Abidov et al. Journal of Cardiovascular Magnetic Resonance (2018) 20:87 https://doi.org/10.1186/s12968-018-0510-7 REVIEW Open Access Aminophylline shortage and current recommendations for reversal of vasodilator stress: an ASNC information statement endorsed by SCMR Aiden Abidov1, Vasken Dilsizian2, Rami Doukky3, W. Lane Duvall4, Christopher Dyke5, Michael D. Elliott6, Fadi G. Hage7, Milena J. Henzlova8, Nils P. Johnson9, Ronald G. Schwartz10, Gregory S. Thomas11 and Andrew J. Einstein12* Abstract Pharmacologic reversal of serious or intolerable side effects (SISE) from vasodilator stress is an important safety and comfort measure for patients experiencing such effects. While typically performed using intravenous aminophylline, recurrent shortages of this agent have led to a greater need to limit its use and consider alternative agents. This information statement provides background and recommendations addressing indications for vasodilator reversal, timing of a reversal agent, incidence of observed SISE with vasodilator stress, clinical and logistical considerations for aminophylline-based reversal, and alternative non-aminophylline based reversal protocols. Overview and safe reversal of SISE from vasodilator stress during The purpose of this document is to provide cardiac imaging pharmacologic stress myocardial perfusion imaging (MPI) specialists performing vasodilator stress testing with specific with single photon emission computed tomography recommendations regarding options for the reversal of (SPECT), positron emission tomography (PET), or vasodilator stress. The timeliness of this document is cardiovascular magnetic resonance (CMR). associated with recurrent shortages of aminophylline, which has been used in most laboratories for reversal of serious Indications for vasodilator stress reversal and intolerable side effects (SISE) from vasodilator stress. ASNC 2016 imaging guidelines for SPECT nuclear cardi- This information serves as a summary of expert opinion ology procedures[1] support using aminophylline for on this topic developed by the American Society of Nuclear reversing the effects of vasodilator stress testing with Cardiology (ASNC) and endorsed by the Society for adenosine, regadenoson and dipyridamole when SISE are Cardiovascular Magnetic Resonance (SCMR). This docu- encountered. The guidelines reflect evidence that most ment covers general indications for reversal of SISE from vasodilator stress-related adverse effects are self-limiting vasodilator stress, the standard reversal procedure using and do not require reversal. Serious adverse effects can be intravenous (IV) aminophylline, and alternative options effectively aborted with IV administration of aminophyl- based on evidence and expert opinion for effective line, a xanthine derivative and a nonselective adenosine receptor antagonist [2], with the exception of seizures. * Correspondence: [email protected] Intravenous lorazepam should be the first-line interven- This article is co-published in the journals Journal of Nuclear Cardiology and tion for seizures and methylxanthine use is not recom- Journal of Cardiovascular Magnetic Resonance, and is available at https:// doi.org/10.1007/s12350-018-01548-0 and https://doi.org/10.1186/s12968-018- mended for reversal of adenosine or regadenoson effects 0510-7 respectively. under these circumstances because of the concern for 12 Department of Medicine, and Department of Radiology, Columbia possible lowering of the seizure threshold and potential University Irving Medical Center and New York-Presbyterian Hospital, 622 West 168th Street PH 10-203, New York, NY 10032, USA risk of exacerbating seizures [3], based on limited evidence Full list of author information is available at the end of the article and the preponderance of expert opinion. © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Abidov et al. Journal of Cardiovascular Magnetic Resonance (2018) 20:87 Page 2 of 6 Based on the 2016 guidelines[1], indications for rever- high likelihood of ischemic heart disease, the possibility of sal of vasodilator stress using IV aminophylline (50 to a “false-negative” scan should be considered and further 250 mg intravenously at least 1 min after the tracer testing with an alternative stress agent (such as dobuta- injection) include the following: mine) should be considered. For stress CMR, a reversal agent can be given once first-pass stress perfusion images 1. Severe hypotension (systolic blood pressure (BP) have been acquired. ≤80 mmHg) or symptomatic hypotension; 2. Development of symptomatic, persistent Mobitz II Incidence of observed side effects with second degree or complete heart block; vasodilator stress 3. Significant cardiac arrhythmia (e.g. ventricular Based on published evidence, the vasodilator stressor tachycardia); agents used in current cardiology practice are safe and 4. Wheezing; have a very low observed rate of serious adverse effects 5. Severe chest pain associated with ST depression of (Table 1). Mild, easily reversible adverse effects are fre- 2 mm or greater, or ST elevation of 1 mm or quent. Perceived shortness of breath associated with rega- greater; denoson is commonly seen and does not reflect elevated 6. Signs of poor perfusion (pallor, cyanosis, cold or pulmonary capillary wedge pressure, but may reflect a clammy skin); central nervous system effect [11]. Gastrointestinal side 7. Intolerable symptoms such as nausea, vomiting, or effects are overall mild/transient and are more frequently abdominal pain. observed in patients with end-stage renal failure undergo- ing regadenoson stress [5, 6]. It is important for clinicians to identify patients at Table 2 [3] provides more detailed information regard- risk for SISE who may need prompt reversal of vaso- ing SISE associated with vasodilator stress agents which dilator stress agent. Those at risk include patients with essentially represents a list of indications for the reversal borderline low systolic BP (< 100 mmHg), baseline 1st procedure (with the exception of seizures). As can be or 2nd degree atrioventricular block, reactive airway seen from these data, the rate of occurrence of clinical disease, or acute coronary syndrome presentation [4]. situations matching the list of indications for reversing Patients with end-stage renal disease tend to have vasodilator stress is very infrequent. higher frequency of regadenoson-induced gastrointes- Considering combined evidence of serious adverse tinal side effects [5, 6]. effects of clinically utilized vasodilator agents and actual For CMR stress with regadenoson, in addition to SISE, guidelines-endorsed indications for aminophylline use, a pharmacologic reversal may be required for a minority of nuclear cardiology or CMR laboratory will encounter examinations (< 25%) in which rest perfusion imaging is occasional cases that require vasodilator stress reversal. needed for artifact differentiation observed on stress The rate of these cases has not been definitively assessed imaging. In such a case, given the half-life of regadenoson but it is certainly less than 10% and may be as low as 1% and the short window between stress and rest CMR perfu- based on Tables 1 and 2. With periodic shortage of ami- sion imaging, vasodilator stress reversal may be deemed nophylline, selective use of reversal agents is a reason- necessary if there is concern for residual drug effect. able alternative to routine use and does not compromise safety or effectiveness of testing. Timing of a reversal agent Few studies have examined how early following radioiso- Aminophylline-based vasodilator stress reversal: tope administration a reversal agent for vasodilator Clinical and logistical considerations stress can be administered without influencing the Despite the data demonstrating that only a fraction of results of perfusion imaging. vasodilator stress studies require a reversal procedure, The majority of myocardial uptake of the radioisotope present day cardiac imaging laboratories utilize IV occurs within 1–2 min following the radioisotope injection aminophylline much more frequently and with high [7–10]. Thus, it is important to maintain vasodilator-in- regional variability. In different clinical practices in duced myocardial hyperemic state during this period. the US, the proportion of vasodilator stress tests with However, if a very serious adverse event were to occur, the aminophylline use ranges from less than 3 to 100% vasodilator should be reversed immediately. If vasodilator [12], the latter being in an attempt to prevent any agent reversal occurs in the first minute following radio- possible adverse effects of the vasodilator stress. isotope injection, the “stress” perfusion could well be com- Randomized controlled trials demonstrate use of ami- promised. Therefore, following a premature reversal of nophylline is safe, well tolerated, and effective in vasodilator stress, if myocardial perfusion imaging is improving overall patient satisfaction with