Thursday, May 16, 2013

Pyridoxine (B6) for Refractory Status Epilepticus: "Fly Like A G6"

The case: TR is a one-year-old infant who presents to your emergency department with a tonic-clonic seizure. According to the paramedics, the seizure has lasted for approximately 10 minutes. She has no known past medical history. Vital signs are relatively stable, and a bedside blood glucose is performed, revealing a level of 105 mg/dL. She has a weight of 10 kg. IV access is established and 1 mg of lorazepam IV push is administered. The seizure stops within five minutes of administration of lorazepam, and this is followed by a post-ictal period that lasts for 20 minutes. After 20 minutes, TR seizes again, and a second dose of lorazepam 1 mg IV is administered. Despite this, TR still continues to seize for a period of 10 minutes, and the decision is made to administer a loading dose of fosphenytoin 200 mg IV. Despite this, TR still continues to seize. The pediatric ED attending physician turns to you and states:

"I am not crazy about the idea of intubating the patient and inducing a coma. Do you think pyridoxine is worth a try?"

First, let me start off with some definitions. Status epilepticus is characterized as either continuous seizures that last for more than five minutes, or two or more seizures without full recovery of consciousness between seizures. Refractory status epilepticus (RSE) is defined as the persistence of SE despite treatment with benzodiazpines and an antiepileptic drug (AED) (1, 2).

In terms of the treatment algorithm for SE, we generally start off with a benzodiazepine, followed by an AED if the seizure continues to persist, of which there are a number of agents to choose from: phenytoin, fosphenytoin, levetiracetam, valproic acid, phenobarbital, and lacosamide. If the seizure continues to persist despite treatment, a coma is induced in the patient using a sedative such as midazolam, pentobarbital, or phenobarbital (1).

Pyridoxine (vitamin B6) is a water-soluble vitamin that plays a role in a number of physiological enzymatic processes in the human body. Its biologically active form is pyridoxal-5'-phosphate (P5P). The following diagram illustrates the role of pyridoxine in the production of gamma aminobutyric acid (GABA):


In essence, low concentrations of pyridoxine and/or dysfunction in glutamic acid decarboxylase can lead to deficient concentrations of GABA, which can induce seizure activity. There are a number of current established uses of pyridoxine, which include the management of intoxications secondary to isoniazid, monomethylhydrazine (e.g. Gyromitra mushroom), and ethylene glycol ingestion (3, 4). 

It also has a role in pyridoxine-dependent seizures (PDS). This disorder was first described in 1954, and it is a rare autosomal recessive disorder that typically occurs within the first few weeks of the life of the neonate. It occurs secondary to mutations in the ALDH7A1 (antiquitin) gene, which leads to accumulations in the enzyme known as D1-piperideine-6-carboxylase. This enzyme inactivates P5P, which would ultimately prevent production of GABA. Patients can present with a wide array of symptoms, but the most common presentation is status epilepticus that is refractory to AEDs (5, 6, 7, 8).

Several case reports do highlight the utility of pyridoxine in patients presenting with SE refractory to AEDs. In addition, pyridoxine may also play a role in older patients who present with SE after discontinuation of maintenance treatment with oral pyridoxine in those patients who have an established diagnosis of PDS (6, 9, 10, 11). However, there are some challenges that may be encountered by clinicians in the emergency department in recognizing SE secondary to PDS. There is really no way of determining and recognizing that the patient does have PDS if it is the patient's first episode of SE. In addition, our primary concern is to stabilize patients in SE in order to prevent progression to irreversible morbidity and/or mortality. 

Times really have not changed when it comes to recommendations regarding pyridoxine for RSE. Authors of an editorial published in 1998 suggested that pyridoxine should be administered to patients experiencing seizures who are refractory to intravenous benzodiazepines. In addition, the most recent guidelines for SE recommend the use of pyridoxine in young children who experience SE in case PDS is the cause of SE (1).

In terms of dosing recommendations of IV pyridoxine for RSE, keep in mind that the dose is not weight-based, even in our pediatric patient. It is recommended that patients receive a loading dose of 100 mg IV, which may be repeated every 10 minutes up to five doses or until there is manifestation of response. From our own experience, pyridoxine works within minutes of administration; cessation of convulsions occurs almost instantaneously, and if seizure activity is being monitored through an electroencephalogram, normalization of the pattern can be observed immediately (12, 13).

It is recommended that all hospitals should keep 10 g of IV pyridoxine in stock for emergency administration (14, 15). Since the 1-mL vial containing 100 mg/mL is commercially available, this is equivalent to 100 vials. This is important, especially when if one suspects that SE is secondary to a toxic ingestion such as isoniazid, where the maximum dose that is recommended for this ingestion is 5 g. However, a number of studies have been conducted that have shown us the reality of stock in most hospitals. One study was a survey that was conducted of over 200 general and pediatric hospitals. It was found that IV pyridoxine was not on formulary in 9% of all general hospitals surveyed. In addition, only 20% of both general and pediatric hospitals had IV pyridoxine available in the emergency department. A second study showed that inadequate initial doses of IV pyridoxine was administered in 85% of patients evaluated, which can potentially lead to delayed improvement in clinical outcomes if waiting for additional stock to arrive from local area hospitals. It is especially convenient that IV pyridoxine is relatively inexpensive (only $2.50 per 100 mg/mL vial).

Anecdotally, we have administered IV pyridoxine at a dose of 100 mg to select patients with RSE with positive results. It can be considered a reasonable option for the management of RSE in patients without a clear etiology when traditional therapies are ineffective. Sufficient stock should be ensured to administer an adequate initial dose to patients in whom a toxicologic etiology of RSE is highly suspected.

Pop culture does recommend to be "fly like a G6", which I wholeheartedly agree with.

 

However, to make it relevant to the management of RSE, my recommendation is to "try out the B6."
 

References: 
1. Brophy GM, Bell R, Claassen J, et al. Neurocrit Care 2012; 17:3-23. 
2. Bleck TP. Curr Opin Crit Care 2005; 11:117-120. 
3. Lheureux P, Penaloza A, Gris M. Eur J Emerg Med 2005; 12:78-85. 
4. Minns AB, Ghafouri N, Clark RF. Pediatr Emerg Care 2010; 26:380-381.
5. Gospe SM. Pediatr Neurol 2002; 26:181-185.
6. Russell KE, Mulligan SR, Mallory LA. Pediatr Neurol 2012; 47:141-143.
7. Gospe SM. Curr Opin Neurol 2006; 19:148-153. 
8. Basura GJ, Hagland SP, Wiltse AM, et al. Eur J Pediatr 2009; 168:697-704.
9. Yoshii A, Takeoka M, Kelly PJ, et al. J Child Neruol 2005; 20:696-698.
10. Goutieres F, Aicardi J. Ann Neurol 1985; 17:117-120. 
11. Yoshikawa H, Abe T, Oda Y. J Child Neurol 1999;14:687-690.
12. Abend NS, Dlugos DJ. Pediatr Neurol 2008; 38: 377-390. 
13. Shorvon S, Ferlisi M. Brain 2012; 135:2314-2328.
14. Dart RC, Goldfrank LR, Chyka PA, et al. Ann Emerg Med 2000; 36:126-132.
15. Marraffa JM, Cohen V, Howland MA. Am J Health Syst Pharm 2012; 69:199-212.