Return of IC Adenosine for FFR: History, Dose and Technique

Intravenous adenosine has been the standard for fractional flow reserve (FFR) for more than 3 decades and has been used successfully in generating the data sets demonstrating superior FFR-guided outcomes in FAME and other studies. Recently, there has been discussion about the limitations of intravenous adenosine for measuring FFR. Hemodynamic variability has caused many to ask exactly when we should measure the correct FFR (Table 1). In this context, several thought leaders in coronary physiology recommend returning to intracoronary (IC) adenosine. I thought it might be worthwhile to discuss how IC adenosine came to be used, its best dosing, and a couple tips on technique for administration.

History of IC adenosine

IC adenosine was first proposed in 1986 by Robert Wilson, MD, to measure coronary flow reserve.¹ After studying with Dr. Melvin Marcus, the world-famous coronary physiologist at the University of Iowa, Dr. Wilson developed an intracoronary Doppler catheter to measure coronary flow and demonstrated the visual-functional mismatch between angiography and physiology in man. The coronary Doppler catheter evolved from an earlier device with a Doppler crystal attached to a suction cup placed on the coronary artery during coronary bypass surgery to a 1F angioplasty-style catheter with a crystal angled at the tip. The catheter was introduced into the flow field of the coronary artery lumen percutaneously. In 1991, we developed a Judkins catheter with a Doppler crystal embedded on the inferior aspect of the tip. This catheter was soon made obsolete by an angioplasty guide wire with a Doppler crystal tip developed by Dr. Jerry Segal. The Doppler flow wire could measure flow in any artery in any location in the heart (Figure 1).² With this tool, coronary flow and reserve could be directly measured inside the heart during cardiac catheterization. Coronary angioplasty then became a very good human model to evaluate ischemia, drugs, and the physiologic outcomes of balloons and stents on the blocked coronary artery.    

The IC method of hyperemia

Before adenosine, Dr. Wilson used intracoronary papaverine to produce maximal coronary hyperemia.³ The IC method used 2 syringes connected by a stopcock. One syringe contained 10-12mg of paparverine; the other, normal saline for a flush. The stopcock was connected to the coronary guide catheter manifold (Figure 2). After positioning the Doppler guidewire in the coronary artery across a stenosis, guide catheter pressure was checked to ensure no catheter obstruction was present. After acquiring a stable Doppler signal, the operator turned the stopcock, injected the paparverine over about 2-3 seconds, turned the stopcock again to inject the saline flush, and then turned back to pressure, watching the Doppler signal. The paparverine hyperemic effect on flow velocity peaked in about 15-30 seconds and lasted about 2-3 minutes. Unfortunately, papaverine also produced prolongation of the QT interval and several patients had torsade de pointe (ventricular fibrillation) and needed to be defibrillated. This side effect did not bode well for continued use of papaverine.

Adenosine replaces papaverine

Living by the dictum, necessity is the mother of invention, Wilson’s landmark investigation¹ into adenosine as a better hyperemic agent was truly timely. He found that relatively low doses of IC adenosine (16-20mcg) could produce equivalent hyperemia to IC papaverine. In addition, IV adenosine in doses of 150mcg/kg also produced the equivalent response. Following Dr. Wilson’s lead, our lab also verified the IC adenosine doses and also noted that IV bolus adenosine could equal the IC papaverine for coronary vascular resistance (CVR) measurements.⁴ With adenosine, the measurement of CVR by intracoronary Doppler became a standard technique in the cath lab for the study of the human coronary circulation. Within a short time thereafter, an angioplasty-type pressure sensor guide wire was introduced along with the concept of FFR. As recommended by the FFR founders, Drs. Pijls and DeBruyne, IV adenosine was preferred because it produced prolonged, steady state hyperemia with more time to observe the distal and aortic pressure ratio (Pd/Pa) and perform pullback pressure recordings. IC bolus adenosine could also be used, but serial lesions and pullback pressures required multiple injections. While I favored IC adenosine for CVR and FFR measurements, I eventually converted to an all-IV adenosine user after several pressure wire representatives shared their frustrations about how the IC bolus technique was not uniformly followed among operators, resulting in questionable, if not erroneous, FFR readings. To simplify the FFR technique and remove one source of error, I then advocated that all labs begin their FFR experience with IV adenosine as a hands (read, operator)-free signal acquisition method.  

IV adenosine variability

After years of widespread use of IV adenosine as the standard method of FFR hyperemia, several investigators reported what many had seen in practice, that IV adenosine did not always produce a stable Pd/Pa ratio and, at times, no stable period could be identified. Johnson⁵, Seto⁶, and others⁷ reported various patterns of pressure changes induced by IV adenosine. Moreover, the 3 most common patterns of adenosine variability may not repeat themselves in the same patient on a second infusion (Figure 3). Johnson et al5 have demonstrated that the lowest distal/aortic pressure ratio (Pd/Pa) — referred to as a “smart minimum” — during the adenosine infusion is the right value with the highest reproducibility. The “smart minimum” FFR is the lowest Pd/Pa without pressure wave artifact that occurs any time after the adenosine effect has begun. Most FFR signal monitors have incorporated software automatically computing and displaying the lowest Pd/Pa. The operator and team must continue to view the recording to ensure FFR is the smart value and not just “a value” that might be artificial.

Thus, as noted above, the best and most reproducible point at which to take the FFR (Pd/Pa during hyperemia) is the minimum Pd/Pa ratio, excluding any artifact.  

The causes of IV adenosine variability are not precisely known, but most likely relate to the venous return, with an initial rapid stimulus of the coronary hyperemia, followed by systemic hypotension to a degree, with reduced venous return, reduced hyperemia, and then a return of hyperemia as the adenosine again stimulates the coronary circulation. The phasic nature of the adenosine response corresponds in many cases to the respiratory cycle, as noted years ago by Dr. Wilson.  

IC adenosine has some advantage over the IV route, including less variability, quickly achieving maximal hyperemia (albeit short lived), and ease of use. IC adenosine may be problematic for ostial lesion assessment (due to a need to unseat the guide catheter) and offer limited ability to obtain a continuous pressure pullback curve to assess diffuse versus focal coronary disease. Also, remember that IC adenosine in the right coronary artery (RCA) produces transient heart block, lasting from 10-30 seconds, depending on the dose.  

Dosing and method of IC adenosine

There are many reports of different doses of IC adenosine, ranging from 16mcg to 700mcg. The most common dose used for CVR was 30-50mcg for the RCA and 50-100mcg for the left coronary artery (LCA). The most recent IC dose investigation by Adjedj et al⁸ provides a modern and definitive demonstration that the optimal doses appear to be 100mcg for the RCA and 200mcg for the LCA. These doses will eliminate any uncertainty regarding whether the operator achieved maximal hyperemia and whether enough adenosine was given to get the most accurate FFR. The concentration of IC adenosine should be mixed to provide 10 or 20mcg/ml. One liter of the adenosine/saline mix can supply an entire lab’s needs for the day.  

The method can be summarized as follows:

1. Using standard FFR methodology⁹, zero the pressure wire and guide catheter to atmosphere on the cath table. Introduce the pressure wire into the guide catheter and match the pressure to the aortic pressure near the coronary ostium.
2. Pass the pressure wire beyond the target lesion. Observe the aortic and guide wire pressure signals. Ensure no guide catheter damping obscures the coronary flow as evidenced by a damped signal.
3. Connect the adenosine/saline stopcock assembly (Figure 2) to the coronary pressure manifold, inject the adenosine quickly, followed immediately by 5-10ml of saline, and quickly return to pressure recording.
4. Wait 5 seconds before beginning the automatic Pd/Pa recording (have the recording technologist/nurse count to 5 before pressing the “go (record)” button).
5. Observe the hyperemic effect occurring within 10-15 seconds and use the lowest Pd/Pa during hyperemia as the FFR. Repeat as necessary. Because of the very short-lived effect of IC adenosine (60-90 seconds), duplicate measurements can be obtained quickly and this is also a good practice.

The bottom line  

For FFR and coronary flow reserve (CFR) measurements, IV and IC adenosine produce identical maximal hyperemia. For those concerned with excess variability of IV adenosine, IC adenosine can be used with confidence. Labs should also become familiar with other options for hyperemia⁹ (Table 2) for use in the rare patient with contraindications to adenosine. Lastly, I look forward to sharing a discussion about the use of contrast media producing submaximal hyperemia to improve our use of the resting Pd/Pa for decision-making in a forthcoming CLD Clinical Editor’s page.

References 

1. Wilson RF, Wyche K, Christensen BV, Zimmer S, Laxson DD. Effects of adenosine on human coronary arterial circulation. Circulation. 1990; 82: 1595-1606.
2. Segal J, Kern MJ, Scott NA, King SB III, Doucette JW, Heuser RR, Ofili E, Siegel R. Alterations of phasic coronary artery flow velocity in humans during percutaneous coronary angioplasty. J Am Coll Cardiol. 1992; 20: 276-286.
3. Wilson RF, White CW. Intracoronary papaverine: An ideal coronary vasodilator for studies of the coronary circulation in conscious humans. Circulation. 1986; 73: 444-451.
4. Kern MJ, Deligonul U, Tatineni S, Serota H, Aguirre F, Hilton TC. Intravenous adenosine: continuous infusion and low dose bolus administration for determination of coronary vasodilatory reserve in patients with and without coronary artery disease. J Am Coll Cardiol. 1991; 18: 718-729.
5. Johnson NP, Johnson DT, Kirkeeide RL, Berry C, DeBruyne B, Fearon WF, Oldroyd KG, Pijls NHJ, Gould KL. Repeatability of fractional flow reserve (FFR) despite variations in systemic and coronary hemodynamics. J Am Coll Cardiol Intv. 2015; 8(8): 1018-1027.
6. Seto AH, Tehrani DM, Bharmal MI, Kern MJ. Variations of coronary hemodynamic responses to intravenous adenosine infusion: Implications for fractional flow reserve measurements. Catheter Cardiovasc Interv. 2014; 84: 416-425.
7. Tarkin JM, Nijjer S, Sen S, et al. Hemodynamic response to intravenous adenosine and its effect on fractional flow reserve assessment: results of the Adenosine for the Functional Evaluation of Coronary Stenosis Severity (AFFECTS) study. Circ Cardiovasc Interv. 2013; 6(6): 654-661.
8. Adjedj J, Toth GG, Johnson NP et al. Intracoronary adenosine. Dose-response relationship with hyperemia. J Am Coll Cardiol Intv. 2015; 8: 1422-1430.
9. Fearon WF. Invasive coronary physiology for assessing intermediate lesions. Circ Cardiovasc Interv. 2015 Feb; 8(2): e001942. doi: 10.1161/CIRCINTERVENTIONS.114.001942.