Thursday, April 23, 2015

Pediatric Readiness in Emergency Departments: Where is Pharmacy?

Over the past week, this article, which was published online ahead of print in JAMA Pediatrics (1), has made its rounds through the Twitter-verse:


The investigators of this study aimed to assess the readiness of emergency departments across the United States in the provision of care to pediatric patients. This was based on the joint policy statement put forth by the American Academy of Pediatrics (AAP) related to guidelines for the care of children in the emergency department. (2) Other areas evaluated included the influence of pediatric emergency care coordinators, positions primarily held by physicians and nurses, in this process as well as areas for future improvement.

With a relatively high response rate of nearly 83%, which represented 24 million pediatric visits to the emergency department on an annual basis, most representatives of emergency departments indicated a reported median weighted pediatric readiness score of 68.9 at the time the 55-question assessment was completed in 2013. This was an increase from a median weighted pediatric readiness score of 55 when a similar analysis was conducted a decade earlier in 2003. Not surprisingly, emergency departments who cared for a larger volume of pediatric patients had higher median scores than those with lower volumes (89.8 versus 61.4 [p < 0.001]).

Upon reviewing the various categories included in the assessment, which included the existence and provider type for the position of pediatric emergency care coordinators; specialty areas of board certification and/or training of providers; competencies; and policies, processes, and procedures in place such as quality improvement, weight measurements, equipment, mental health plans, and disaster plans, and the level of readiness in each of these categories as it related to the care of pediatric patients, I noted one area in particular that was not addressed in this study. It actually struck a cord with me and led me to ponder a bit.

Perhaps it is because of my professional background and I may be slightly biased. However, some of it may also have to do with the (un)known headway and/or challenges in this area that may not be necessarily considered upfront. In fact, a colleague of mine even asked me my thoughts related to this particular area, which prompted me to write about the topic in this post.

The question that came to me is as follows:

How can pharmacists and the provision of their services and clinical expertise be incorporated into pediatric readiness of emergency departments?

To the investigators' credit, they do note that as it relates to weighing pediatric patients, an estimated one-third of those who responded to the assessment indicated that emergency department providers record patient weights in units of kilograms only, which has been widely recognized as a safety initiative in the prevention of errors related to drug dosing. (3)

But there is so much more to the story. In fact, in 2006, the Institute of Medicine put forth recommendations for improving the care of pediatric patients in the emergency department, and one of those recommendations included the development of appropriate formulations, dosage and labeling guidelines, and techniques for administration of medications in effort to maximize effectiveness and safety for pediatric patients in the emergency department. (4) In addition, in the joint policy statement from the AAP, there is brief mention of ensuring that dosage formulations and concentrations of medications are suitable for the pediatric population. (2)

The following list highlights various areas where pharmacists can become involved in pediatric readiness of emergency departments, and where noted, there are some descriptions of these areas in the literature. By no means is this an all-inclusive list.
  • Gaining support for integration from key stakeholders of the emergency department as it relates to pharmacy-based needs for pediatric patients of the department and targeted areas for improvement over both the short and long terms
  • Attaining certification for responding to pediatric emergencies and resuscitations (e.g. pediatric advanced life support [PALS]) (5)
  • Developing dosing guidelines and concentrations of common oral and parenteral medications used in the pediatric population, which may extend to:
    • Dilution strategies for developing various concentrations of oral and parenteral medications
    • Bedside dosing tables for calculating doses and volumes necessary for administration of medications, especially in the setting of volume limitations in this population (6)
  • Developing effective standards in order for the preparation and labeling of medications to occur in a safe manner
  • Recognition of various diseases states and associated complications that may lead to visits to the emergency department in the pediatric population 
  • Recognition of off-label uses of medications commonly used in the pediatric emergency department (7)
  • Recognition of adverse effects associated with medications in general (8)
  • Involvement in education and training of physicians, mid-level providers residents, and nurses in areas related to clinical pharmacology and dosing calculations associated with pediatric resuscitation and toxicological emergencies (9, 10)
  • Involvement in education and training of fellow pharmacists, pharmacy technicians, and pharmacists-in-training (e.g. students) in various competencies associated with drug delivery and monitoring in the pediatric population in the emergency department (11)
  • Ensuring that outpatient prescriptions for medications are prescribed using appropriate standards and units of measurement prior to discharge with counseling provided to the patient and/or caregiver(s) (12, 13)
These various elements, while seemingly small and often underaddressed, are a key piece of the puzzle as it relates to pediatric readiness in the emergency department. With these elements, providers in emergency departments will be equipped with the tools necessary for enhancing their readiness when it comes to the delivery of skilled and expert care to pediatric patients.

References:
  1. Gausche-Hill M, Ely M, Schmuhl P, et al. A National Assessment of Pediatric Readiness of Emergency Departments. JAMA Pediatr 2015 April 13 [Epub ahead of print]. 
  2. Joint Policy Statement: Guidelines for Care of Children in the Emergency Department. Pediatrics 2009; 124:1233-1243.
  3. Alessandrini EA, Knapp J. Measuring Quality in Pediatric Emergency Care. Clin Pediatr Emerg Med 2014; 12:102-112.
  4. Committee on the Future of Emergency Care in the United States Health System; Board on Health Care Services; Institute of Medicine. Emergency Care for Children: Growing Pains.Washington, DC: National Academy Press; 2007.
  5. Eppert HD, Reznek AJ. ASHP Guidelines on Emergency Medicine Pharmacist Services. Am J Health Syst Pharm 2011; 68:e81-95.
  6. Campbell MM, Taeubel MA, Kraus DM. Updated Bedside Charts for Calculating Pediatric Doses of Emergency Medications. Am J Hosp Pharm 1994; 51:2147-2152.
  7. Phan H, Leder M, Fishley M, et al. Off-Label and Unlicensed Medication Use and Associated Adverse Drug Events in a Pediatric Emergency Department. Pediatr Emerg Care 2010; 26:424-430.
  8. Zed PJ, Black KJ, Fitzpatrick EA, et al. Medication-Related Emergency Department Visits in Pediatrics: A Prospective Observational Study. Pediatrics 2015; 135:435-443.
  9. Kraus DM, Stifter J, Hatoum HT. Program to Improve Nurses' Knowledge of Pediatric Emergency Medications. Am J Hosp Pharm 1991; 48:97-101.
  10. Porter E, Barcega B, Kim TY. Analysis of Medication Errors in Simulated Pediatric Resuscitations by Residents. West J Emerg Med 2014; 15:486-490.
  11. Small L, Schuman A, Reiter PD. Training Program for Pharmacists in Pediatric Emergencies. Am J Health Syst Pharm 2008; 65:649-654.
  12. Wingert WA, Chan LS, Stewart K, et al. A Study of the Quality of Prescriptions Issued in a Busy Pediatric Emergency Room. Public Health Rep 1975; 90:402-408.
  13. Committee on Drugs. Metric Units and the Preferred Dosing of Orally Administered Liquid Medications. Pediatrics 2015; 135:784-787.

Thursday, April 9, 2015

Dispersion of Repolarization and Arrhythmogenicity

If you ask 5 cardiologists and 5 toxicologists about the best way to predict the risk of Torsade de Pointes (TdP) in a patient with a prolonged QT, you will likely get 11 different answers. 

Here is what we know: 

  • A corrected QT (QTc) interval > 500 msec is associated with an increased risk of TdP (1). 
  • Not every patient with a QTc interval > 500 msec develops TdP (1). 
  • Not every patient with TdP has a QTc > 500 msec (1). 

You may be thinking this does not make sense, and you are right: there is certainly a gap in our understanding of this phenomenon. There must be many variables that determine a patient’s risk of TdP that are not explained by the QT interval, or even the QTc. And speaking of the QTc, which of the available correction methods provides the best estimation of risk? What about in patients with tachycardia? Bradycardia? Wide QRS? 

Obviously, there are many unanswered questions about predicting TdP. Yet the QTc is often regarded as a deciding factor for determining a patient’s risk of fatal ventricular arrhythmias and whether or not certain medications can be used. 

QT Dispersion

One of the potential explanations for the discrepancy between QTc prolongation and TdP risk is QT dispersion. The QT is typically measured in one lead on a 12-lead EKG (usually a limb lead) (1). Ideally, it is measured manually, and, in the perfect world, a patient-specific correction factor is used to adjust for extreme heart rates (2). But in actuality, if the QT were measured in all 12 leads, there could be significant intra-patient variation between the interval lengths (1). 

This variation is the result of regional heterogeneity of the action potentials occurring across the myocardium (3). This leads to areas of functional refractoriness within the cardiac tissue that creates the perfect environment for re-entrant ventricular arrhythmias or early afterdepolarizations (EADs), resulting in TdP (1). 

QT dispersion, or spatial dispersion, can be quantified:

QT Dispersion = max QT interval – min QT interval on a 12-lead EKG 

Theoretically, QT dispersion may be a better surrogate marker for ventricular repolarization abnormalities than standard QTc measurements (3). Reported normal values of QT dispersion vary from 10-70 msec, but in general extreme values (>100 msec) are associated with an increased risk of death (4). 

Select medications and their dispersion potentials are listed in Table 1 (5). One notable example is amiodarone; this drug is a notorious QT prolonger, but is rarely associated with TdP and is considered safe even in patients that developed TdP on other antiarrhythmic agents. This may be partially explained by amiodarone’s ability to decrease QT dispersion by causing a homogenous prolongation of repolarization across all types of ventricular cells (6).


However, although medications known to cause TdP have been shown to increase dispersion, increased dispersion has not been shown to correlate with the incidence of TdP (7). In a retrospective study by Yamaguchi et al. of 27 patients with acquired prolonged QT, patients with TdP were more likely to have increased dispersion, but in logistic regression analysis, QT dispersion was not identified as an independent risk factor for TdP (8). QT dispersion has, however, been shown to predict mortality in various disease states including chronic obstructive pulmonary disease and end-stage renal disease, with controversial prognostic value in patients with heart disease (4, 9, 10). Much of the excitement over the applicability of QT dispersion in the 1990s has simmered down, leading investigators to seek out other indexes of repolarization abnormalities.

Transmural Dispersion of Repolarization 

Of the three types of cells in the ventricle wall (endocardial, epicardial, and midmyocardial or M cells), the M cells are the most influential contributors to regional differences, especially those located within the intraventricular septum (11). M cells are known to prolong repolarization more than any other type of myocardial cell, and this is traditionally explained by differences in ion channel expression (11).

The refractoriness generated across the myocardial wall from the delayed recovery of M cells is called transmural dispersion of repolarization (TDR) (11). Experimental models have demonstrated that TdP risk may be the result of an enhancement of TDR rather than an overall increase in QT dispersion across the entire myocardium (12). This is because the M cells appear to be most sensitive to effects on the HERG K channel and some medications may selectively prolong repolarization there (12). In contrast, amiodarone (non-selective) may shorten repolarization in the M cells, leading to more uniformity (12). TDR can be represented by:

TDR = (Tpeak – Tend)/QT 

Here, Tpeak is the peak of the t-wave and Tend is the end of the t-wave, as measured in a precordial lead (13). Tpeak has been found to correspond to repolarization of epicardial cells, while Tend corresponds to repolarization of M cells (13). In the study previously mentioned by Yamaguchi et al., (Tpeak-Tend)/QT was identified as an independent risk factor for TdP, with a sensitivity of 80% and specificity of 88% (8). There is, however, still controversy over what this ratio represents and whether it can be clinically useful in risk stratification.

Currently, neither QT dispersion or TDR monitoring are mentioned as a strategy in the 2010 AHA/ACC guideline on the prevention of TdP in hospitals and are not considered standard of care (14). Regardless, clinicians should be aware that the QTc is not a definitive prognostic tool for evaluating repolarization abnormalities, and although the most reliable method of predicting TdP remains unknown, an assessment of dispersion of repolarization may prove to be more accurate than the familiar QTc interval.

Author:

Maria Cardinale, PharmD, BCPS
PGY-2 Critical Care Pharmacy Resident
Yale-New Haven Hospital, New Haven, CT

References:
  1. Bednar MM, Harrigan EP, Anziano RJ, Camm AJ, Ruskin JN. The QT interval.  Prog Cardiovasc Dis 2001; 43:1-45.
  2. Isbister GK. How do we assess whether the QT interval is abnormal: myths, formulae and fixed opinion. Clin Tox 2015; 53(4):189-91.
  3. Day CP, McComb JM, Campbell RW. QT dispersion: an indication of arrhythmia risk in patients with long QT intervals. Br Heart J 1990; 63(6):342-4.
  4. Malik M, Batchvarov VN. Measurement, Interpretation and Clinical Potential of QT Dispersion. J Am Coll Cardiol 2000; 36(6):1749-66.
  5. Krantz MJ, Lowery CM, Martell BA, et al. Effects of Methadone on QT-Interval Dispersion. Pharmacotherapy 2005; 25(11):1523-9.
  6. Hii JTY, Wyse DG, Gillis AM, et al. Precordial QT Interval Dispersion as a Marker of Torsade de Pointes: Disparate Effects of Class Ia Antiarrhythmic Drugs and Amiodarone. Circulation 1992; 86:1376-2.
  7. Celi A. QT Dispersion: Time for a Revival? Intern Emerg Med 2006; 1(4):262-3.
  8. Yamaguchi M, Shimizu M, Ino H, et al. T wave peak-to-end interval and QT dispersion in acquired long QT syndrome: a new index for arrhythmogenicity. Clin Sci (Lond) 2003; 105(6):671.
  9. Zulli R, Donati P, Nicosia F, et al. Increased QT dispersion: a negative prognostic finding in chronic obstructive pulmonary disease. Intern Emerg Med 2006; 1: 279-86.
  10. Guney M, Ozkok A, Caliskan Y, et al. QT dispersion predicts mortality and correlates with both coronary artery calcification and atherosclerosis in hemodialysis patients. Int Urol Nephrol 2014; 46(3):599-605.
  11. Antzelevitch C. M Cells in the Human Heart. Circulation Research 2010; 106:815-7.
  12. Said T, Wilson L, Jeyaraj D, et al. Transmural Dispersion of Repolarization as a Preclinical Marker of Drug-induced Proarrhythmia. J Cardiovasc Pharm 2012; 60(2):165-71.
  13. Arteyeva NV, Goshka SL, Sedova KA, et al. What does the Tpeak – Tend interval reflect? An experimental and model study. J Electrocardiol 2013; 46(4):296.e1-296.e8.
  14. Drew BJ, Ackerman MJ, Funk M, et al. American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology, Council on Cardiovascular Nursing, American College of Cardiology Foundation. Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation.  J Am Coll Cardiol. 2010; 55(9):934.

Peer Reviewer Comments:
This well-written piece on factors that may contribute to the potential for arrhythmias definitely offers some food for thought in the clinical setting. These phenomena of QT dispersion and transmural dispersion of repolarization that Maria has described may help explain some disparities that we see in clinical practice associated with the QT interval and associated effects. One question that has to be answered include whether or not these same effects hold true not only when medications are used therapeutically, but also in the setting of a toxic ingestion as well. However, it seems that there are currently there are no rules or regulations put forth by the FDA related to evaluation of these effects prior to the approval of new agents, and whether or not this will change in the future in incorporating these (not so novel) phenomena remains to be seen. However, if equipped with the appropriate resources to further evaluate the effects of QT dispersion and transmural dispersion of repolarization, these effects may shed some light on the clinical conundrums in select patients who unexplainably experience Torsades de Pointes that we may manage in our day-to-day practice.
--Nadia Awad, PharmD, BCPS

Wednesday, April 1, 2015

Can Agents for Hereditary Angioedema Be Used to Avoid Intubation in Patients Presenting with a Compromised Airway?

A middle-aged male with no known history of hereditary angioedema (HAE) and a questionable medication history presents to your ED with oropharyngeal angioedema. He has received the usual cocktail of intramuscular epinephrine along with an intravenous antihistamine, H2-receptor antagonist, and corticosteroid with no improvement in symptoms. The EM resident asks you for the correct dose of C1-esterase inhibitor (C1-INH). Oh, and it is needed STAT because the decision has been made to perform rapid sequence intubation on the patient…and in the meantime, can you also help draw up the RSI medications?

What would you do in this scenario? It may be instinct to rattle off the agent and dosing recommendation, click “verify” and then call the central pharmacy to tell them that you need the C1-INH in the next 30 seconds while preparing the medications needed for RSI at the same time. We all know that’s not how it works, especially in a larger institution. But even if we could obtain it in a very short time frame, is that really the right place to focus our efforts? At this point, the RSI medications have been drawn up, the respiratory therapist is at the head of the bed pre-oxygenating the patient, and the attending physician is talking about intubation strategies with the EM resident. It is clear that this patient needs to be intubated, no matter how soon the drug is received.

There are a few targeted therapies available on the market for acute attacks of HAE, which include plasma-derived C1-INH, recombinant C1-INH, ecallantide, and icatibant. Of note, fresh frozen plasma has also been studied for treatment of acute HAE attacks, but its use remains controversial.1 The reported time to symptom relief for each of these agents varies, as trials describe different endpoints and have used various methods to measure these endpoints (i.e. time to first symptom relief, time to 50% symptom relief, or time to complete symptom resolution).2-4 Regardless, we do know that if protection of the airway is of concern, this will not be reversed with prompt administration of these agents. It is important to remember that these drugs do not immediately reverse the edema. Instead, their mechanisms of action prevent further edema from developing.5 If the airway is close to or has already become compromised, then perhaps the clinical utility of these drugs is futile at that particular point in time, since airway management becomes the priority.6

Icatibant was recently studied for ACE-inhibitor induced angioedema in a multicenter, double-blind, randomized trial.7 Patients received either icatibant 30 mg SC (n = 13) or prednisolone 500 mg IV plus clemastine 2 mg (n = 14). All patients achieved complete resolution of edema and those who received icatibant achieved complete resolution more quickly (8 hours versus 27.1 hours, p = 0.002). More patients in the icatibant group achieved complete resolution of symptoms within 4 hours of treatment (5 of 13 versus 0 of 14, p = 0.02). Three patients in the conventional therapy group required further rescue treatment with icatibant and more steroids and one patient required tracheotomy. Despite these results, it is important to note that the median time to onset of symptom relief reported in this study was two hours in the icatibant group.

C1-INH has also recently been studied in a historical control case series of ACE-inhibitor induced angioedema in adult patients.8 Patients received plasma-derived C1-INH 1000 units (n = 10) compared to historical controls who received a conventional corticosteroid/antihistamine treatment (n = 47). None of the patients who received C1-INH required intubation, while five of the patients who received conventional treatment required airway protection. Time to complete resolution of symptoms was 10.1 hours in the C1-INH group versus 33.1 hours in the standard treatment group. While this looks like a tempting option and may be beneficial in decreasing the duration of intubation and mechanical ventilation, it is important to realize that the mean time to first improvement of symptoms was 88 minutes in the C1-INH group.

While neither of these two studies necessarily suggests using these agents as a last resort in the attempt to stave off intubation, nor do any of the studies in acute attacks of HAE, there is potential for misuse of these medications.

In the case of the above patient scenario, it does not seem appropriate to treat with an HAE agent at this particular point in time, since the drug has not been demonstrated to prevent intubation in patients presenting with airway compromise. After protecting the airway via intubation, I would not empirically administer any of these agents. Instead, I would advocate for providers to consult with allergy and immunology specialists to help direct further care. I suspect that most institutions do not have all of these medications available on formulary, if any at all. While it is not always about the cost, it is important to realize that these agents may cost upwards of $4,000 to 10,000 or more per dose and certain agents may not be an appropriate choice for all patients. While these medications may be acute treatment options for HAE and a treatment prospect for ACE-inhibitor induced angioedema, we must not forget that they do not instantaneously reverse edema and may not prevent intubation in a patient who may already be exhibiting airway compromise.

Author:

Sheena Merwine, Pharm.D. (@MerwinePharmD)
PGY2 Critical Care Pharmacy Resident
Duke University Hospital, Durham NC

Reviewed by: Craig Cocchio, Pharm.D., BCPS and Nadia Awad, Pharm.D., BCPS

References:

1. Prematta M, Gibbs J, Pratt E, et al. Fresh frozen plasma for the treatment of hereditary angioedema. Ann Allergy Asthma Immunol 2007; 98:383-8.

2. Craig T, Levy R, Wasserman R, et al. Efficacy of human C1 esterase inhibitor concentrate compared to placebo in acute hereditary angioedema attacks. J Allergy Clin Immunol 2009; 124(4):801-8.

3. Lumry W, Li H, Levy R, et al. Randomized placebo-controlled trial of the bradykinin B2 receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema: the FAST-3 trial. Ann Allergy Asthma Immunol 2011; 107(6):529-37.

4. Riedl M, Bernstein J, Li H, et al. Recombinant human C1-esterase inhibitor relieves symptoms of hereditary angioedema attacks: phase 3, randomized, placebo-controlled trial. Ann Allergy Asthma Immunol 2014; 112:163-9.

5. Zuraw B. Hereditary angioedema. N Engl J Med 2008; 359(10):1027-36.

6. Moellman J, Bernstein J, Lindsell C, et al. A consensus parameter for the evaluation and management of angioedema in the emergency department. Acad Emerg Med 2014; 21:469-84.

7. Bas M, Greve J, Stelter K, et al. A randomized trial of icatibant in ACE-inhibitor induced angioedema. N Engl J Med 2015; 372(5): 418-25.

8. Greve J, Bas M, Hoffmann T, et al. Effect of C1-esterase Inhibitor in angiotensin-converting enzyme inhibitor-induced angioedema. Laryngoscope 2015 Jan 13 [Epub ahead of print].