Tuesday, April 30, 2013

Fast Facts About Kcentra, The "New" Four-Factor PCC in the United States

Here are some fast facts clinicians should be aware of regarding Kcentra:
  • Kcentra is marketed in over 25 countries around the world by CSL Behring as Beriplex® or Confidex®.
  • It is four-factor PCC, containing factors II, VII, IX, and X, in varying amounts, based on the size of the vial. It also contains Proteins C and S as well as heparin and antithrombin III. The table below provides a breakdown of the contents per 500 units of Kcentra, which comes out to approximately 25 mL upon reconstitution: 
  • The final concentration of factor IX per vial upon reconstitution ranges from 20 to 31 units/mL
  • Kcentra has currently been approved in the United States for the reversal of life-threatening hemorrhage secondary to warfarin.
  • The weight-based dosing regimen of Kcentra is based on the initial INR. The dose is maximized as follows in patients weighing greater than 100 kg 
    • INR of 2 to less than 4: 25 units/kg (maximum dose: 2500 units)
    • INR of 4 to 6: 35 units/kg (maximum dose: 3500 units)
    • INR of greater than 6: 50 units/kg (maximum dose: 5000 units)
  • The manufacturer does not recommend re-dosing Kcentra, as this has not been evaluated in clinical trials.
  • Vitamin K (phytonadione) should be administered along with Kcentra to sustain the levels of vitamin K-dependent clotting factors.  
  • The recommended rate of administration of Kcentra is 0.12 mL/kg/min (approximately 3 units/kg/min), up to a maximum rate of 8.4 mL/min (210 units/min) via IV infusion.
  • In terms of storage and shelf life:
    • Should be stored at temperatures between 2 and 25°C (36 to 77°F).
    • Stable for 36 months from the date of manufacture, up to the expiration date on the packaging of the product.
    • After reconstitution, the product is stable for 4 hours. 
  • As could be expected, adverse events associated with the use of Kcentra include thromboembolic complications; those reported from the clinical trials include myocardial infarction, deep vein thrombosis, and cerebrovascular accidents. 
  • Other common adverse events that patients experienced in the clinical trials of Kcentra include arthralgia (3.9%), headache (7.8%), hypotension (4.9%), and nausea and vomiting (3.9%).  
  • The clinical trials of Kcentra excluded those patients with a history of thromboembolic events occurring within the previous three months; use of Kcentra is not recommended in this patient population. 
Stay tuned for future posts regarding Kcentra, including a review of the clinical trials as well as the incorporation of the product into our practice.

1.  Kcentra (prothrombin complex concentrate [human]) [package insert]. CSL Behring, LLC; 2013.

Kcentra, Octaplex, USA 4-Factor PCCs

In the coming weeks we will live update how we will incorporate the new 4-factor PCC products into our institutional formulary and practice.
Exciting developments to come!

Monday, April 29, 2013

Nimodipine Shortage: What About Nicardipine

Drug shortages continue to wreak havoc on health care in US hospitals.  It seems every day there is yet another drug, more critical to medicine than the last, that’s unavailable due to shortages. Over the past few weeks, nimodipine has been going, going, gone.  Now reaching for alternatives, in this case, is proving difficult as a result of limited data on alternatives leaving many in a troubling situation.  Nicardipine, diltiazem, magnesium and other investigational agents are now being considered.  This discussion implies other treatment modalities are consistent with normal practices (ie, surgical intervention, triple-H therapy).

It’s important to consider the therapeutic goals of these treatments: reducing the occurrence of cerebral vasospasm after subarachnoid hemorrhage.  Though nimodipine has not conclusively been shown to prevent vasospasm, it has demonstrated reduction in cerebral ischemia and reduction in the incidence of poor neurological outcome at 3 months.1 Thus, when reviewing the data supporting these other treatments; cerebral vasospasm is essentially a surrogate marker for secondary cerebral ischemia and poor neurological outcomes.

Nicardipine would seem logical as an alternative to nimodipine. From the same class of CCB, similar pharmacokinetics and the availability of an IV dosage form in the US.  However, the clinical, randomized data has not shown an improvement in neurological outcome in SAH patients. In a randomized-placebo controlled trial conducted in the early 1990’s, nicardipine reduced the incidence of symptomatic vasospasm vs placebo.2 At three months, there was no difference in GOS and NIHSS.  While this study didn’t show an overall benefit for nicardipine, it is important to note that the study was stopped early and therefore underpowered, because nimodipine became commercially available in the USA during enrollment. The resulting power of the study was not the original 0.9, but 0.7. In addition, fewer patients in the nicardipine arm received adjuvant therapy for symptomatic vasospasm vs placebo, potentially reflecting under-treatment of those patients.  What I walk away with from this study is that nicardipine 1) does not worsen outcomes vs placebo and 2) has not been adequately studied to say there is no benefit. At worse, it is certainly an option if nimodipine is not available. A follow up study was published, but only compared high vs low dose nicardipine, with no placebo (or nimodipine) arm.3

It’s been postulated that nimodipine may have some other, yet to be identified, effect other than its calcium channel blockade.4 This could be an explanation why nicardipine has not shown a similar benefit.  A newer CCB of the same class, clevidipine, has not been studied in the setting of SAH, and it is not know whether it would have outcomes resembling nimodipine, or nicardipine; certainly an area for future study.

After SAH, there are multiple pathophysiologic events that lead to cerebral vasospasm. With the old cliché, that ‘the exact mechanism is poorly understood,’ it seems that vasospasm results from depletion of nitric oxide, or the existence of extravasated oxyhemoglobin disrupting vascular endothelium-smooth muscle communication causing the production of endothelin-1 as well as a myriad of inflammatory cytokines.4  To me, it would seem that rather than address each pathophysiological derangement individually (statins, ET-1 antagonists, methylene blue??); there might be more appropriate ‘global’ therapies that may play a role. 

Ultimately, there is no good answer to the nimodipine shortage with our current understanding and existing data.  I can’t help but consider the situation we are in now with nimodipine and what is to come with other medications with unique actions and therapeutic niches.  Why can’t there be an IV acetaminophen shortage?

  1. Pickard JD, Murray GD, Illingworth R, Shaw MD, Teasdale GM, Foy PM, Humphrey PR, Lang DA, Nelson R, Richards P, et al.: Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid hemorrhage: British aneurysm nimodipine trial. BMJ 1989, 298:636-642
  2. Haley EC Jr, Kassell NF, Torner JC, Truskowski LL, Germanson TP. A randomized trial of two doses of nicardipine in aneurysmal subarachnoid hemorrhage. A report of the Cooperative Aneurysm Study. J Neurosurg. 1994 May;80(5):788-96
  3. Haley EC Jr, Kassell NF, Torner JC. A randomized controlled trial of high-dose intravenous nicardipine in aneurysmal subarachnoid hemorrhage. A report of the Cooperative Aneurysm Study. J Neurosurg. 1993 Apr;78(4):537-47
  4. Siasios I, Kapsalaki EZ, Fountas KN. Cerebral Vasospasm Pharmacological Treatment: An Update. Neurology Research International;13: 1-20

Thursday, April 25, 2013

Cocaethylene: Not Your Old Coca-Cola

We all know that the effects produced from the toxic ingestion of cocaine and alcohol as separate entities are excessive stimulation and pronounced depression, respectively. So what are the effects of the toxic ingestion of both compounds together?

Enter cocaethylene...and it is far from the Coca-Cola produced during your great grandmother's time.

Cocaethylene (also known as ethylbenzoylecgonine) is produced from the concomitant ingestion of cocaine and alcohol. It is formed by the liver through a transesterification reaction of cocaine that occurs in the presence of ethanol through the activity of the nonspecific enzyme, cocaine carboxylesterase.

Like cocaine, cocaethylene blocks the reuptake of dopamine in the central nervous system and increases the extracellular concentration of dopamine in the accumbens nucleus, which produces euphoria and other similar effects. This effect may potentiate the toxicity of cocaine. However, cocaethylene has very little activity on the serotonergic system. In addition, the half-life of cocaethylene is longer than that of cocaine (nearly 2 hours for cocaethylene, compared to 40 minutes for cocaine), which can lead to prolonged toxicity. In addition, the LD50 of cocaethylene is lower than that of cocaine, which can be of potential concern in the patient who presents with concomitant ingestion of cocaine and alcohol.

The order of ingestion is important here, as the ingestion of ethanol preceding the ingestion of cocaine will not only lead to the formation of cocaethylene, but will also increase the plasma levels of cocaine and lead to a prolonged euphoric effect.

In terms of manifestations of toxicity, animal models have demonstrated that cocaethylene has myocardial depression effects and can decrease stroke volume, contractility, and mean arterial pressure. In addition, it has also been shown to increase the incidence of EKG abnormalities and lead to life-threatening dysrhythmias in a dose-dependent manner as a result of its greater potent effects on sodium channel blockade. It has also been shown to have inhibitory properties on the potassium and calcium channels in the heart, and one case report has described a patient who experienced QTc prolongation and Torsades de Pointes as a result of a dual ingestion of cocaine and ethanol.

It is difficult to extrapolate the effects that cocaethylene has demonstrated in animal studies to human patients, but it is important to be mindful of the effects of the combination of cocaine and alcohol and the potential for the formation of cocaethylene in the setting of such a dual ingestion.

Jatlow P. Cocaethylene: pharmacologic activity and clinical significance. Ther Drug Monit 1993; 15:533-536. [PMID: 8122289]
Andrews P. Cocaethylene toxicity. J Addict Dis 1997; 16:75-84. [PMID: 9243342]
Hearn WL, Rose S, Wagner J, et al. Cocaethylene is more potent than cocaine in mediating lethality. Pharmacol Biochem Behav 1991; 39:531-533. [PMID: 1946594]
Wilson LD, French S. Cocaethylene's effects on coronary artery blood flow and cardiac function in a canine model. J Toxicol Clin Toxicol 2002; 40:535-546. [PMID: 12215047]
Wilson LD, Henning RJ, Suttheimer C, et al. Cocaethylene causes dose-dependent reductions in cardiac function in anesthetized dogs. J Cardiovasc Pharm 1995;26:965-973. [PMID: 8606535]
Wilson LD, Jeromin J, Garvey L, et al. Cocaine, ethanol, and cocaethylene cardiotoxicity in an animal model of cocaine and ethanol abuse. Acad Emerg Med 2001;8:211-222. [PMID: 11229942]
Xu YQ, Crumb WJ, Clarkson CW. Cocaethylene, a metabolite of cocaine and ethanol, is a potent blocker of cardiac sodium channels. J Pharmacol Exp Ther 1994; 271:319-325. [PMID: 7965731]

Monday, April 22, 2013

Push-Dose Phenylephrine: Experience and Important Points

Originating in anesthesia, promoted in emergency medicine by EMCrit.org and EMRAP, the utilization of push dose pressors has been growing. While there doesn’t exist much data to back up its use, I think the clinical experience speaks for itself.  In my experience has been generally good with recommending push dose phenylephrine aka. “Neostick,” if the dose is appropriate (80-100 mcg, not 20mcg) and the timing is appropriate (not after hours of hypotension).  Likewise, expectations of response differ depending on the clinical scenario; from buying a few minutes to allow for central line placement, or increasing SBP by about 5-10 mmHg.

The actual compounding of the Neostick is important to discuss both with everyone in the ED on your team.  I’ve had to review cases where the intent was to use push dose epinephrine, but due to poor (or lack of) communication, the entire syringe was pushed instead of 1 mL.  If you have pharmacists in your ED, get them involved early, or better yet, before considering push dose pressors.  They can inform you regarding hospital policy for IV mixing outside of the pharmacy, how they would recommend mixing the pressor syringe, or the availability of commercially premade syringes.

While compounding instructions exist on other sites, I have my own method. I’ve adapted to the method describe below as a result of poor response during my initial experience with push dose pressors, even at relatively high doses of phenylephrine.  I started to become concerned that the final concentration of phenylephrine in the syringe was not what was desired since I was mixing 1mL into a 100mL bag of NS.  Additionally, it is not widely known outside the walls of the pharmacy that commercially available IV piggyback bags contain various amounts of overfill. For example, in a 100mL NS contains approx. 109mL. So adding 1mL will make the total volume 110mL and therefore, a more dilute final concentration. In pharmacy there is a general rule that unless you are adding > 10% of the volume of the bag, you do not need to account for over fill. In this instance, however, since you’re withdrawing a small amount from the bag, which is highly dependent on the final concentration, the overfill must be taken into consideration.

The adapted method can be done in one of two ways. Again, discuss this within your own practice site to see which one others (and yourself) are comfortable with BEFORE being in a situation where a Neostick is needed STAT.

My method:
Step 1: To account for overfill and the volume to be administered, take a 100mL IVPB bag of NS, withdraw and waste 10mL.
Step 2: Add 1mL of phenylephrine 10mg/mL (from a vial). The concentration in the bag is now truly 10,000 mcg / 100mL (100 mcg/mL)

A more confusing method that I wouldn’t recommend doing if you aren’t an experienced pharmacist,

Method 2:
Step 1: Withdraw 1mL of phenylephrine (10mg/mL) in a 10 mL syringe.
Step 2: With the same syringe, draw up an additional 9mL of NS to a total volume of 10mL. Now you have a 10mg/10mL syringe.
Step 3: Next, waste 9mL from that syringe, leaving 1mL, or 1mg.
Step 4: Repeat the dilution in step 2, yielding a final concentration of 100mcg/mL. (1mg in 10mL syringe or 1000 mcg/10mL)

Thursday, April 18, 2013

The Trauma Cupid's Arrow: Intracardiac Epinephrine

A patient is wheeled into your trauma bay after a nasty head-on collision on a major highway. According to the paramedics, the downtime and length of anoxia in the patient is unknown, and because of this, the patient is intubated. Vital signs are unobtainable, and pulses are lost on the scene. The patient is now in pulseless electrical activity (PEA), and cardiopulmonary resuscitation is initiated. The decision is made to perform an emergent thoracotomy.

The process is underway and it is time for the next epinephrine dose. The trauma surgeon calls out, "Alright, let's use intracardiac epinephrine."

Wait...what? Perhaps this movie scene pops into your head as you hear the order:

Very few case reports and small anecdotal studies describe the use of intracardiac epinephrine in the setting of emergent thoracotomy in traumatic cardiac arrest.

Here are some pointers to remember regarding this technique for administration:
  • The dose is the same dose that is used in the guidelines for advanced cardiovascular life support (ACLS): 1 mg.
  • Use whatever epinephrine product you have available, whether it be the 1:10,000 (1 mg/10 mL) or 1:1,000 (1 mg/mL) concentration; both concentrations have been studied and are acceptable for use.
  • In terms of needle size and length:
    • The best bet to use is an 18-gauge or 22-gauge needle; anything smaller than this is generally not recommended due to the potential for vascular injury to the cardiac tissue.
    • A 1.5-inch needle should be sufficient. Interestingly enough, a number of pharmaceutical companies have manufactured epinephrine specifically for intracardiac injection, which is available in a pre-filled syringe with a 3.5-inch needle attached (fancy, but can create "trauma drama" and probably not truly necessary).
  • Cardiac compressions should be discontinued temporarily while intracardiac administration occurs to prevent injury to the person performing chest compressions.
  • The epinephrine should be administered as rapid push and directly injected into the chamber of the left ventricle while cardiac massage is ongoing. This can be achieved by lifting the heart outwards to allow for easier visualization of the left ventricle.
  • Chest compressions can be resumed once the dose has been administered.
  • The dose of intracardiac epinephrine of 1 mg can be repeated every 3 to 5 minutes, as per the ACLS algorithm.
Some complications that patients may experience include ventricular and coronary artery laceration, pneumothorax, and cardiac tamponade. Because of this, an organized method is necessary for this technique in order to ensure appropriate administration.

Monday, April 15, 2013

Digoxin, Potassium and Calcium

Very little of what we do on a daily basis, as pharmacists, fit into discrete silos.  In contrast to our didactic education (or mine, at least), chapters are studied focusing on specific disease states, medication classes are analyzed individually and cases are discussed with rarely more than one problem.  Of course learning to walk before you run through study and comprehension of the basic components and methods of problem solving is critical. However, it leaves one to their own devices, or post-graduate training, to synthesize not just knowledge but understanding how various different elements of a problem may change your treatment plan.

As the textbooks go, in the setting of hyperkalemia, insulin-dextrose, sodium bicarbonate, albuterol, sodium polystyrene sulfonate, and calcium are appropriate treatment strategy in combination.  However, in a similar setting of hyperkalemia associated with digoxin therapy, caution is advised when considering calcium. The basis of this is theoretical: additional calcium with an already increased intracellular concentration of calcium leading to altered contraction of myofibrils, delayed conduction and/or altered sarcoplasmic reticulum and mitochondrial functioning.  The evidence supporting this theory is often questioned due to its age (articles dating back to 1930s, see below) as well as more recent investigations have not associated with the administration of calcium in this setting with deleterious effects.  Such a clinical controversy yields a precarious dilemma when discussing the role of calcium in this setting, often dividing a room full of clinicians.

But more on the practical side of things, the role of calcium becomes less clear in the hypothetical clinical scenario where you may have a patient with signs and symptoms consistent with severe hyperkalemia (ecg changes, hemodynamic instability and generalized weakness) but the picture could be attributed to not just the patient’s digoxin, but also a CCB like verapamil or a beta-blocker as well. A broad spectrum approach is employed including transcutaneous pacing and DigiFAB administered empirically with a hyperkalemia cocktail, except for the calcium.  With few lab results back including a potassium of 9, twenty minutes later and still no change in the patient’s condition, is it now time for calcium? 

Operating in the silo of hyperkalemia in the setting of digoxin, it would seem risky based on the theory.  However, parallel to other situations, while there may be similarities between real life cases and text book learning, often there are other difficult to predict confounding elements.  Acknowledging the risks of calcium, but also understanding the evidence both of the literature and each given patient scenario that make up those real life confounders, calcium can be seen as a reasonable option.
In my experience instances in which DigiFAB was needed and calcium was concomitantly administered, . In two situations, it was not known that the patient was taking digoxin at the time of calcium administration and the other patient was known to be taking digoxin.  In all three situations, calcium did not lead to “stone-heart,” and seemed to help.  It should be said that theory behind the caution makes sense, and calcium should be considered with caution, if not withheld, in situations where digoxin is known to be involved. But, as described, and often encountered, it isn’t always that simple. 

Gold H, Edwards DJ. The effects of ouabain on heart in the presence of hypercalcemia. Am Heart J. 1927;3:45-50.
Lieberman AL. Studies on calcium VI: some interrelationships of the cardiac activities of calcium gluconate and scillaren-B. J Pharmacol Exp Ther. 1933;47:183-192
Bower JO, Mengle HAK. The additive effect of calcium and digitalis. JAMA. 1936;106:1151-1153
Smith PK, Winkler AW, Hoff HE. Calcium and digitalis synergism: the toxicity of calcium salts injected intravenously into digitalized animals. Arch Intern Med. 1939;64:322-328
Nola GT, Pope S, Harrison DC. Assessment of the synergistic relationship between serum calcium and digitalis. Am Heart J. 1970;79:499-507
Wagner J, Salzer WW. Calcium-dependent toxic effects of digoxin in isolated myocardial preparations. Arch Int Pharmacodyn. 1976;223:4-14
Khatter JC, Agbanyo M, Navaratnam S, et al. Digitalis cardiotoxicity: cellular calcium overload as a possible mechanism. Basic Res Cardiol. 1989;84:553-563
Kne T, Brokaw M, Wax P. Fatality from calcium chloride in a chronic digoxin toxic patient (abstract). J Toxicol Clin Toxicol. 1997;5:505

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