Thursday, September 26, 2013

Kcentra Administration, Revisited

In an earlier post, the nuances associated with the administration of Kcentra was discussed. One point of contingency was associated with the dilution and rate of infusion of Kcentra. The package insert provides the following information with regards to the rate of administration:

"Administer by intravenous infusion at a rate of 0.12 mL/kg/min (approximately 3 units/kg/min) up to a maximum rate of 8.4 mL/min (approximately 210 units/min)."

The package insert also provides additional information with regards to dilution. Rather, it should not be further diluted in any diluent solution and should be given through a separate line.

This leaves us in a bit of a pickle. As the post mentioned, instilling the total volume of Kcentra in an empty evacuated bag may prove to be difficult, especially since they are on shortage and the product is generally needed for immediate administration. In addition, depending on the type of infusion pump available at your institution, one has to account for the tubing volume in which the medication remains in following completion of the infusion. My institution has actually resorted to the use of pediatric syringe pumps for infusion of Kcentra. However, there is a limit on the syringe volume that these syringe pumps can support (most of the time, up to 60 mL), and multiple syringes would have to be drawn up and prepared for infusion of the medication through such pumps.

So what is one to do? You cannot dilute the stuff nor can you give the medication faster than 8.4 mL/min...or can you?

There is still no information available regarding further dilution of Kcentra, which would ease both the reconstitution and administration process. However, I did come across UK transfusion guidelines for Beriplex (same product as Kcentra but goes by a different name in Europe). It recommends for each 500-unit vial of Beriplex/Kcentra is to be reconstituted in 20 mL of diluent that is provided with the product. The recommendation is to draw up the reconstituted 20 mL of product into a syringe and administer as an intravenous injection over 2 to 3 minutes. This makes sense, as you technically would not be exceeding the above recommended infusion rate provided by the manufacturer in the package insert. Granted, if using the maximum 5000-unit dose of Kcentra, this may be quite timely as you would need multiple 20-mL syringes, but it may be a reasonable alternative method for administration without having to go through the efforts of retrieving an evacuated container that may or may not be on shortage or finding and programming a pump that may or may not be flushed with diluent following the infusion.

In addition, I came across a study that looked the effects of the rate of infusion of Beriplex on both safety and efficacy in reversing life-threatening hemorrhage secondary to warfarin. This prospective, international, multicenter study consisted of 43 patients; six of the patients received the product at a rate greater than 10 mL/min, and four of these patients had administration rates that exceeded 15 mL/min, which I found very interesting. What is even more reassuring was that the rate of infusion had no impact on these outcome measures, which demonstrates that in such settings of emergent reversal, administration of 4-factor PCC at rapid rates may be an option.

If only the manufacturer of Kcentra can outright state this to be the case...then we would not be in such a conundrum.

Thursday, September 5, 2013

Paging Goldilocks to the ER: Acute Pain Management in the Emergency Department, Part II

In an earlier post, I discussed some of the nuances associated with the administration of opioid analgesics (particularly morphine and hydromorphone) in the emergency department. This post will review some of the studies that have been recently conducted to evaluate the safety and efficacy of these agents for acute pain management in patients who present to the emergency department. 

  • Chang AK et al.; Ann Emerg Med 2013: 
    • This was a prospective study that evaluated the safety and efficacy of administering an initial dose of hydromorphone 2 mg IV compared to an initial dose of hydromorphone 1 mg IV followed by a second optional dose of hydromorphone 1 mg administered 15 minutes later (“1 + 1” protocol). 
    • Patients in both groups were assessed at 60 minutes to determine the level of analgesia on a standard pain scale ranging from 0 to 10 and if additional pain medication was needed.
    • Patients were included in the study if between 21 and 64 years of age at the time of presentation and presented with acute pain (less than or equal to seven days in duration) to the emergency department with a systolic blood pressure (SBP) greater than 90 mmHg and oxygen saturation greater than 95%. 
    • Excluded patients included those with a history of chronic pain, use of opioid analgesics within the previous seven days of presentation, and those who weighed less than 150 pounds.
    • Nearly 70% of the 334 patients enrolled in the study had an initial pain score of 9 or 10, with most of the pain localized to the abdomen. Weight of patients in both treatment groups ranged from 165 to 220 pounds (75 to 100 kg). 
    • For those patients who received an initial dose of hydromorphone 2 mg IV, 67.5% declined additional analgesic medication at 60 minutes. 
    • 61% of patients who received an initial dose of hydromorphone 1 mg IV did not require an additional dose at 15 minutes, with 67.3% of patients in this group declining additional analgesic medication at 60 minutes. 
    • Only 1 patient in the “1 + 1 protocol” group experienced oxygen desaturation to less than 95% with the initial bolus; the incidence of all other adverse events were similar between both treatment groups.
Previous studies conducted by the same investigators:
  • J Opioid Manag 2009; 5:75-80.
    • A single dose of hydromorphone 2 mg IV was associated with rapid analgesia, with one-third of patients experiencing oxygen desaturation to less than 95%.
  • Ann Emerg Med 2011; 58:352-359.
    • The use of a “1 + 1” protocol of hydromorphone as described above was found to achieve superior pain control in both intent to treat and per protocol analyses with a difference of greater than 10% in pain control compared to those patients who received usual standard care with any dose, interval, and frequency of an intravenous opioid analgesic administered at the discretion of the emergency medicine physician.
  • Acad Emerg Med 2013; 20:185-192.
    • A single dose of hydromorphone 2 mg IV was found to be decrease the need of additional analgesic medication at 30 minutes post-administration in 77.4% of patients compared to 65.8% with the same outcome who received usual care with any dose, interval, and frequency of an intravenous opioid analgesic administered at the discretion of the emergency medicine physician. 

Here are two studies that evaluated the use of morphine as an analgesic for acute pain management in the emergency department.

  • Ann Emerg Med 2005; 46:362-367.
    • The aim of this study was to evaluate the proportion of patients who achieved less than a 50% reduction in the level of pain using a pain scale ranging from 0 to 10 following the administration of a single, weight-based dose of morphine 0.1 mg/kg IV. 
    • Patients were included if between the ages of 21 and 65 at the time of presentation to the emergency department with acute pain lasting for no more than seven days in duration. 
    • In the 119 patients, two-thirds experienced less than a 50% decrease in pain following administration of this weight-based dose of morphine.
    • The authors concluded that this dose of IV morphine does not provide adequate analgesia in the majority of patients who present to the emergency department, which may potentially suggests the need for evaluation of higher doses to be used in this setting. 
  • Follow up study: Ann Emerg Med 2007; 49:445-453. 
    • A double-blind, placebo controlled study was conducted in 280 patients presenting to the emergency department with acute pain who were randomized to receive intravenous morphine at a dose of 0.10 mg/kg or 0.10 mg/kg followed by an additional 0.05 mg/kg at 30 minutes for a total dose of 0.15 mg/kg. 
    • The primary outcome was to determine the mean difference in pain score from baseline to 60 minutes following administration of the agent. 
    • At 60 minutes, patients in the morphine 0.10 mg/kg IV group had a mean pain score of 4.5 versus 5.3 in those patients who received morphine 0.15 mg/kg IV (difference of 0.8), with similar rates of adverse events between both treatment groups. 
    • Although this was found to be statistically significant in favoring a higher analgesic dose of morphine at 0.15 mg/kg IV, this difference was not found to be clinically significant, according to the authors threshold of at least 1.3 units on the pain scale. 
    • The authors do suggest that there is a potential to evaluate higher doses of morphine (suggested at 0.2 mg/kg IV divided into two doses of 0.1 mg/kg given five minutes apart). Interestingly enough, the maximum single dose of morphine used in this study in both treatment groups was 10 mg, which reflects that there is some hesitancy of administering relatively high doses of morphine. 
The question has come up with regards to the use of nurse-driven titration protocols for acute pain management for patients in the emergency department. While several studies (see selected references below) have demonstrated their potential benefits in reducing the time to analgesia without the need for evaluation by physician in order for administration of the agent to occur, much effort would have to take place in order to ensure patients meet very stringent inclusion criteria and that nurses are appropriately trained to deliver such a protocol with proper reevaluation of the patient with each subsequent dose of medication administered. The article here provides some recommendations for such a dosing protocol as well as other dosing strategies for the management of acute severe pain in the emergency department. 

So you may be wondering…what is the best agent to manage acute pain for patients in the emergency department? The short answer- there really isn’t one. Many clinicians will treat based on their level of comfort with these agents and the traditional practice of prescribing opioid analgesics for the management of acute pain for patients in the emergency department. From my own perspective, having transitioned to an institution where the hydromorphone 1 mg IV is the “go-to” opioid analgesic and dose used by our emergency medicine physicians for patients in the emergency department, it seems to adequately control the pain of most patients and poses a relatively minimal risk for adverse effects, and to me, nurses again are generally comfortable giving such doses as opposed to equianalgesic yet “higher” doses of morphine. However, to each, his or her own. 

Selected References for Nurse-Driven Titration Protocols:
1. Emerg Med (Fremantle) 2002; 14:249-254. [PMID: 12487041]
2. Can J Emerg Med 2005; 7:149-154. [PMID: 17355670]
3. Contemp Nurse 2012; 43:29-37. [PMID: 23343230]
4. Emerg Med J 2005; 22:30-32. [PMID: 15611538]
5. Emerg Med Australas 2013; 25:316-323. [PMID: 23911022]

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