Chest
editorialsIntravenous Dipyridamole Infusion Causes Severe Bronchospasm in Asthmatic Patients
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Cited by (20)
A semi-quantitative translational pharmacology analysis to understand the relationship between in vitro ENT1 inhibition and the clinical incidence of dyspnoea and bronchospasm
2017, Toxicology and Applied PharmacologyAdenosine contributes to the pathophysiology of respiratory disease, and adenosine challenge leads to bronchospasm and dyspnoea in patients. The equilibrative nucleoside transporter 1 (ENT1) terminates the action of adenosine by removal from the extracellular environment. Therefore, it is proposed that inhibition of ENT1 in respiratory disease patients leads to increased adenosine concentrations, triggering bronchospasm and dyspnoea. This study aims to assess the translation of in vitro ENT1 inhibition to the clinical incidence of bronchospasm and dyspnoea in respiratory disease, cardiovascular disease and healthy volunteer populations. Four marketed drugs with ENT1 activity were assessed; dipyridamole, ticagrelor, draflazine, cilostazol. For each patient population, the relationship between in vitro ENT1 [3H]-NBTI binding affinity (Ki) and [3H]-adenosine uptake (IC50) to the incidence of: (1) bronchospasm/severe dyspnoea; (2) tolerated dyspnoea and; (3) no adverse effects, was evaluated. A high degree of ENT1 inhibition (≥ 13.3x Ki, ≥ 4x IC50) associated with increased incidence of bronchospasm/severe dyspnoea for patients with respiratory disease only, whereas a lower degree of ENT1 inhibition (≥ 0.1x Ki, ≥ 0.05x IC50) associated with a tolerable level of dyspnoea in both respiratory and cardiovascular disease patients. ENT1 inhibition had no effect in healthy volunteers. Furthermore, physicochemical properties correlative with ENT1 binding were assessed using a set of 1625 diverse molecules. Binding to ENT1 was relatively promiscuous (22% compounds Ki < 1 μM) especially for neutral or basic molecules, and greater incidence tracked with higher lipophilicity (clogP > 5). This study rationalises inclusion of an assessment of ENT1 activity during early safety profiling for programs targeting respiratory disorders.
Pulmonary function monitoring during adenosine myocardial perfusion scintigraphy in patients with chronic obstructive pulmonary disease
1999, Mayo Clinic ProceedingsTo determine whether adenosine could be safely administered to patients with chronic obstructive pulmonary disease (COPD) for coronary vasodilatation during perfusion scintigraphy without causing bronchospasm.
The study was divided into two phases. In the monitoring phase, patients with COPD were pretreated with an inhaled bronchodilator (albuterol) and had pulmonary function monitored during the infusion of a graduated dose of adenosine. Eligibility for entry into this phase of the study was determined on the basis of results of pulmonary function testing (PFT) during resting. Once we had shown that adenosine could be safely administered to patients with COPD, an implementation phase was begun. Entry did not require resting PFT, and patients were administered adenosine without monitoring of pulmonary function. Differences between patients with normal pulmonary function or mild COPD and those with more severe COPD were analyzed statistically.
Of 94 patients entered into the monitoring phase, none had obvious bronchospasm. The dosage of adenosine was reduced in four patients because of a decrease in forced expiratory volume in 1 second (FEV1) of 20% in comparison with baseline (FEV1 before administration of albuterol). The mean FEV1 decreased slightly from 1.83 L after administration of albuterol to 1.78 L during the maximal adenosine dose. Patients with a remote history of asthma, positive result of a methacholine challenge test, or mild COPD (FVC1 60 to 80% of the maximal predicted value for age) did not differ significantly in their response to infusion of adenosine from those with moderate or severe COPD (FEV1 30 to 59% of the maximum predicted for age). Of 117 patients in the implementation phase, 2 had bronchospasm during infusion of adenosine that was quickly terminated by stopping the administration in one patient and reducing the dose of adenosine in the other.
This study shows that adenosine can be safely administered intravenously to selected patients with known or suspected COPD to produce coronary vasodilatation for myocardial perfusion imaging. Patients who are within the guidelines established for this study should be considered for adenosine coronary vasodilatation with use of bronchodilator pretreatment, a graduated dose of adenosine, and regular chest auscultation during the infusion.
Patients with stable chronic obstructive pulmonary disease can safely undergo intravenous dipyridamole thallium-201 imaging
1998, American Heart JournalBackground Patients with chronic obstructive pulmonary disease are usually excluded from intravenous dipyridamole thallium-201 testing. We developed a nurse-administered protocol to screen and pretreat patients so they could be safely tested.
Methods and Results We prospectively screened patients referred for intravenous dipyridamole thallium testing and retrospectively reviewed a comparison group of patients who had undergone intravenous dipyridamole testing before our bronchospasm protocol. We studied 492 consecutive patients referred for intravenous dipyridamole thallium testing, separating those with complete data (n = 451) into two groups: group A (n = 72), patients assessed to be at risk for intravenous dipyridamole-induced bronchospasm who received our bronchospasm treatment protocol; and group B (n = 379), patients assessed to be free of risk, who did not receive our bronchospasm protocol. Group C (n = 89) was a retrospective comparison group of patients who had undergone intravenous dipyridamole testing before initiation of the protocol. Patients were considered at risk for an adverse event if any of the following were present: peak flow ≤400 ml at the time of the test (spirometry by nurse) that increased to >400 ml after bronchodilator treatment, wheezing audible with stethoscope, history of chronic obstructive pulmonary disease or asthma or dyspnea on exertion at less than four blocks, or resting respiratory rate >18 breaths/min. The test was considered contraindicated if resting oxygen saturation was <85%, respiratory rate ≥36 breaths/min, or peak flow measured by peak flowmeter <400 ml after bronchodilator inhalant (albuterol or metaproterenol sulfate by spacer) at a dose of up to six puffs. One minute after injections of thallium-201, patients at risk were given 50 mg aminophylline by slow intravenous injection. We looked for major and minor adverse effects and divided them into three categories: (1) minor events (transient headache, abdominal discomfort, or nausea), wheezing (audible by stethoscope but without marked respiratory distress), (2) marked events (severe bronchospasm or severe ischemia defined as wheezing audible with or without stethoscope, respiratory rate >20 breaths/min or increased by 10 from pretest evaluation, oxygen desaturation to <90%, hypoventilation [reduced respiratory rate with decreased mental status], respiratory arrest, chest pain, horizontal ST-segment depression ≥1 mm on the electrocardiogram in any lead, symptomatic hypotension), or (3) other intravenous dipyridamole-induced side effects (persistent headache, dizziness, flushing, nausea, dyspnea, and ischemic chest pain) or anginal equivalent. The protocol properly identified patients with impaired pulmonary function. There was no difference in the frequency of adverse marked events among groups A, B, or C (1% vs 4% vs 2%, p = 0.25). Patients in group A had more minor side effects than those in group B (53% vs 35%, p = 0.004). Specifically, patients in group A were more likely to wheeze (39% vs 1%, p = <0.001), but wheezing in group A was self-limited or responded to treatment as described in the protocol. The prevalence of positive thallium-201 scans in group A (44%) compared with group C (49%) was not different (p = 0.15).
Conclusions A nurse-administered risk assessment and pretreatment protocol (1) properly identified patients with impaired pulmonary function, (2) permitted completion of intravenous dipyridamole testing in patients at risk for bronchospasm without an increased incidence of marked adverse events, and (3) did not appear to influence the interpretation of the thallium test. (Am Heart J 1998;136:307-13.)
Dipyridamole-thallium versus dobutamine echocardiographic stress testing: A clinician's viewpoint
1995, American Heart JournalSafety of dipyridamole testing in patients with cerebrovascular disease
1995, The American Journal of CardiologySevere undiagnosed coronary artery disease is a major cause of morbidity and mortality in patients with carotid stenoses.22,23 Our study demonstrates that dipyridamole testing carries a very low risk of neurologic complications in patients with cerebrovascular disease.
Safety of dipyridamole testing in 73,806 patients: The Multicenter Dipyridamole Safety Study
1995, Journal of Nuclear CardiologyBackground Dipyridamole imaging is widely used as an alternative to exercise testing to identify and risk stratify patients with coronary artery disease. Safety data on intravenous dipyridamole stress testing has been derived largely from individual institutional data.
Methods and Results Data were collected retrospectively by 85 coinvestigators from 73,806 patients who underwent intravenous dipyridamole stress imaging in 59 hospitals and 19 countries to determine the incidence of major adverse reactions during testing. The dose of dipyridamole infused was 0.56 mg/kg in 64,740 patients, 0.74 mg/kg in 6551 patients, and 0.84 mg/kg in 2515 patients. Combined major adverse events among the entire 73,806 patients included seven cardiac deaths (0.95 per 10,000), 13 nonfatal myocardial infarctions (1.76 per 10,000), six nonfatal sustained ventricular arrhythmias (0.81 per 10,000) (ventricular tachycardia in two and ventricular fibrillation in four), nine transient cerebral ischemic attacks (1.22 per 10,000), (with speech or motor deficit), one stroke, and nine severe bronchospasms (1.22 per 10,000) (one intubation and eight near intubations). In addition to the safety data, detailed demographic, peripheral hemodynamic, side effect, and concomitant drug data were examined in a subgroup of 3751 patients. End points from subsets of patients were compared with those of the group as a whole. Multivariate analysis revealed that dipyridamole-induced chest pain was more common in patients less than 70 years old (p=0.0017), those with a history of coronary revascularization (p=0.002), or patients taking aspirin (p=0.0001). Minor noncardiac side effects were less frequent among the elderly (p=0.0053) and more frequent in women (p=0.0001) and patients taking maintenance aspirin (p=0.0034). When a patient was judged on the basis of the adequacy of hemodynamic response to be a dipyridamole “nonresponder” (<10 mm Hg drop in systolic blood pressure and 10 beats/min increase in heart rate), the only significant predictor was angiotensin-converting enzyme inhibitor intake (p=0.0025). Inferoposterior hypoperfusion was significantly more frequent in patients with dipyridamole-induced hypotension: 57% (44/77) (p<0.0001) of those who had hypotension and 89% (8/9) (p=0.0076) who had severe symptomatic bradyarrhythmias displayed inferoposterior defects on thallium scanning. Caffeine levels were determined in 391 consecutive patients: levels greater than 5 mg/L were observed in only eight patients (2%), suggesting that methylxanthine levels sufficient to alter the hemodynamic response to dipyridamole resulting in suboptimal hyperemic stress are unlikely when patients take nothing by mouth after midnight.
Conclusion The risk of serious dipyridamole-induced side effects is very low and is comparable to that reported for exercise testing in a similar patient population.