Make It Work: Levocarnitine for Valproic Acid Toxicity

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.

Out With the Old, In With the New: Sulfanegen for Cyanide Toxicity

Look out, Tox/EM/Pharm World: there is a new antidote for cyanide toxicity coming soon to an ED near you.

It goes by the name of sulfanegen.

The compound is being developed as a joint collaborative effort between the University of Minnesota and a startup pharmaceutical company called Vytacera Pharma, Inc.

In terms of how sulfanegen exerts its antidotal effects in the setting of cyanide toxicity, it is actually a water-soluble prodrug of 3-mercaptopyruvate (3-MPV). The endogenous enzyme 3-mercaptopyruvate sulfur transferase (3-MPST) catalyzes the transfer of sulfur from 3-MPV to cyanide to result in the formation of thiocyanate and pyruvate. 3-MPV is relatively unstable when administered intravenously due to the fact that it is rapidly inactivated in the bloodstream, so sulfanegen was developed to overcome this effect.

So why the need? Compared to rhodanese, the enzyme that we get the most bang for our buck for through the administration of our trusty three-agent Cyanide Antidote Kit, a significantly greater amount of 3-MPST exists in the tissue of the brain, specifically in the cerebellum. In addition, the advantage of making use of 3-MPST as an alternative pathway for the detoxification of cyanide is the fact that 3-MPST is available in both the mitochondria and cytoplasm, whereas rhodanese is present only in the mitochondria of hepatic and renal tissues. This is somewhat concerning in the setting of cyanide toxicity, as the organs where much of the damage occurs are the heart and brain.

So you may be thinking...why not just use hydroxocobalamin, then? The other potential advantage with sulfanegen is the fact that it can be administered very rapidly...in fact, it begins to exert its effects in under three minutes. With hydroxocobalamin, a 15-minute IV infusion is necessary before any effect can be demonstrated. Another benefit of sulfanegen: it can be administered as both an IM and IV injection, which is certainly not the case with hydroxocobalamin, where the IM route was attempted in a previous study, due to the large volume required for administration.

Interestingly enough, sulfanegen has been in development since the early 1990s and is in the final stages of development and testing for efficacy and safety. The hope is that the compound will receive approval by the FDA under the Animal Rule, where only animal studies proving efficacy and Phase I studies conducted in humans proving safety are necessary.

It will be interesting to see the results of the safety studies conducted in humans and how the FDA approval process overall will unfold. Some food for thought regarding this new antidote:

• What will its place in therapy be for cyanide toxicity? Prophylactic? First-line? Salvage therapy? 
• What will be the optimal route of administration (IM or IV)?
• Is there a potential for re-dosing of sulfanegen if the first dose is not effective?
• What potential adverse events are to be experienced with treatment?
• Will dual therapy with three-agent antidotal therapy (amyl nitrite, sodium nitrite, sodium thiosulfate) or hydroxocobalamin be indicated in severe cases of cyanide toxicity such as mass casualty events?
• How much will sulfanegen cost? Will the benefits of treatment offset the costs associated with therapy?

Only time will tell us the answers to these and other questions regarding the utility of sulfanegen for the treatment of cyanide toxicity.

References:
Belani KG, Singh H, Beebe DS, et al. Cyanide toxicity in juvenile pigs and its reversal by a new prodrug, sulfanegen sodium. Anesth Analg 2012; 114:956-961. [PMID: 22392971]
Brenner M, Kim JG, Lee J, et al. Sulfanegen sodium treatment in a rabbit model of sub-lethal cyanide toxicity. Toxicol Appl Pharmacol 2010; 248:269-276. [PMID: 20705081]
Chan A, Cranshaw DL, Monteil A, et al. The combination of cobinamide and sulfanegen is highly effective in mouse models of cyanide poisoning. Clin Toxicol 2011; 49:366-373. [PMID: 21740135] 
Kim JG, Lee J, Mahon SB, et al. Noninvasive monitoring of treatment response in a rabbit cyanide toxicity model reveals differences in brain and muscle metabolism. J Biomed Opt 2012; 17:105005. [PMID: 23223999]

Silibinin for Amatoxin Poisoning: Preventing the Last [Thanksgiving] Supper?

Ingestion of cyclopeptide mushrooms can lead to irreversible hepatotoxicity that may potentially be life-threatening. The mechanism by which hepatotoxicity occurs is through the activity of α-amanitin, which is taken up by hepatocytes and inhibits DNA-dependent RNA polymerase II, preventing DNA transcription into mRNA, which consequently halts the process of protein production. This causes injury of organ systems that are highly dependent on protein synthesis, such as the gastrointestinal mucosa, kidneys, and liver, which eventually leads to tissue necrosis. In addition, it is hypothesized that the activity of this toxin can lead to the production of free oxygen radicals that further exacerbate hepatocellular necrosis. It is reported that the lethal dose of α-amanitin in humans is 0.1 mg/kg body weight, which is equivalent to as little as one fresh mushroom (30 to 50 grams).

The most difficult part in terms of the management of cyclopeptide mushroom poisoning is the fact that there is no standard antidote that has been proven to be effective, and in many instances, their use is somewhat controversial. Those that have been tried include activated charcoal, high doses of intravenous penicillin G, intravenous N-acetylcysteine, intravenous cimetidine, and hemoperfusion. Aggressive hydration is indicated to prevent injury to the kidneys. In cases of severe cyclopeptide mushroom poisoning, liver transplantation may be warranted.

Quite recently, however, there has been some talk regarding silibinin, a water-soluble derivative of silymarin (milk thistle), as an antidote for the treatment of cyclopeptide mushroom poisoning. It has been used in Europe for decades for the treatment of acute amatoxin poisoning, and is currently being investigated as a study drug in the United States for the same indication. It is thought to act through competitive inhibition of the transporter system that is necessary for uptake of amatoxin into hepatocytes. Not only does this interrupt primary circulation of amatoxin, but it also disrupts enterohepatic recirculation of the toxin as well, the latter process being relevant to toxicity since many patients present long after complete absorption of the cyclopeptide. Silibinin seems to also possess anti-inflammatory and antioxidant properties, preventing injury and oxidative stress to the liver in the setting of amatoxin poisoning; it may also stimulate protein synthesis, thereby preventing further damage to the liver, allowing for regeneration of injured tissue within the liver and restoration of hepatic function.
 
The dosing schedule for silibinin as an investigational antidote for highly suspected or confirmed amatoxin ingestion in patients at least two years of age is as follows:

• Loading dose of 5 mg/kg IV infused over one hour followed by a maintenance infusion of 20 mg/kg/day 
• Infusion is to be continued until coagulopathy has resolved and liver function tests normalize

At this point, you may be asking where the evidence is to show that silibinin improves long-term clinical outcomes in patients with amatoxin poisoning. The short answer is that there is not a whole lot of evidence to support this hypothesis. Although there are plenty of published case reports that show its potential benefit in acute toxicity, a retrospective study conducted by Zilker and colleagues (Clin Toxicol 2005; 43:438) demonstrated that there are simply not enough cases of amatoxin poisoning to draw a meaningful conclusion regarding the effectiveness of silibinin when compared to other therapies.

Some logistical issues regarding drug procurement include the following:

• Because this is a study drug, in the setting where ingestion of amatoxin is highly suspicious, consultation with the toxicology service and/or local poison control center is necessary.
• Contact would need to be made with the principal investigator of the open-label multicenter study in order to enroll the patient(s) into the study and retrieve the drug.
• Arrangements would have to be made to have the drug flown in and couriered to the institution.
• An emergency investigational new drug application with the study protocol would need to be completed and approved by an institutional review board prior to administration of the agent.

These factors are important to consider because a delay in treatment with silbinin for amatoxin poisoning by more than 48 hours has been shown to be associated with a more severe course of coagulopathy and hepatic injury.

Since a trial is ongoing in the United States and the adverse events associated with treatment are relatively benign (facial flushing and rash), the potential benefits of silibinin do seem to outweigh the risks associated with treatment. Perhaps the results of the trial may shed some light regarding its place in therapy for amatoxin poisoning.

Name two circumstances when a selective serotonin reuptake inhibitor (SSRI) overdose may be potentially dangerous.

1. massive overdose 
2. citalopram (Celexa) overdose which can cause QT prolongation and seizures 

Otherwise, SSRI overdoses are generally benign. 


Source

Peer VIII: Physcian's Evaluation and Educational Review in Emergency Medicine, American College of Emergency Physicians

25 y/o female presents with low grade fever, vomiting, rigors and headache 1/2 hour after injecting heroin. Vitals notable for temp of 100.5. Physical unremarkable. WBC 12, other labs normal. After IV hydration and antiemetics patient feels much better 2 hours later. What is her likely diagnosis?

Cotton fever. As part of the processing of heroin prior to injection many drug users strain the drug through cotton to rid it of impurities. This process, however, can sometimes introduce other impurities into the drug such as Enterobacter agglomerans or other nonspecific pyrogenic components which produce the symptoms described in the vignette. Treatment is supportive and symptoms generally self resolve within 24 hours. While cotton fever is a benign febrile disorder, vigilance should be maintained as there are many not-so-benign causes of fever in the intravenous drug user.


Source

Ramik, D. and Mishriki, Y. "The Other 'Cotton Fever'" Infectious Disease in Clinical Practice. May 2008.

Marx: Rosen's Emergency Medicine, 7th ed.

Shannon: Haddad and Winchester's Clinical Management of Poisoning and Drug Overdose, 4th ed.

Name six potentially toxic drugs that can be removed by dialysis.

1. carbamazepine
2. lithium 
3. salycilates
4. theophylline
5. toxic alcohols (ethlene glycol, isopropanol, methanol)
6. valproic acid 

With the exception of the toxic alcohols, a drug level can be obtained pretty easily for these drugs at most hospitals.

Source

Hudson, K. and Sinert, R.  "Renal Failure: Emergency Evaluation and Management"  Emerg Med Clin N Am.  2011.

How does hydrogen sulfide, the gas that smells like rotten eggs, cause death?

Similar to cyanide it impairs oxygen utilization and induces lactic acidosis via anaerobic metabolism. The gas is a byproduct of the decomposition of organic materials and occurs in caves, volcanoes, sulfur springs, sewers, swamps, petroleum processing, paper production, and leather finishing and manufacturing. Treatment is supportive. Hyperbaric oxygen and induction of methemoglobin via amyl or sodium nitrate are controversial but may be helpful.


Source

Irwin & Rippe's Intensive Care Medicine, 5th ed.

When are the standard acetylcysteine protocols for acetaminophen overdose not enough?

Click here to read a great post from The Poison Review by Dr. Leon Gussow.

Can a patient exhibit signs of lithium toxicity despite normal serum blood levels?

Yes. It is brain concentration rather than the serum level which determines symptoms.


Source

Sansone, M. and Ziegler, D. "Lithium Toxicity: A Review of Neurologic Complications" Clinical Neuropharmacology. 1985.

How long should a patient who overdosed on opiates and required narcan for respiratory resuscitation be observed in the ED prior to discharge?

About 5 hours.

Half life of narcan is 1 hour. At five half-lives, or 5 hours, the initial dose of narcan is 97% eliminated and if the patient has not required another dose of narcan for recurrent respiratory depression by this point, it is probably safe to discharge the patient home.

Click on image to enlarge

Source

Naloxone: Drug information. Lexi-Comp

Image source: http://www.nes.scot.nhs.uk/prescribing/topics/TDM/fig2.gif

Serotonin syndrome, neuroleptic malignant syndrome, anticholinergic toxidrome and malignant hyperthermia can present similarly with hyperthermia, tachycardia, confusion and hypertension. What clinical characteristics help distinguish between these entities?

click to enlarge

Source

Boyer, E.  and Shanahan, M.  "The Serotonin Syndrome"  N Engl J Med.  March 17, 2005.

A patient consumed 3 grams of aspirin over a 24 hour period to treat his lower back pain. Aspirin level is 5 mg/dL. Is this toxic?

No.

Maximum recommended adult dose is 4 g/day.

Toxicity generally occurs if acute ingestion of 150 - 200 mg/kg or chronic ingestion of 100 mg/kg/day x 2 or more days.

Serum levels greater than 90 - 100 mg/dL in acute ingestion and greater than 60 mg/dL in chronic ingestion are considered dangerous.


Source

Olson, K. "Poisoning and Drug Overdose"  4th ed.

Aspirin: Drug Information.  Lexi-Comp.  Up To Date. 

Which medications could be fatal to a toddler if ingested in just 1 dose unit?

Type in name of drug. Get treatment for overdose.

It's that simple.

Hazardous Substances Data Bank: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB

Thanks to Michelle Lin of Academic Life in Emergency Medicine for informing me of this great resource.

Which patients are appropriate for outpatient alcohol detoxification?

Patients who meet the following criteria are candidates for outpatient alcohol detox.

• CIWA score 8 - 15. CIWA less than 8 may not need detox unless last alcohol consumption was less than 8 hours ago and withdrawal symptoms have not yet manifest. CIWA greater than 15 will likely benefit from inpatient detox.
  
• able to take po meds
  
• have a reliable close contact who can stay with the patient throughout the detox period (3-5 days) and monitor the patient
  
• able to attend daily medical visits
  
• no unstable psych or medical condition
  
• not pregnant
  
• no history of DTs or alcohol withdrawal seizures
  

Source

Volpicell, J and Teitelbaum, S. "Ambulatory alcohol detoxification" Up to Date. 8 Sep 2009.

Patient usually takes 8 mg of dilaudid po q 4 hours. What is the approximate equianalgesic dose IV?

IV dilaudid is 5x "stronger" than PO.

Hence, 8/5 = 1.6 mg IV


Source

Winshall, J. and Lederman, R. Tarascon Internal Medicine & Critical Care Pocketbook. 4th ed.

Pt with history of heavy ETOH abuse presents for psych eval; last drink 3 d ago. Is the pt out of the woods for alcohol withdrawal syndromes?

No.

DT's can begin up to 4 days after the last drink.


Source

Hoffman, R. and Weinhouse, G. "Management of moderate and severe alcohol withdrawal syndromes" Up to Date. 4 Feb 2009.

Which of the following are nondihydropyridine calcium channel blockers: diltiazem, verapamil, nifedipine, amlodipine?

diltiazem and verapamil.

Nondihydropyridines have significant affect on heart rate and cardiac contractility where as the dihydropyridines such as nifedipine and amlodipine primarily have vasodilatory action and minimal effect on cardiac inotropy or chronotropy.


Source

Shanon: Haddad and Winchester's Clinical Management of Poisoning and Drug Overdose, 4th ed.

What is the prognosis for an adult who ingests seventy-five 200 mg ibuprofen tablets?

Good. Seventy-five 200 mg tablets = 15,000 mg or 4.6 times the maximum recommended daily dosage (3600 mg). With this amount, the patient will often experience gastrointestinal upset (nausea, vomiting, abdominal pain) as well as mild neurological symptoms (drowsiness, lethargy, ataxia, nystagmus, tinnitus, disorientation).

However, at greater amounts 5 - 10 times the recommended max daily dose, lethal complications such as coma, GI bleed, renal failure and metabolic acidosis can ensue.


Source

Olson, K. MD. Poisoning & Drug Overdose 4th ed. 2004.

Where's the closest hyperbaric chamber?

Click here to find out.