Month: January 2013

Make It Work: Levocarnitine for Valproic Acid Toxicity

by Nadia I. Awad, posted in EM PharmD Blog

In the past couple of months, we have had a number of patients present to our ED with acute overdose secondary to the ingestion of valproic acid (VPA). When reading further about toxicity secondary to VPA, I was surprised to find that on an annual basis, there are approximately 8,000 reported cases of VPA toxicity in the United States. There are a number of concerns with VPA toxicity that one should be mindful of:

  1. The type of formulation that the patient ingested; specifically, the release mechanism of the product, as serial VPA levels may be elevated for an extended period of time and result in prolonged toxicity
  2. The cerebral and metabolic manifestations of acute VPA toxicity, specifically the CNS depression, possible hepatotoxicity, and hyperammonemia with encephalopathy, may result in impaired consciousness, focal neurological deficits, and increased risk of seizures.
Long-term VPA therapy and acute VPA toxicity are both associated with depleted levels of carnitine. Carnitine normally serves as a cofactor for the transport of long-chain fatty acids from the cytosol into the mitochondria to facilitate the β-oxidative metabolism of VPA to non-toxic metabolites. This occurs through a number of mechanisms, which include:

  • Combination of VPA with carnitine to form valproylcarnitine, which undergoes urinary elimination
  • Reduced production of carnitine via inhibition of butyrobetaine hydroxylase, which is essential in its synthesis
  • Decreased tubular reabsorption of carnitine with concomitant VPA
  • Decreased transport of carnitine from the extracellular space into the mitochondria through blockage of the carnitine transporter found on the cell membrane

With depleted levels of carnitine, the metabolism of VPA shifts from mitochondrial β-oxidation to ω-oxidation in the cytosol. Toxic metabolites that form as a result of the ω-oxidative process include 2-propyl-4-pentanoic acid and propionic acid, which have been demonstrated to be associated with cerebral edema and hyperammonemia, respectively. Propionic acid inhibits the mitochondrial enzyme required for elimination of ammonia (carbamyl phosphate synthetase I), which results in the accumulation of ammonia in the bloodstream. Depletion of carnitine also indirectly impairs the function of the urea cycle, which can result in further accumulation of ammonia as well.

So, supplemental therapy with levocarnitine, the commercially available active isomer of carnitine, in the setting of VPA toxicity theoretically makes sense. Levocarnitine should allow for metabolism of VPA through the β-oxidative pathway to take place, and restoration of the urea cycle should allow for elevated ammonia levels to normalize and lessen the severity of encephalopathy. In addition, the binding of levocarnitine to VPA may actually provide some benefit in toxicity to enhance the elimination of VPA.

A retrospective review of eight cases of VPA toxicity was conducted in patients who received both oral and intravenous levocarnitine as varying dosing schedules, and all patients recovered from the toxicity without demonstrating any adverse effects from treatment. Another study also demonstrated similar results, with early administration demonstrating improved clinical outcomes in acutely toxic patients. However, levocarnitine has not been demonstrated to shorten the recovery time of CNS depression in patients with VPA toxicity.

Levocarnitine is relatively inexpensive and safe and has been found to be associated with transient nausea, vomiting, and gastrointestinal upset as adverse effects. Interestingly enough, the oral formulation is only 15% bioavailable and has a fishy odor, making it somewhat unpleasant on the palate. Seizures have been reported in patients both with and without a history of seizures, but this is quite rare.

Here are some suggested recommendations for levocarnitine therapy in VPA toxicity:

  • Indications for administration of levocarnitine for VPA toxicity: 
    • Hyperammonemia
    • VPA level greater than 450 mg/L
    • Acute ingestions of VPA greater than 100 mg/kg
    • Patients who exhibit a decreased level of consciousness
  • Administer a loading dose of 100 mg/kg IV followed by a maintenance dose of 50 mg/kg IV every 8 hours (maximum of 3 g per dose). 
  • Continue treatment until ammonia levels are restored to normal and clinical improvement occurs. 
  • It is important to note intravenous levocarnitine is removed through hemodialysis, and so the timing of the dose will need to be adjusted in patients with severe VPA toxicity who require hemodialysis as adjunctive supportive treatment. 

So, levocarnitine is not so “risky business”…but it is a reasonable treatment approach for patients with acute VPA toxicity. Essentially, like many things in emergency medicine pharmacotherapy, this is an instance of using what you have and making it work.

A Brief History of Dexmedetomidine

by empharmd, posted in EM PharmD Blog

In a departure from previous guideline recommendations for sedation, the new Pain, Agitation, and Delirium guidelines in CCM have moved away from benzodiazepines as first line sedatives.  Taking over are propofol or dexmedetomidine who now occupy the first line sedative of choice position.  While many of us in the ED are familiar with propofol and have amassed an understanding of its practical use, dexmedetomidine is equally unfamiliar. 
Dexmedetomidine is a central alpha-2 agonist, similar to clonidine, but ~8 times more specific for the central alpha-2 receptor.  Physiologically, this translates into more sedation, less vasodilation and some opioid sparing effects.  While dexmedetomidine has been around since 1999, it hasn’t seen much action in the ED for a number of reasons: we use benzos first line, propofol is typically ready-made in the automatic dispensing cabinet, dexmedetomidine is still branded (ie, expensive), etc.)  However, with these new recommendations in CCM, an expiring patent in June/July of 2013 and drug shortages, dexmedetomidine will be a useful sedative to be aware of.
            Similar to other short acting sedatives, the initial data with this drug was from surgical procedural sedation and post-op sedation. Though a safe study and consistent patient population, they don’t offer much by way of emergency department sedation of newly mechanically ventilated patients.  These initial trials also left silly restrictions in the package insert: max dose of 0.7mcg/kg/hr and max duration of 24 hours.  These restrictions existed not for evidence based safety concerns; rather, they simply weren’t studied beyond the above dose and duration.
More applicable data from mechanically vented patients in medical and surgical ICUs was delivered in the MEDNS and SEDCOM trials. Aside from demonstrating similar efficacy with either lorazepam or midazolam, dexmedetomidine was associated with less delirium. From a safety perspective, patients who received dexmedetomidine had a higher incidence of bradycardia. However, this difference disappeared when the bradycardia was considered to be clinically significant. The MENDS and SEDCOM trials each used dexmedetomidine for more than 24 hours (and has been studied for up to 30 days) and at doses of 0.8 mcg/kg/hr to 1.5mcg/kg/hr without excessive hypotension or bradycardia.
            The real question, when it comes down to it for the emergency department, is why should one use dexmedetomidine over propofol?  Each agent is short acting, easily titratable, causes hypotension, and recommended above benzodiazepines.  Naturally, few studies have compared these two head-to-head.  What data do exist, dexmedetomidine and propofol demonstrated similar efficacy at achieving and maintaining time in target RASS. Interestingly, propofol this time was associated with more delirium. This was an interesting finding since propofol has not been linked to delirium until this trial, and could be a result of methodological deficiencies and small sample size. Still, even a cause and effect relationship between benzodiazepine use and ICU delirium has yet to be demonstrated. The data only places a strong association between benzos and delirium.
            To me, it would seem that dexmedetomidine fits as an alternative to propofol in the ED. An alternative that could, and probably will be used whenever the next propofol shortage hits.  Before then, read up on dexmedetomidine.
A great review in the Annals of Pharmacotherapy from 2009that I highly recommend. 

Rethinking the Utility of DDAVP for ICH Secondary to Antiplatelet Agents

by Nadia I. Awad, posted in EM PharmD Blog

A number of retrospective studies have demonstrated conflicting data regarding the association of morbidity and mortality secondary to intracerebral hemorrhage (ICH) in patients being treated with antiplatelet agents.1-4 In addition, an association between the severity of ICH as well as the conversion of a minor head trauma to an ICH secondary to the prehospital use of antiplatelet agents has yet to be determined.

I was intrigued by this and evaluated a number of institutional protocols that have been developed for the reversal of antiplatelet therapies in the setting of life-threatening hemorrhage such as ICH. To my surprise, I found desmopressin (DDAVP) listed as a potential reversal agent across the board. This piqued my interest and as I dug a little deeper to learn more, I found the waters to be even murkier.

Let me backtrack a bit. DDAVP is an analog of vasopressin that acts by increasing plasma concentrations of factor VIII and von Willebrand factor (vWf) through endothelial stimulation, which leads to improvement in platelet adhesion resulting in a shortened activated partial thromboplastin time (aPTT) and bleeding time. For this, it is indicated for the treatment of hemophilia A and mild-to-moderate von Willebrand disease.

As we know, aspirin as well as ticlopidine, clopidogrel, and prasugrel irreversibly inhibit platelet aggregation through different mechanisms. Aspirin irreversibly binds to the cyclooxygenase-1 and -2 (COX-1 and COX-2) enzymes via protein acetylation, inhibiting the downstream production of thromboxane A2, which is necessary for platelet aggregation. Ticlopidine, clopidogrel, and prasugrel selectively inhibit the P2Y12 portion of ADP receptors, all of which irreversibly prevent the activation of the GPIIb/IIIa complex that is necessary for platelet aggregation.

So what is the rationale for the use of DDAVP in this setting?

It has been hypothesized that the production of vWf induced by DDAVP may directly crossbind and stimulate the GPIIb/IIIa receptor, which may induce platelet aggregation. However, there is little evidence to show that this can occur in the setting of irreversible inhibition of platelet aggregation secondary to antiplatelet agents. One case report demonstrated that an IV infusion of 0.3 mcg/kg of DDAVP partially reversed the antiplatelet activity of clopidogrel and aspirin after carotid endarterectomy, which was exhibited through the use of platelet mapping thromboelastography.

However, there have been no studies to date that have assessed the effectiveness of desmopressin for the reversal of ICH secondary to antiplatelet therapies.

Like any other drug, DDAVP is not without its risks. Although its effects are immediate, they are transient and last for approximately 24 hours. In addition, there is some debate in the literature regarding the increased risk of arterial thrombosis associated with its use.

Perhaps the IMPACT Proof of Concept study will shed some light regarding the utility of DDAVP in improving platelet activity and thereby reversing ICH secondary to antiplatelet therapy.

But for now, I am not totally convinced.

References:
1. Mina AA, Knipfer JF, Park DY, et al. Intracranial complications of preinjury anticoagulation in trauma patients with head injury. J Trauma 2002; 53:668-672.
2. Jones K, Sharp C, Mangram AJ, et al. The effects of preinjury clopidogrel use on older trauma patients with head injuries. Am J Surg 2006; 192:743-745.
3. Sansing LH, Messe SR, Cucchiara BL, et al. Prior antiplatelet use does not affect hemorrhage growth or outcome after ICH. Neurology 2009; 72:1397-1402.
4. Ohm C, Mina A, Howells G, et al. Effects of antiplatelet agents on outcomes for elderly patients with traumatic intracranial hemorrhage. J Trauma 2005; 58:518-522.