, years

 39  

Female

13   

Race

White

Black

Hispanic

Asian

 

28

9

2

1

  
 

20 mg/kg (n= 20)

 30 mg/kg (n= 20)  

Weight, kg (standard deviation [SD])

 91.8 (27.8) 73.2 (14.2)  

Valproate dose, mg (SD)

 1834.0 (556.1) 2190.6 (439.3)  

Results

Endpoint

20 mg/kg (n= 20)

30 mg/kg (n= 20)

p-Value

Local tolerance (SD)

Pain/burning

Paresthesia

Duration

 

5.5 (2.5)

2.9 (3.2)

2.1 (0.5)

 

5.9 (2.3)

2.3 (3.3)

2.3 (0.4)

 

0.71

0.67

0.31
 

6 mg/kg/min infusion rate (n= 20)

10 mg/kg/min infusion rate (n= 20)

  

Local tolerance (SD)

Pain/burning

Paresthesia

Duration

 

5.4 (2.2)

1.0 (2.5)

2.2 (0.6)

 

5.9 (2.7)

4.5 (2.9)

2.1 (0.2)

 

0.63

0.005

0.47

The results of the repeated measures analysis showed that there were no significant changes in MAP (p= 0.7) and HR (p= 0.9) over time

Adverse Events

 There were 3 complaints of sedation and 1 complaint of nausea among treated patients. No patients reported a decline in level of consciousness

Study Author Conclusions

 Rapid administration of undiluted valproate is safe and well tolerated at infusion rate up to 10 mg/kg/min and doses of up to 30 mg/kg. The lack of serious cardiovascular, neurological, hepatic, or local adverse effects supports the use of VPA in emergent situations.

InpharmD Researcher Critique

Based on the weight of patients, the max infusion rate could have exceeded a 200 mg/min infusion rate. However, there is a lack of investigation for patients that would have received high infusion rates due to their weight.



References:

Limdi NA, Knowlton RK, Cofield SS, et al. Safety of rapid intravenous loading of valproate. Epilepsia. 2007;48(3):478-483. doi:10.1111/j.1528-1167.2007.00989.x