May 2013 FAQs

What available alternatives are there to papaverine for the prevention and management of vasospasm during cardiac procedures?

Papaverine injection has been unavailable for several months and has posed significant challenges for many hospitals. Currently, American Regent is the sole supplier of papaverine injection and is experiencing manufacturer delays. The 30 mg/mL (2 mL and 10 mL) vials are currently on back order and a release date cannot be estimated.1

Background

Papaverine is a smooth muscle relaxant that is approved by the Food and Drug Administration for relief of vascular spasm associated with acute myocardial infarction (coronary occlusion), angina pectoris, peripheral and pulmonary embolism, peripheral vascular disease in which there is a vasospastic element, and certain cerebral angiospastic states.2,3 In addition, it is used for the treatment of visceral spasm, as in ureteral, biliary, or gastrointestinal colic. Off-label, papaverine injection is used for the prevention and management of vasospasm during harvesting of the radial artery (RA), saphenous vein (SV), internal mammary artery (IMA), and internal thoracic artery (ITA) for cardiothoracic procedures such as coronary artery bypass grafting (CABG).4

Vasospasms can occur during CABG surgery, both during harvesting and when the graft is connected.5 There are several causes of vasospasm, including surgical trauma, local release of vasoconstrictors, and neural and hormonal factors. Vasospasms may occur in the perioperative period due to release of catecholamines. Both in vitro and in vivo research has been conducted to determine the best pharmacologic agent to prevent or reverse vasoconstriction. In vitro studies have stimulated vasospasms by exposing the tissues to different concentrations of various vasoconstrictors and measuring the response of these segments to vasodilators to determine comparative efficacy. In vivo studies have been conducted to determine if vasodilators may prevent or reverse vasospasm. Papaverine has been considered the “gold standard” prophylactic treatment for intraoperative vasospasm. It is a phosphodiesterase inhibitor which raises cyclic guanosine monophosphate (cGMP) in smooth muscle cells and acts directly on calcium channels. At high concentrations, it relaxes vessels; however, there is a risk of endothelial damage when administered intraluminally. Additionally, it has a short duration of action and is unstable in non-acidic solutions. Several pharmacological agents have been investigated for use in prevention of vasospasm during harvesting of arteries and veins and intraoperatively. This document summarizes the use of possible alternatives to papaverine for CABG.

Alternative agents

Calcium Channel Blockers

Calcium channel blockers (CCBs) are most commonly used with harvesting of the RA.6 They inhibit calcium influx and contractility on smooth muscles by selective blockade of the L-type voltage-operated calcium channels. They are highly potent agents with a long duration of action. However, adverse effects including bradycardia, hypotension, arrhythmia, and heart block, as well as their contraindication in patients with poor left ventricular function, limit their use.6,7

Diltiazem

Diltiazem has significant chronotropic and inotropic effects.6 Although extensively studied, it has shown to be one of the least effective CCBs in preventing vasospasm. In vivo and in vitro studies have shown that it does not completely eliminate RA constriction. 4-10 Compared to other CCBs or nitroglycerin, diltiazem is less effective in antagonizing the effects of various vasoconstrictors including endothelin-1, angiotensin II, vasopressin, and potassium chloride. A study by Acar and colleagues used a dose of 1 mcg/kg/minute intraoperatively and immediately postoperatively.11 A study by Tabel et al compared diltiazem to nitroglycerin for the prevention of vasospasm on perioperative IMA harvesting. Doses of 0.05 to 0.1 mg/kg/hour intravenous (IV) diltiazem were initiated prior to harvesting and continued throughout the isolation period. The results showed that diltiazem provided higher IMA flow and was more effective in preventing vasospasm compared to nitroglycerin.12

Verapamil

Verapamil has been found to be more potent than diltiazem but when used alone, it is not effective on vasospasm of the RA.6 Verapamil has proven benefit when used in combination with glyceril trinitate.13,14 Glyceril trinitate is a potent vasodilator effective in reversing contraction of the IMA but less effective in preventing spasm.5 Glyceril trinitate releases nitric oxide into the muscle cell, thus stimulating the release of cGMP. This, in combination with the action of verapamil, leads to calcium removal from the cell and reverses spasm. Formica and colleagues conducted a study to compare a glyceryl trinitrate (an alternative name for nitroglycerin)-verapamil (GV) solution versus papaverine for the treatment of ITA spasm. 14 The GV solution consisted of glyceril trinitate 2.5 mg, verapamil 5 mg, 8.4% sodium bicarbonate 0.2 mL, heparin 500 units, and 300 mL Ringer’s lactate solution. The solution was administered either topically or intraluminally. The results showed that the intraluminal administration of GV solution produced a more rapid vasodilation and reduced endothelial damage compared to papaverine. There was no statistically significant difference between the agents when administered topically.

Nicardipine

Nicardipine belongs to the dihydropyridine class of CCBs.3 He et al conducted an in vitro study to examine the effects of a nicardipine and nitroglycerin cocktail for the ITA and RA in patients undergoing CABG.13 The cocktail contained 30 µmol/L of nicardipine and 60 µmol/L of nitroglycerin. The combination induced almost full relaxation of the ITA and RA. The authors concluded that the cocktail has a rapid onset of action, results in full relaxation of the muscle, can be used prophylactically, and protects the endothelial and smooth muscle function of the ITA and RA.

Amlodipine

Amlodipine, an oral CCB, is more vascular selective than other CCBs and has less effects on the myocardium.3,5 An in vitro study was conducted to evaluate its effects on vasoconstrictors, including potassium chloride, human IMA, and urotensin II in patient undergoing CABG.15 The results showed that amlodipine prevented vasospasm with some but not all vasoconstrictors. The applicability to clinical practice is unknown since it was an in vitro study.

Nifedipine

Nifedipine is the prototype of the dihydropyridine class of CCBs.3 It is highly potent on RA conduits, especially potassium mediated constriction.5,6 Nifedipine has a limited effect in reducing spasm of norepinephrine mediated vasospasms and oral availability limits its use. 5

Nitrates

Nitroglycerin

Nitroglycerin is a vasodilator that works by releasing nitric oxide, which raises cGMP levels, thus reducing the calcium concentration and causes relaxation in the smooth muscle.3,5,6 It is more effective in reducing spasms compared to other vasodilators in in vitro studies. 17-22 Nitroglycerin has been shown to be more effective in the prevention of spasms as opposed to the reversal.6 A variety of routes of administration have been used in clinical studies, including IV, intracoronary, and intraarterial. Various doses have been studied such as 0.1 mcg/kg/minute IV, 50 mcg intracoronary, and 100 to 200 mcg interarterially.17-22 Limitations to the use of nitrates include tachyphylaxis and withdrawal symptoms.

Sodium Nitroprusside

Sodium nitroprusside, a potent vasodilator at a low dose, is not routinely used due to the adverse effect of hypotension at high doses.6

Phosphodiesterase inhibitor

Milrinone

Milrinone is phosphodiesterase inhibitor that directly works on cardiac and vascular muscle.3,6 It seems to exert a greater effect on the IMA compared to the RA.6 Liu and colleagues conducted a study to investigate the in vitro effect of milrinone on human ITA.23 The results showed that milrinone significantly prevented norepinephrine-induced contractions, an effect that was concentration-dependent. Milrinone was shown to be more potent than papaverine but less potent than nitroprusside and glyceril trinitate. Milrinone exerts a combination of positive inotropic and vasodilator effects, which is beneficial in the treatment of vasospasms in patients undergoing CABG.

An in vivo study was conducted to evaluate intraluminal milrinone for vasodilation of the RA.24 Once the RA was clamped, 30 mL of a milrinone solution (2 mg/30 mL normal saline) was injected and then the RA was immersed in a heparin-milrinone solution. The patients were administered an intraoperative milrinone loading dose of 50 mcg/kg over 10 minutes followed by a milrinone continuous infusion of 0.5 mcg/kg/minute for 24 hours. Diltiazem was started on postoperative day 1 and continued for 1 year. The short-term results are favorable due to a lack of ischemic complications.

Conclusion

Papaverine, a phosphodiesterase inhibitor, has been commonly used for the prevention and management of vasospasm during harvesting of the RA, SV, IMA, and ITA for cardiothoracic procedures such as CABG. Vasospasms can be caused by many factors; veins and arteries may respond differently to vasoconstrictors and thus the response to a pharmacologic agent to cause vasodilation may be different. Published data are limited by in vitro study designs and small patient populations. Additionally, standard dosing is not available for these agents. As a result of the papaverine shortage, many hospitals have faced challenges to find the most appropriate pharmacologic therapy. It appears that nitroglycerin, combined with verapamil, is commonly used.6 Clinicians should work closely with surgeons for recommendations on alternative agents.

References

1. Wheeler M. Papaverine injection. American Society of Health-Systems Pharmacists Current Drug Shortages Web site. March 11, 2013. http://www.ashp.org/DrugShortages/Current/Bulletin.aspx?id=781. Accessed April 22, 2013.

2. Papaverine [package insert]. Shirley, NY: American Regent; 2010.

3. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2013. http://clinicalpharmacology-ip.com/default.aspx. Accessed April 22, 2013.

4. Chanda J, Canver C. Reversal of preexisting vasospasm in coronary artery conduits. Ann Thorac Surg. 2001;72(2):476-480.

5. Rosenfeldt FL, He GW, Buxton BF, Angus JA. Pharmacology of coronary artery bypass grafts. Ann Thorac Surg. 1999;67(3):878-888.

6. Attaran S, John L, El-Gamel A. Clinical and potential use of pharmacological agents to reduce radial artery spasm in coronary artery surgery. Ann Thorac Surg. 2008;85(4):1483-1489.

7. Shapira OM, Alkon JD, Macron DS, et al. Nitroglycerin is preferable to diltiazem for prevention of coronary bypass conduit spasm. Ann Thorac Surg. 2000;70(3):883-889.

8. Ding R, Feng Q, Li H, et al. A comparative study on in vitro effects of topical vasodilators in human internal mammary, radial artery, and great saphenous vein. Eur J Cardiothorac Surg. 2008;34(3):536-541.

9. Conant AR, Shackcloth MJ, Oo AY, Chester MR, Simpson AW, Dihmis WC. Phenoxybenzamine treatment is insufficient to prevent spasm in the radial artery: the effect of other vasodilators. J Thorac Cardiovasc Surg. 2003;126(2):448-454.

10. Kalus JS, Lober CA. Calcium-channel antagonists and nitrates in coronary artery bypass patients receiving radial artery grafts. Ann Pharmacother. 2001;35(5):631-635.

11. Acar C, Jebara VA, Portoghese M, et al. Revival of the radial artery for coronary artery bypass grafting. Ann Thorac Surg. 1992;54(4):652-660.

12. Tabel Y, Hepağuşlar H, Erdal C, et al. Diltiazem provides higher internal mammary artery flow than nitroglycerin during coronary artery bypass grafting surgery. Eur J Cardiothorac Surg. 2004;25(4):553-559.

13. He GW, Fan L, Furnary A, Yang Q. A new antispastic solution for arterial grafting: nicardipine and nitroglycerin cocktail in preparation of internal thoracic and radial arteries for coronary surgery. J Thorac Cardiovasc Surg. 2008;136(3):673-680.

14. Formica F, Ferro O, Brustia M, et al. Effects of papaverine and glycerylnitrate-verapamil solution as topical and intraluminal vasodilators for internal thoracic artery. Ann Thorac Surg. 2006;81(1):120-124.

15. Bai XY, Liu XC, Jing WB, Yang Q, Tang XD, He GW. Effect of amlodipine in human internal mammary artery and clinical implications. Ann Thorac Surg. 2010;90(6):1952-1957.

16. Buxton B, Hayward PA, Wan S. Invited commentary. Ann Thorac Surg. 2010;90(6):1957-1958.

17. Kiemeneij F,Vajifdar BU,Eccleshall SC,Laarman G,Slagboom T, van der Wieken R. Evaluation of a spasmolytic cocktail to prevent radial artery spasm during coronary procedures. Catheter Cardiovasc Interv. 2003;58(3):281-284.

18. Ferguson ME, Pearce FB, Hsu HH, Misra VK, Kirklin JK. Coronary artery spasm during angiography in a pediatric heart transplant recipient: subsequent prevention by intracoronary nitroglycerin administration. Tex Heart Inst J. 2010;37(4):469-471.

19. Dharma S, Shah S, Radadiya R, Vyas C, Pancholy S, Patel T. Nitroglycerin plus diltiazem versus nitroglycerin alone for spasm prophylaxis with transradial approach. J Invasive Cardiol. 2012;24(3):122-125.

20. Cable DG, Caccitolo JA, Pearson PJ, et al. New approaches to prevention and treatment of radial artery graft vasospasm. Circulation. 1998;98(19 Suppl):II15-II22.

21. Jesuthasan LS, Angus JA, Rosenfeldt FL. In vitro comparison of glyceryl trinitrate-verapamil with other dilators of human saphenous vein. ANZ J Surg. 2003;73(5):313-320.

22. He GW, Rosenfeldt FL, Angus JA. Pharmacological relaxation of the saphenous vein during harvesting for coronary artery bypass grafting. Ann Thorac Surg. 1993;55(5):1210-1217.

23. Liu JJ, Doolan LA, Xie B, Chen JR, Buxton BF. Direct vasodilator effect of milrinone, an inotropic drug, on arterial coronary bypass grafts. FANZCA. J Thorac Cardiovasc Surg . 1997;113(1):108-113.

24. García-Rinaldi R, Soltero ER, Carballido J, Mojica J. Intraluminal milrinone for dilation of the radial artery graft. Tex Heart Inst J. 1999;26(3):189-191.

Prepared by: University of Illinois at Chicago – May 2013

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What are the alternatives to alteplase for catheter clearance?

Introduction

Central venous catheters (CVCs) are a vital component in the care of patients in various settings such as acute and critical care, nutrition, surgery, cardiology, oncology, and hemodialysis.1 Catheter occlusion due to thrombosis is a potential complication associated with CVCs, which can be treated with a thrombolytic to help restore catheter patency. Historically, human-derived urokinase and streptokinase were used for this indication. However, due to concerns of infection transmission with urokinase and high rates of anaphylaxis with streptokinase, these agents are no longer used. Of the 3 available recombinant tissue plasminogen activators (alteplase, reteplase, tenecteplase), alteplase is currently the only Food and Drug Administration (FDA) approved agent for treating catheter occlusions. When compared to placebo in a double-blind, multicenter trial, the Cardiovascular thrombolytic used to Open Occluded Lines (COOL) study, alteplase 2 mg/2 mL restored catheter patency (defined as successful withdrawal of 3 mL of blood and subsequent infusion of 5 mL of saline) in significantly more patients (17% vs. 74%, respectively) after 2 hours of an initial dose. Close to 90% of catheter patency was achieved after 1 or 2 treatment doses. No treatment-related events, including bleeding, were observed. Additionally, a small double-blind, randomized study of 50 patients that compared alteplase 2 mg to urokinase 10,000 units demonstrated significantly higher catheter clearance rates with alteplase (89% vs. 59%, respectively). Several other open-label study, prospective cohort, and retrospective reviews have similarly reported successful CVC clearance rates ranging from 83% to 93%.

Alteplase shortage and alternatives

Alteplase, manufactured by Genentech, is commercially available as Activase® and Cathflo Activase®.2,3 Activase is indicated for use as a thrombolytic in patients with acute myocardial infarction, ischemic stroke, and pulmonary embolism. It is available as a sterile, lyophilized powder in 50 mg and 100 mg vials with sufficient diluent to reconstitute to a 1 mg/mL concentration.2 Cathflo Activase®, the formulation indicated for restoration of CVC patency, is supplied as a sterile, lyophilized powder in 2 mg vials that is reconstituted with 2 mL of sterile water for injection.3 In March 2013, Genentech announced that some vials of Cathflo Activase® were found to contain rubber particulate matter upon reconstitution. 4 The manufacturer has advised pharmacists to avoid using the product if particulate matter is visually detected after reconstitution. If particulate matter is not visually apparent, filtration with a 5 micron filter is recommended to remove potentially present particles. In light of this issue, Cathflo Activase® is currently available only on allocation. The supply of Activase®, however, has not been affected. As a result of limited availability, alternatives to Cathflo Activase® need to be explored.

Alteplase aliquots
The recommended alteplase dose for catheter clearance is significantly lower (2 mg) compared to doses recommended for cardiovascular emergencies (50 mg to 100 mg).2,3 As the product is preservative-free, it must be used within a short time after reconstitution. Prior to the availability of Cathflo Activase®, several studies were conducted evaluating the stability and efficacy of preparing and storing aliquots of Activase® in order to minimize drug waste.5-11 Aliquots were prepared by reconstituting a 50 mg or 100 mg vial to final concentrations ranging from 0.5 mg/mL to 2 mg/mL. Volumes of 1 to 2 mL of the reconstituted solution were then drawn into various types of containers and stored at different temperatures for specified time periods. Preparation of the aliquots was conducted under sterile conditions with one study specifically describing preparation in a class 10000 clean room under a certified horizontal class 100 laminar airflow hood.7 Outcomes evaluated included in vitro bioactivity of alteplase, microbiological contamination and/or efficacy in catheter clearance. Tables 1 and 2 provide a description of the studies that evaluated these outcomes of aliquoted alteplase solutions.

Table 1. Clinical efficacy of prolonged storage of alteplase aliquots.5-7

a Catheter patency was assessed by successful withdrawal of blood and subsequent infusion of saline.
b The method of assessing patency was not described.

Table 2. Stability/sterility of prolonged storage of alteplase aliquots.8-11

a Type of storage container not specified.

Reteplase
Although not FDA approved, the use of reteplase for catheter clearance has been evaluated in some studies.12-14 A retrospective evaluation of the use of 0.4 units of reteplase demonstrated overall restoration of catheter function in 83% of 98 treatments administered.12 Catheter function was defined as the ability to complete a dialysis session for dialysis catheters or the successful infusion of intravenous solutions in nondialysis catheters. Of these 98 treatments, 74% resulted in catheter clearance after a single dose of reteplase, and when a second dose was administered in 11 cases, 73% were successful. In a small dose-escalation trial of pediatric oncology patients, an initial dose of reteplase 0.1 units increased to a maximum of 0.4 units, cleared 12 out of 15 (80%) occluded catheters without adverse events.13 Catheter clearance was defined as the ability to withdraw blood or infuse through the line. A larger, open-label prospective study of 139 oncology patients was conducted to evaluate reteplase efficacy in clearing occluded catheters.14 Reteplase 0.4 units was administered with assessment of catheter patency after 30- and 60-minute dwell times with patency defined similar to the pediatric oncology trial. An additional dose was administered after 60 minutes with patency assessments at 90 and 120 minutes. The success rate for catheter patency at 30 minutes was 66.9%, and the cumulative success rate at 120 minutes was 94.7%. Adverse events due to treatment were not observed.

Reteplase is commercially available as a lyophilized powder in single-use vials containing 10.4 units.15 These trials utilized aliquots of reteplase to administer the lower dose of 0.4 units. Unfortunately, reteplase is currently on shortage from the manufacturer with an unknown date of availability.16

Tenecteplase
In a phase III double-blind, randomized, placebo-controlled study, 97 patients with dysfunctional nonhemodialysis catheters received an initial dose of either 2 mg tenecteplase (initial tenecteplase group) or placebo (initial placebo group) followed by a second dose of tenecteplase in both groups if catheter patency was not achieved after 120 minutes of the first dose.17 Catheter patency was defined as the ability to withdraw/infuse a specified amount of blood/saline depending on patient weight An initial dose of tenecteplase restored catheter patency in 60% of patients compared to 23% of patients in the placebo group (absolute difference 37%, 95% confidence interval [CI] 18% to 55%, p=0.0002). When a second dose of tenecteplase was administered in both groups, 88% of patients in the initial tenecteplase group and 85% of patients in the initial placebo group had catheter patency restored within 120 minutes of the second tenecteplase dose. Two cases of deep vein thrombosis were reported; one of which was considered to be drug-related. No other bleeding complications occurred.

The efficacy of tenecteplase 2 mg in improving blood flow rate (BFR) in patients with dysfunctional hemodialysis catheters was compared to placebo in a phase III, double-blind, randomized trial of 149 patients.18 Treatment success was defined as a BFR ≥ 300 mL/min and an increase of ≥ 25 mL/min from baseline 30 minutes before and at the end of the dialysis session. Treatments were given a 1-hour dwell time. A significantly greater number of patients receiving tenecteplase (22%) demonstrated treatment success compared to placebo (5%) with an absolute difference of 17% (95% CI 6% to 27%, p=0.004). Catheter-related bloodstream infections occurred in 1 tenecteplase patient and 3 placebo patients; thrombosis occurred in 1 tenecteplase patient. Adverse events including intracranial hemorrhage, major bleeding, embolism, or other catheter-related complications were not observed.

A single-arm, open-label study of 246 adults and children with dysfunctional catheters evaluated restoration of catheter patency using 2 mg tenecteplase with a dwell time of 120 minutes.19 Catheter patency was defined as the ability to withdraw/infuse a specified amount of blood/saline depending on patient weight. Treatment success was achieved in 72% (95% CI 66% to 78%) of patients after a single dose and 81% (95% CI 76% to 86%) of patients after a second dose. Two cases of catheter-related bloodstream infections occurred. Other adverse events that occurred in more than 1 patient included fever, neutropenia, and nausea. No bleeding or embolic events were reported.

Tenecteplase is available as a lyophilized powder in 50 mg vials with sufficient diluent to reconstitute to a 5 mg/mL concentration.20 The concentration used in the trials was 2 mg which suggests that the reconstituted solution was aliquoted. Although the method of dose preparation was not discussed in these 3 trials, one published study has evaluated the stability of a lower concentration reconstituted solution.21 In vitro stability testing of tenecteplase 1 mg/mL prepared from 2 mg tenecteplase powder stored in glass vials demonstrated adequate bioactivity (<15% reduction) for up to 72 hours when stored at 37°C.

Conclusion
With the current limited availability of alteplase, alternatives for treatment of CVC thrombosis are needed. The stability, sterility, and efficacy of aliquots prepared from Activase® have been established in several reports. Based on the wide range of storage durations studied and the lack of a consensus on the most appropriate storage method, choosing a shorter duration of storage may be the most prudent. The methods involved in preparation of aliquots are considered to have a medium risk contamination according to the United States Pharmacopeia (USP) Chapter 797 and require stringent sterility testing. 22 Of utmost importance is the environment in which the aliquots are prepared. Criteria for sterile conditions, aseptic technique, and sterility testing must be followed.

The use of alternative agents is another consideration. Reteplase, although studied for this use, is not an option at this time due to its current shortage. Tenecteplase has been shown to be effective and limited data suggests 72-hour stability of a 1 mg/mL reconstituted solution, although the storage in this study was at 37°C. Current availability of tenecteplase, however, is limited to the 50 mg powder and additional studies are needed to determine the stability of diluted solutions under normal storage conditions, such as refrigeration.

References
1. Baskin JL, Reiss U, Wilimas JA, et al. Thrombolytic therapy for central venous catheter occlusion. Haematologica. 2012; 97(5):641–650.

2. Activase [package insert]. South San Francisco, CA. Genentech, Inc. 2011

3. Cathflo Activase [package insert]. South San Francisco, CA. Genentech, Inc. 2010.

4. Current drug shortage bulletins: Alteplase recombinant. American Society of Health-Systems Website. http://www.ashp.org/DrugShortages/Current/Bulletin.aspx?id=1001. Update April 17, 2013. Accessed April 22, 2013.

5. Deitcher SR, Fesen MR, Kiproff PM, et al. Safety and efficacy of alteplase for restoring function in occluded central venous catheters: results of the Cardiovascular Thrombolytic to Open Occluded Lines trial. J Clin Oncol. 2002;20(1):317-324.

6. Timoney JP, Malkin MG, Leone DM, et al. Safe and cost effective use of alteplase for the clearance of occluded central venous access devices. J Clin Oncol. 2002;20(7):1918-1922.

7. Isaac BF. Efficacy of cryopreserved recombinant alteplase for declotting thrombosed central catheters. Ann Pharmacother. 2000;34(4):533-534.

8. Alkatheri A. Stability of recombinant tissue plasminogen activator at−30 °C over one year. Pharmaceuticals. 2013;6(1):25-31.

9. Davis SN, Vermeulen L, Banton J, Schwartz BS, Williams EC. Activity and dosage of alteplase dilution for clearing occlusions of venous-access devices. Am J Health Syst Pharm. 2000;57(11):1039-1045.

10. Wiernikowski JT, Crowther M, Clase CM, Ingram A, Andrew M, Chan AKC. Stability and sterility of recombinant tissue plasminogen activator at –30ºC. Lancet. 2000;355(9222):2221-2222.

11. Calis KA, Cullinane AM, Horne MK. Bioactivity of cryopreserved alteplase solutions. Am J Health Syst Pharm. 1999;56(15):2056-57.

12. Owens L. Reteplase for clearance of occluded venous catheters. Am J Health Syst Pharm. 2002;59(17):1638-1640.

13. Terrill KR, Lemons RS, Goldsby RE. Safety, dose, and timing of reteplase in treating occluded central venous catheters in children with cancer. J Pediatr Hematol Oncol. 2003;25(11):864-867.

14. Liu CY,Jain V,Shields AF, Heilbrun LK. Efficacy and safety of reteplase for central venous catheter occlusion in patients with cancer. J Vasc Interv Radiol. 2004;15(1):39–44.

15. Retevase [package insert]. Bedminster, NJ. EKR Therapeutics, Inc. 2009.

16. Current drug shortage bulletins: Reteplase injection. American Society of Health-Systems Website. http://www.ashp.org/DrugShortages/Current/Bulletin.aspx?id=569. Update April 12, 2013. Accessed April 22, 2013.

17. Gabrail N, Sandler E, Charu V, et al. Double-blind, placebo-controlled study of tenecteplase for restoration of function in dysfunctional central venous catheters. J Vasc Interv Radiol. 2010;21(12):1852-1858.

18. Tumlin J, Goldman J, Spiegel DM, Roer D, Ntoso KA. A phase III, randomized, double-blind, placebo-controlled study of tenecteplase for improvement of hemodialysis catheter function: TROPICS 3. Clin J Am Soc Nephrol. 2010;5(4);631-636.

19. Tebbi C, Costanzi J, Shulman R, et al. A phase III, open-label, single-arm study of tenecteplase for restoration of function in dysfunctional central venous catheters.

J Vasc Interv Radiol . 2011;22(8);1117-1123.

20. TNKase [package insert]. South San Francisco, CA. Genentech, Inc. 2008.

21. Lentz YK,Joyce M, Lam X. In vitro stability and compatibility of tenecteplase in central venous access devices. Hemodial Int. 2011;15(2):264–272.

22. CSP Microbial Contamination Risk Levels. USP-797: Pharmaceutical Compounding Sterile Preparations. USP-NF Website. http://www.uspnf.com/uspnf/pub/index?usp=35&nf=30&s=2&officialOn=December%201,%202012 . Accessed April 23, 2013.

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How do methylene blue and isosulfan blue compare for use in sentinel lymph node biopsy?

Introduction
Dyes are used in various clinical settings to stain tissues, including identification of esophageal cancer using Lugol’s solution, endoscopic tattooing of intestinal lesions with India ink, and staining of the ocular membrane with indocyanine green during cataract surgery.1-3

Isosulfan blue and methylene blue are 2 commonly used dyes. Isosulfan blue is marketed under the name Lymphazurin and is available as a 1% solution. The Food and Drug Administration (FDA) approved uses are as an adjunct to lymphography in primary and secondary lymphedema of the extremities; chyluria, chylous ascites or chylothorax; lymph node mapping in primary or secondary neoplasm; and lymph node response to therapeutic modalities.4 It is, however, associated with anaphylactic reactions and interference with pulse oximeter readings and may cause blue staining of the skin.5,6

Methylene blue is available as a 1% dark blue solution with an FDA-approval for the treatment of drug-induced methemoglobinemia.7 In addition, methylene blue has been studied off-label for the prophylaxis and treatment of ifosfamide-induced encephalopathy, treatment of refractory hypotension during cardiac surgery, as a stain for the detection of Barrett’s esophagus, and for visualization of the parathyroid gland during surgery.3,7,8 It must be avoided in patients with glucose-6-phosphatase deficiency (G6PD) as it can cause acute hemolysis.

Concerns about the side effect profile and cost of isosulfan blue has prompted an interest in the use of methylene blue as an alternative dye. However, few direct comparisons of these dyes are available; most published studies have compared these agents for use in lymphatic mapping and biopsy.

The use of methylene blue and isosulfan blue in sentinel lymph node mapping
Both isosulfan blue and methylene blue have been studied in lymphatic mapping and biopsy of sentinel lymph nodes (SLN). Sentinel lymph node biopsy has gained attention as an alternative method to stage early breast cancer and melanoma.9-11 An SLN is the first lymph node encountered by lymphatic fluid draining from a primary tumor. A complete lymph node dissection (CLND) to remove a lymph node for histology was the most accurate method to assess the spread of the cancer to lymph nodes; but this procedure is associated with morbidities such as lymphedema and nerve injury. It had been proposed that since the cancer would metastasize first to only one or a few lymph nodes (the sentinel nodes) before spreading to distant lymph nodes, histology of these sentinel nodes would be representative of the entire node basin. Therefore, biopsy of the SLN would highly predict the regional lymph node status and help select patients who would benefit from subsequent CLND dissection. This approach of SLN biopsy as a less invasive method of staging cancer has been used in other solid neoplasms.12

The SLN can be identified using either a radiolabeled colloid, a dye, or both, with the greatest proportion of successful SLN mapping and lowest false-negative rates associated with using the combination of dye and radiolabeled colloid.10 Isosulfan blue is the most commonly used dye with the SLN identification rates ranging from 65% to 94%.13 In 2001, the shortage of isosulfan blue led to methylene blue being evaluated as an alternative dye that was less expensive and more readily available. There was the concern that methylene blue might not be optimal for SLN localization as it was a smaller molecule and may risk passing from the SLN to additional nodes that might not be sentinel.14 However, studies on the efficacy of methylene blue have shown high localization rates.13,15-17

Efficacy of methylene blue for lymph node mapping
In a retrospective study, 329 patients with tumors <2 cm were randomized to receive either methylene blue or a combination of methylene blue and radiolabeled colloid to localize the SLN.13 A 1% solution of methylene blue was injected locally 10 to 15 minutes prior to skin incision. The SLN identification rates were similar for methylene blue and the combination of methylene blue and radiolabeled colloid, being 96.5% and 98.7% (P = 0.354), respectively. The false negative rates were similar between methylene blue and the combination technique, being 3.7% and 4.1% respectively (P = 0.882).

In a prospective trial, methylene blue and isosulfan blue were compared for SLN mapping in 199 breast cancer patients.14 Following injection of colloid, 3 to 4 mL of methylene blue or isosulfan blue were injected locally near the tumor site. Success was defined as the identification of at least one SLN using either dye or colloid. Positive nodes were detected in 29.9% of patients with isosulfan blue and in 33.9% of patients with methylene blue (P>0.05). The rates of concordance (number of cases with one radioactive and blue SLN) with colloids were 88.5% for isosulfan blue and 92.0% for methylene blue.

In another retrospective study of 112 breast cancer patients, methylene blue 1% was used as an alternative to isosulfan blue for SNL identification. 15 Following the administration of radiolabeled colloid, 5 mL of methylene blue was injected locally. An SLN was identified in 95.5% of patients overall, with a rate of 92% for methylene blue and a 94.9% concordance rate between methylene blue and radiolabeled colloid. A prospective study in 54 patients has also been published, looking at methylene blue (5 mL of a 1% solution) alone as an alternative to isosulfan blue. It reported a successful mapping rate of 91.1% (based on 31 of 34 cases) with no false negative cases.16 However, this high identification rate reported with methylene blue alone could be partly due to the exclusion by the author of the first 20 cases (identification rate of 14 of 20 [70%]), which were considered learning cases, hence reinforcing the operator-dependent component of a successful SLN biopsy. A retrospective study comparing methylene blue and isosulfan blue in 194 breast cancer patients found similar SLN identification rates (99.1% with methylene blue and 100% with isosulfan blue, P > 0.99).17

Methylene blue and isosulfan blue have also been evaluated in the SLN mapping of gastrointestinal tumors and cutaneous melanoma. In a prospective trial of 122 patients comparing SLN identification rates with isosulfan blue versus methylene blue, the dye (2 to 5 mL or 0.5 mL/cm tumor) was injected in the subserosal layer around the gastrointestinal tumor at the discretion of the operating surgeon; the tumors studied ranged from esophageal to colon cancer. 18 The SLN identification rates for isosulfan blue and methylene blue were 96.6% versus 96.7% (P = 1) with a similar total number of SNLs identified per patient (2.71 and 2.82; P = 1), nodal positivity (42% and 26%; P = 0.3), and accuracy (94% and 96%; P = 1), respectively. No patients in either group experienced anaphylaxis, blue hives, or tissue necrosis. However, a pulse oximetry drop of > 5% was seen in 3 patients (5%) given isosulfan blue (vs. 0% with methylene blue; P = 0.244). These findings showed that methylene blue and isosulfan blue could be used for SLN identification in gastrointestinal tumors.

The effectiveness of methylene blue was also compared with isosulfan blue in SLN biopsy for cutaneous melanoma.19 A prospective study of 159 patients with intermediate and high-risk melanomas used isosulfan blue or methylene blue injected intradermally to the skin surrounding the primary melanoma for SLN identification. Following injection of radiolabelled colloid, 1 to 2 mL of either dye was injected after random assignment. The rates of blue dye visualization in SLNs were 58% for isosulfan blue and 62% for methylene blue (P = 0.164). Blue dye visualization in SLNs was higher with methylene blue for head and neck tumors (P < 0.01) and groin tumors (P < 0.001) versus isosulfan blue; no difference was seen for SLN biopsy in the axilla (P = 0.919).

Adverse effects of methylene blue versus isosulfan blue
The main disadvantage of isosulfan blue is the risk of allergic and anaphylactic reactions, which can occur at a rate of 1% to 3% and manifest as blue hives, wheals, or life-threatening anaphylaxis.5 As isosulfan blue is a triphenylmethylane-based dye that is contained in the environment, isosulfan blue sensitization can occur prior to its use in SLN mapping and may not be identified by an allergy history or negative skin test.20 In contrast, anaphylaxis with methylene blue is rare. Local skin necrosis and inflammation have been reported when methylene blue was injected superficially and intradermally. The incidence of skin necrosis reported varied from none to 5% in some studies.2,17 Stradling et al reported 21% of patients given methylene blue for SLN developed skin lesions (either erythematous, necrotic, or superficial ulceration).22 This effect is thought to be due to inhibition of nitric oxide leading to vasospasm and tissue ischemia; or to the activation of macrophages resulting from formaldehyde and deaminized oxidized products that subsequently led to a local inflammatory lesion.21,22 Due to these toxic effects on local tissue, it has been proposed to restrict methylene blue to deep parenchymal injections where tissue perfusion is maximized.22

In an effort to reduce the risk of adverse skin reactions to methylene blue, a group of researchers investigated the efficacy of using diluted methylene blue for SLN mapping in breast cancer patients.2 Methylene blue was used as full-strength (10 mg/mL), diluted to either 5, 3.3, or 2.5 mg/mL (intermediate-strength), and as a dilute formulation of 1.25 mg/mL. Their findings showed higher SLN identification rates with the intermediate and dilute methylene blue (88% and 92%) compared to full-strength methylene blue (74%; P = 0.004 vs. 92%). The diluted methylene blue (1.25 mg/mL) group had the lowest incidence of local inflammatory reaction.

SUMMARY
Both isosulfan blue and methylene blue have been used successfully in SLN biopsy for some cancers, with methylene blue showing similar efficacy to isosulfan blue for node identification. The potentially higher cost and risk of anaphylaxis of isosulfan blue make methylene blue an attractive alternative in lymphatic mapping, with most available information limited to breast cancer. Future studies are needed to explore the use of methylene blue in other areas of SLN mapping and to determine if it is associated with fewer adverse events than isosulfan blue.

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Prepared by:
Yee Ming Lee, PharmD
PGY-1
University of Illinios at Chicago
May 2013

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