March 2013 FAQs

What are aminophylline alternatives for the reversal of adenosine agonists used in pharmacologic stress testing?

Introduction

The use of pharmacologic agents in combination with myocardial perfusion imaging (MPI) is a common method for coronary artery disease evaluation. In the United States approximately 50% of the 10 million MPI studies conducted annually are performed with the aid of pharmacologic agents.1 Generally, pharmacologic MPI (or pharmacologic stress testing) is reserved for patients who have a contraindication to exercise testing. This includes patients with an inability to ambulate appropriately and those who have a left-bundle branch block or an electronically paced rhythm.

Pharmacologic agents can aid in MPI studies by producing similar effects on the heart to those seen during normal exercise.2-4 The pharmacologic agents fall into 2 categories, direct-acting agents (adenosine agonists) and indirect-acting agents (dobutamine).4 Adenosine agonists cause coronary vasodilation which in turn increases blood flow rates. Normal arteries will show normal blood flow reserve, a 3 to 5 times increase in flow after administration. Stenotic arteries will have a significantly decreased flow reserve. The flow reserve of stenotic arteries is inversely proportional to the degree of stenosis. Dobutamine works in a different manner, one which mimics the effects of physical exercise.2 It increases the inotropic and chronotropic effects of the heart causing an increase in myocardial oxygen demand. The desired outcome of this is to provoke ischemia and produce either a flow or a wall abnormality. Because dobutamine produces an increase in myocardial oxygen demand it can put patients at risk for ischemia. Ischemia is less likely when adenosine agonists are used.

Nonselective Adenosine Agonists

The diagnostic sensitivity of pharmacologic stress testing with adenosine and dipyridamole is thought to range from 83% to 97%, while the specificity is thought to be between 38% and 94%.3,4 The utility of these agents has expanded from simply identifying the presence of ischemia to estimation of the burden and location of the ischemic area.

Adenosine is an endogenous substance that binds to 4 distinct subtypes of receptors, A1, A2a, A2b, and A3. 2 These receptors are responsible for the desired outcomes and the potential adverse effects associated with pharmacologic stress testing. The adenosine A2a receptor is involved in vasodilation of coronary arteries. The nonselective adenosine agonists commonly used in pharmacologic stress testing are adenosine and dipyridamole.4 The administration of adenosine directly causes increases in the amount of adenosine at the site of the receptor. However, the mechanism of action for dipyridamole is slightly different. Normally adenosine is transported back into the cell via facilitated transport.3 Dipyridamole works by inhibiting this cellular reuptake mechanism causing an increase in endogenous adenosine at the adenosine receptor.

Adenosine has a very short half-life (approximately 12 seconds) while dipyridamole has a longer half-life of approximately 90 minutes.2 Both agents are rapid-acting. Due to the fact that the half-life of adenosine is so short, the duration of the test is often only 4 to 8 minutes. For dipyridamole the duration of the exam is longer, around 10 to 12 minutes.

Selective Adenosine A­2A Agonist

The novelty of a selective adenosine agonist is found in the idea that if an agent is selective for the A2a receptor it will maintain its effectiveness at causing coronary vasodilation while reducing undesirable adverse effects.5 It is from this idea that there has been a push for selective adenosine agonists. Currently, regadenoson is the only selective Food and Drug Administration (FDA)-approved A2a agonist for use in pharmacologic stress testing, and its use is becoming increasingly popular. It is believed that it holds 68% of the market compared to 15% held by adenosine, 13% by dipyridamole, and 4% by dobutamine.1 The onset of regadenoson is generally seen in less than 1 minute, and the peak effect lasts from 2 to 3 minutes.

Regadenson is administered as a single dose bolus and with its rapid onset and short duration, a normal study lasts roughly 2 to 3 minutes.2 Although it is a selective agent, regadenoson is not devoid of adverse effects. As the dose increases, the selectivity for the A2a is lost and adverse effects appear.2 The risk of adverse effects may be greater in smaller patients because a universal dose is administered, and the threshold for selectivity may be exceeded.

Adenosine Agonist Adverse Effects

The 4 subtypes of adenosine receptors are found throughout the body and are believed to be the cause of the adverse effects of adenosine agonists. 2,5 The most severe adverse effects include bronchospasm, caused by the A2b receptor found on the bronchial tree, or bradycardia/heart block, caused by A1 receptor found in the atrioventricular node. Additionally, the coronary vasodilation can cause a coronary steal effect, producing myocardial ischemia. More common adverse effects are those caused by systemic vasodilation.2 This produces symptoms that include headache, lightheadedness, flushing, nausea, hypotension, and tachycardia. These symptoms can cause severe discomfort for the patient. Adverse effects are more common with adenosine than with dipyridamole or regadenoson, but they rarely are a cause of premature cessation of the study. 2,6 As mentioned before, the half-life of dipyridamole is significantly longer than the duration of the study, which creates a situation where adverse effects may persist after the exam is completed. Additionally, it is thought that regadenoson has a triphasic half-life. In the first 2 to 4 minutes you have maximal coronary hyperemic effects. After this, there is a prolonged period where adverse effects from the drug may persist.7 This time frame is roughly 15 to 30 minutes after the administration of regadenoson and may require the need for reversal if found to be bothersome by the patient.

Reversal of Adenosine Agonists

Aminophylline

Aminophylline has been commonly used as the antidote for adenosine and dipyridamole stress testing.7,8 It is thought that aminophylline preferentially binds to the A2a receptor, displacing bound adenosine, causing the reversal of adverse effects.2,3 It is commonly used in dipyridamole studies to reverse the prolonged effects of the agent. However, aminophylline is used less often with adenosine due to adenosine’s incredibly short half-life. Adverse effects normally seen with adenosine resolve shortly after cessation of the infusion.

Traditionally, 240 mg of aminophylline has been given to promptly reverse the adverse effects of dipyridamole.8 Additional literature reports the use of aminophylline doses ranging from 80 to 240 mg infused over 1 to 3 minutes at a rate of 80 mg/minute.7 Aminophylline in doses ranging from 50 to 250 mg and given at rates of 50 to 100 mg over 30 to 60 seconds has been used to diminish the adverse effects of regadenoson.9 These adverse effects include heart block, ST-segment depression, transient ischemic attacks, abdominal pain, musculoskeletal pain, symptomatic hypotension, and bronchospasm.

However, with recent drug shortages aminophylline may not be available for the reversal of adenosine agonists. In these cases alternative agents should be evaluated for their effectiveness at reversing the adverse effects of adenosine agonists.

Theophylline

Unfortunately, there is minimal literature pertaining to the reversal of adenosine agonists outside of aminophylline. Aminophylline is 79% theophylline by weight.10 Based on this information there is one report in the literature on the use of theophylline in substitution for aminophylline. 11 Johnson and colleagues suggest that to find the dose of theophylline you could simply take 80% of the dose of aminophylline. However, theophylline is supplied as a more dilute solution than aminophylline; 0.8 mg/mL compared to 25 mg/mL, respectively. To get around this they suggest administering 50 mg of theophylline over 1 minute. This practice would deliver approximately 60 mL of fluid. They report that out of 154 patients only 11 required a repeat dose. Although this report was specific to dipyridamole reversal, it is reasonable to believe a similar practice could be implemented for adverse effects caused by adenosine or regadenoson.

Unfortunately, the only other information regarding potential agents of reversal comes from literature on drugs that may interfere or alter the results of adenosine stress tests. For theophylline, one review found that therapeutic levels (10 to 20 mg/L) of theophylline reduced the coronary blood flow velocity induced by adenosine.12

Caffeine

There has been quite a bit of controversy regarding whether or not caffeine antagonizes the effects of adenosine agonists. It is generally believed that the caffeine in a single cup of coffee is not enough to alter the results of a stress test using adenosine or dipyridamole.12 However, in 1 study, 8 patients who had reversible perfusion defects on a dipyridamole stress test were given a caffeine infusion of 4 mg/kg 30 minutes prior to a repeat test.13 The resulting average plasma caffeine level was 9.7 mg/L. When patients were given the repeat test, 4 of the 8 had blunted ST-segment changes from their baseline test and 6 of 8 had reduction in coronary blood flow. Both of these results suggest that high doses of caffeine may blunt the response to adenosine agonists. For comparison, a single cup of coffee containing 100 mg of caffeine should produce levels of approximately to 3 to 4 mg/L.

Summary

In the face of the aminophylline drug shortage it is reasonable to suggest the use of theophylline for reversal of adenosine agonists. Since theophylline is the active agent in aminophylline the risks in this substitution are minimal. The issue then becomes what to do if theophylline is unavailable as well. Unfortunately, at this time caffeine is not a viable alternative. Data suggest that it may be effective at antagonizing the effects of adenosine agonists; however, an appropriate reversal dose cannot be determined from the available information.

References

1. Zoghbi GJ, Iskandrian AE. Selective adenosine agonists and myocardial perfusion imaging. J Nucl Cardiol. 2012;19(1):126-141.

2. Botvinick EH. Current methods of pharmacologic stress testing and the potential advantages of new agents. J Nucl Med Technol. 2009;37(1):14-25.

3. Hendel RC, Jamil T, Glover DK. Pharmacologic stress testing: new methods and new agents. J Nucl Cardiol. 2003;10(2):197-204.

4. Patel RN, Arteaga RB, Mandawat MK, Thornton JW, Robinson VJ. Pharmacologic stress myocardial perfusion imaging. South Med J. 2007;100(10):1006-1014.

5. Cerqueira MD. The future of pharmacologic stress: selective A2A adenosine receptor agonists. Am J Cardiol. 2004;94(2A):33D-40D.

6. Palani G, Husain Z, Salinas RC, Karthikeyan V, Karthikeyan AS, Ananthasubramaniam K. Safety of regadenoson as a pharmacologic stress agent for myocardial perfusion imaging in chronic kidney disease patients not on hemodialysis. J Nucl Cardiol. 2011;18(4):605-611

7. Picano E, Lattanzi F, Masini M, Distante A, L'Abbate A. Aminophylline termination of dipyridamole stress as a trigger of coronary vasospasm in variant angina. Am J Cardiol. 1988;62(10 Pt 1):694-697.

8.Picano E, Lattanzi F, Masini M, Distante A, L'Abbate A. High dose dipyridamole echocardiography test in effort angina pectoris. J Am Coll Cardiol. 1986;8(4):848-854.

9. Lexiscan [package insert]. Northbrook, IL: Astellas Pharma US, Inc; 2012.

10. Aminophylline [package insert]. Lake Forest, IL: Hospira, Inc; 2009.

11. Johnson NP, Lance Gould K. Dipyridamole reversal using theophylline during aminophylline shortage. J Nucl Cardiol. 2011;18(6):1115.

12 .Salcedo J, Kern MJ. Effects of caffeine and theophylline on coronary hyperemia induced by adenosine or dipyridamole. Catheter Cardiovasc Interv. 2009;74(4):598–605.

13. Smits P, Corstens FH, Aengevaeren WR, Wackers FJ, Thien T. False-negative dipyridamole-thallium-201 myocardial imaging after caffeine infusion. J Nucl Med 1991;32(8):1538-1541.

Written by:

Dallas Schepers, PharmD
PGY1 Pharmacy Resident

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What are the new recommendations for frequency of platelet monitoring in patients with heparin-induced thrombocytopenia?

Introduction

Heparin-induced thrombocytopenia (HIT) is a serious and potentially fatal immune-mediated thrombogenic complication that is associated with both unfractionated heparin (UFH) and low molecular weight heparin (LMWH).1 Early recognition and treatment are essential in preventing morbidity (thrombosis, limb loss) and mortality. Platelet count monitoring is recommended regularly.2-4 The American College of Chest Physicians has published guidelines on the frequency of platelet monitoring. Per the older 8th edition of the CHEST guidelines, the frequency of platelet count monitoring was based on patient characteristics and the risks of developing HIT within select patient populations.3 The incidence for developing HIT was categorized into high (greater than1%), intermediate (0.1% to 1%), and low (less than1%).

The 9th edition of the CHEST guidelines changed the recommendations for platelet monitoring in patients with HIT.4 The authors of these revised guidelines categorized the risk of HIT into only 2 groups (less than 1% and greater than 1%) and recommended platelet monitoring for these 2 groups. Table 1 shows the incidence of HIT according to patient populations and type of heparin exposure per the new CHEST guidelines.

Table 1. Incidence of HIT according to patient population and type of heparin exposure.4

HIT=heparin- induced thrombocytopenia; LMWH=low molecular weight heparin; UFH=unfractionated heparin.

The new recommendations for platelet count monitoring for patients with HIT include the following:

• For patients receiving heparin in whom clinicians consider the risk of HIT to be greater than 1%, platelet count monitoring should be performed every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs first). (Grade 2C)
• For patients receiving heparin in whom clinicians consider the risk of HIT to be less than 1%, it is recommended that platelet counts not be monitored. (Grade 2C)

The following recommendations have not changed:

• For patients exposed to heparin within the past 100 days, the baseline platelet count should be obtained prior to starting UFH/LMWH therapy, and a repeat platelet count be drawn 24 hours later, if feasible. (Although the recommendation remains the same, the authors recognize difficulty in obtaining platelet counts 24 hours after initiation of LMWH in the outpatient setting)
• For patients who present with acute systemic reactions within 30 minutes of an intravenous heparin bolus, a platelet count should be performed.

Table 2 summarizes the updated recommendations for platelet monitoring based on patient population and compares them to the previous recommendations.

Table 2. Summary of changes in recommendations for platelet monitoring.3,4

*as defined in CHEST 8th edition.

HIT=heparin-induced thrombocytopenia; LMWH=low molecular weight heparin; UFH=unfractionated heparin.

Conclusion

The new recommendations for platelet monitoring are based on the risk of HIT (less than1% and greater than1%) for various patient populations and type of heparin exposure. Practitioners must use clinical judgment for platelet monitoring when the incidence of HIT is 1%.

References

1. Witt DM, Nutescu EA, Haines ST. Venous thromboembolism. In: Talbert RL, DiPiro JT, Matzke GR, Posey LM, Wells BG, Yee GC, eds.Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York, NY: McGraw-Hill; 2011. http://www.accesspharmacy.com/content.aspx?aID=7973333. Accessed February 20, 2013.
2. ten Berg MJ, van den Bemt PM, Huisman A, Schobben AF, Egberts TC, van Solinge WW. Compliance with platelet count monitoring recommendations and management of possible heparin-induced thrombocytopenia in hospitalized patients receiving low-molecular-weight heparin. Ann Pharmacother. 2009;43(9):1405-1412.
3. Warkentin TE, Greinacher A, Koster A, Lincoff AM; American College of Chest Physicians. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):340S-380S.
4. Linkins LA, Dans AL, Moores LK, Bona R, Davidson BL, Schulman S, Crowther M; American College of Chest Physicians. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e495S-e530S.
5. Riggio JM, Cooper MK, Leiby BE, Walenga JM, Merli GJ, Gottlieb JE. Effectiveness of a clinical decision support system to identify heparin induced thrombocytopenia. J Thromb Thrombolysis. 2009;28(2):124-131.
6. Rogers BA, Cowie AS. The monitoring of heparin induced thrombocytopenia following surgery: an audit and international survey. J Perioper Pract . 2010;20(2):66-69.

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What are the new guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill patients?

Background

Glycemic control (GC) in critically ill patients became a topic of interest in 2001 after a landmark trial by Van den Berghe et al. determined a significant mortality benefit in patients treated with intensive insulin therapy (maintenance of blood glucose [BG] between 80 and 100 mg/dL).1 However, more recent randomized controlled trials in various intensive care unit (ICU) settings demonstrate conflicting results.2-4 Although GC is beneficial in this patient population, the extent of GC which can be safely achieved without increased risk for hypoglycemia (BG ≤ 70 mg/dL) has not been established. A clinical practice guideline was published in December 2012 by the Society of Critical Care Medicine to help clinicians achieve GC that is considered safe and effective without increasing the risk of significant hypoglycemia.5 This new guideline recommends a target range of 100 to 150 mg/dL for most adult critically ill patients, which differs from the previously published American Association of Clinical Endocrinologists and the American Diabetes Association recommendations that BG should be maintained between 140 and 180 mg/dL in critically ill patients.6 The focus of this guideline is the safe use of insulin infusions in adult ICU patients.

Recommendations

The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to rate the quality of evidence and strength of recommendation.7 Recommendations are classified as strong (Grade 1) or weak (Grade 2). Strong recommendations are listed as “recommendations” and weak recommendations as “suggestions”. There are 18 clinical practice questions addressed in the guideline which are summarized below.

Table 1. Summary of Suggestions and Recommendations.7

*Hypoglycemia defined as BG ≤ 70 mg/dL

†As this guideline was being prepared, the U.S. Food and Drug Administration indicated that many glucose meters have not been tested for patients who are critically ill and this precaution will be added to the label of new devices.

Abbreviations: BG, blood glucose; GC, glycemic control; GV, glycemic variability; ICU, intensive care unit; IQR, interquartile range; LOS, length of stay; POC, point-of-care; SAH, subarachnoid hemorrhage; SD, standard deviation; SH, severe hypoglycemia (< 40 mg/dL); SQ, subcutaneous; TBI, traumatic brain injury.

Summary

The current literature supporting insulin infusion therapy in adult ICU patients is not conclusive with regard to the appropriate extent of GC; therefore, many of the recommendations in these new guidelines are weak recommendations. After the authors’ review of the literature, it is suggested that a BG level of ≥ 150 mg/dL trigger initiation of insulin therapy titrated to maintain BG levels < 150 mg/dL and absolutely < 180 mg/dL. A monitoring system should be implemented to avoid and detect hypoglycemia and glycemic variability. For patients with brain injury, a more stringent goal of avoiding BG ≤ 100 mg/dL is described. Monitoring of BG should occur every 1 to 2 hours for most patients. Finally, the guidelines encourage implementation of a standard insulin infusion protocol in the ICUs to promote the safe and effective use of insulin infusion therapy.

References

1. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359-1367.

2. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354(5):449-461.

3. NICE-SUGAR Study Investigators, Finfer S, Chittock DR, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283-1297.

4. Preiser JC, Devos P, Ruiz-Santana S, et al. A prospective randomised multi-centre controlled trial on tight glucose control by intensive insulin therapy in adult intensive care units: the Glucontrol study. Intensive Care Med. 2009;35(10):1738-1748.

5. Jacobi J, Bircher N, Krinsley J, et al. Guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill patients. Crit Care Med. 2012;40(12):3251-3276.

6. Moghissi ES, Korytkowski MT, DiNardo M, et al. American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Diabetes Care. 2009;32(6):1119-1131.

7. GRADE working group Web site. http://gradeworkinggroup.org/. Accessed February 16, 2013.

8. Martindale RG, McClave SA, Vanek VW, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine and American Society for Parenteral and Enteral Nutrition: Executive Summary. Crit Care Med. 2009;37(5):1757-1761.

Written by:
Shadi Ghaibi, PharmD
PGY-2 Resident Drug Information Group
University of Illinois at Chicago March 2013

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