Early Atropine Protocol Enhances Dobutamine Stress Echocardiography in End-Stage Liver Disease: A Practical Cardiac Risk Stratification Tool Before Liver Transplantation

Introduction

Nearly half of end-stage liver disease (ESLD) patients who are candidates for liver transplantation (LT) experience cardiovascular conditions such as heart failure, coronary artery disease, cardiomyopathies, and arrhythmias [1,2]. Cardiovascular events are now the leading extra-hepatic cause of early morbidity and mortality after LT; large-cohort studies report perioperative cardiovascular complications in 20–30% of recipients and a 30-day cardiovascular mortality rate of 3–8%. These findings underscore the need for an accurate and well-tolerated preoperative cardiac assessment [3–5].

Dobutamine stress echocardiography (DSE) is the recommended method for detecting latent coronary artery disease in ESLD patients, as stated in LT guidelines [6]. Although studies reported a sensitivity range of 13% to 100%, DSE remains widely used due to the limited exercise capacity of this patient group [7]. Studies investigating DSE efficacy frequently highlight chronotropic incompetence, which prevents patients from reaching the target HR, as a major factor contributing to variations in sensitivity rates [8].

This study evaluated the efficacy and adverse effect profile of early atropine administration during DSE in preoperative cardiac assessment of LT recipients.

Material and Methods

We retrospectively studied 69 ESLD patients who underwent DSE between 2020 and 2025 and classified them into 3 groups. Group 1 (n: 24) included patients who achieved the target HR with 40 μg/kg/min dobutamine alone, Group 2 (n: 22) included those who required 40 μg/kg/min dobutamine +1 mg atropine, and Group 3 (n: 23) included patients who received 30 μg/kg/min dobutamine +1 mg atropine (Figure 1). Patients were referred for DSE prior to LT due to the presence of more than 2 classical risk factors for coronary artery disease (CAD). Eligible patients were aged ≥18 years, reached at least 80% of their age-predicted maximal HR during the examination, and had Doppler-derived stroke volume data in the final DSE report that allowed calculation of contractile reserve (CR). Ethics approval was obtained from the Ethics Committee for Medical Research of Demiroğlu Bilim University, with the decision dated November 27, 2024, and numbered 51016662/43342.

Exclusion criteria were hemodynamic instability, unstable angina, recent myocardial infarction, submaximal test results, CR <20% (defined as the absence of an increase in stroke volume above baseline), and inability to assess more than 2 myocardial segments on transthoracic echocardiography. Chronotropic incompetence was defined as failure to reach ≥80% of the age-predicted maximal HR (220 – age) during the dobutamine stage before atropine administration. All negative chronotropic agents (β-blockers, verapamil, diltiazem) were routinely withheld 48 h before DSE in accordance with guideline recommendations.

This was a purely retrospective, observational study evaluating 100 DSE performed in our center. Intravenous dobutamine infusion was initiated at 10 μg/kg/min for 3 minutes and progressively increased to 20 and 30 μg/kg/min every 3 minutes, with a maximum dose of 40 μg/kg/min, until patients reached at least 80% of the target HR. In patients who did not achieve the target HR, 1 mg atropine was administered. During routine practice, attending cardiologists could elect to administer atropine at the end of the 3-minute 30 μg/kg/min stage or at the end of the 3-minute 40 μg/kg/min stage, guided by slow HR increase or patient symptoms (nausea, dyspnea). According to our clinical practice, patients who had a HR <70 bpm despite 3 minutes of 20 μg/kg/min dobutamine infusion or a failure to achieve at least a 10% increase from baseline received early atropine (1 mg) after reaching 30 μg/kg/min dobutamine infusion. At each stage, electrocardiogram (ECG), blood pressure, LVEF, presence of wall motion abnormalities, stroke volume, left ventricular outflow tract (LVOT) or intraventricular gradient presence, and symptoms were recorded. CR was also calculated after peak stress was achieved. The research team retrospectively abstracted the final DSE reports to determine the actual atropine dose used.

The following were specified as endpoints: achievement of the target HR on maximum dobutamine and atropine doses, development of severe or extensive wall motion abnormalities, ST-segment changes on ECG, sustained arrhythmias, severe angina, severe hypertension (≥230/120 mmHg), or intolerable adverse effects. Hypotension was defined as a systolic blood pressure <90 mmHg or a ≥20% drop from baseline.

Continuous variables were tested for normality using the Kolmogorov-Smirnov test. Normally-distributed variables were compared using one-way analysis of variance (ANOVA) and are presented as mean±standard deviation (SD). Categorical variables were compared using the chi-square test, and results are reported as percentages and counts. When sample sizes were small or chi-square assumptions were not met, Fisher’s exact test was applied for categorical variables. For pairwise comparisons, post hoc analysis was performed using the Mann-Whitney U test for continuous variables and Fisher’s exact test for categorical variables. For binary outcomes (eg, target HR achievement, hypotension), 95% confidence intervals (CIs) were calculated with the Wilson score method; CIs for continuous variables were derived from the t test result distribution. A P value <0.05 was considered statistically significant. All statistical analyses were performed using SPSS 29.0. An a priori power analysis for the primary safety outcome (hypotension) was performed with G-Power 3.1 (α=0.05, power=0.80). Detecting a 31% absolute risk reduction (41%→10%) between the standard and early-atropine arms required ≈60 patients in total (≈30 per comparison group). The retrospective cohort ultimately comprised 45 such patients (standard, n=22; early atropine, n=23) within an overall sample of 69. A post hoc calculation with the observed event rates still yielded 72% power, which we deemed acceptable for this exploratory study.

Results

LIMITATION:

This study is constrained by 3 principal limitations. First, it is a retrospective, single-center series with a modest sample size, so causal inference is limited, and larger prospective cohorts are needed to confirm the effect size. Second, although our center followed a guideline whereby patients who failed to raise HR above 70 bpm, or by at least 10%, after 3 minutes at 20 μg/kg/min, received atropine at the 30 μg/kg/min stage, the ultimate choice between early and late atropine still rested with the operator, leaving room for selection bias that only a randomized protocol can eliminate. Third, coronary angiography was performed only in DSE-positive patients, precluding evaluation of false-negative studies and long-term prognostic impact. A multicenter randomized trial with protocol-mandated atropine timing and systematic coronary imaging of both positive and negative DSE cases would address these gaps and clarify the generalizability of our findings.

Discussion

It is now clear that LT recipients experience a high rate of cardiovascular symptoms in the perioperative period. The most common cardiac complications include coronary artery disease (CAD), cirrhotic cardiomyopathy, and arrhythmias [9]. DM, a history of CAD, or peripheral artery disease, and non-alcoholic fatty liver disease (NASH) are considered high-risk criteria for CAD, while hypertension, hyperlipidemia, male sex, age over 50, smoking, and obesity are classic risk factors. Studies recommend stress testing for patients with either 1 high-risk criterion or 2 or more traditional risk factors [10]. However, because this fragile patient group has limited exercise capacity and often experiences dyspnea even with minimal exertion, exercise stress tests are often non-diagnostic. Alternative tests such as DSE, myocardial perfusion scintigraphy (MPS), or computed tomography- coronary angiography (CT-CAG) are generally more suitable for these patients. However, the frequent presence of clinical conditions like renal impairment and volume overload in this population makes CT-CAG, which requires contrast agents, a less preferred option. Although MPS has comparable sensitivity to DSE, DSE is more commonly preferred due to its higher specificity [11]. Additionally, studies show that clinical conditions such as MINOCA, endothelial dysfunction, and coronary vasospasm, which can lead to false-positive DSE results, are also closely associated with adverse cardiac events in ESLD patients [12].

The biggest challenge in assessing the effectiveness of DSE in this patient group is the difficulty of reaching target HR due to chronotropic incompetence. Despite increased sympathetic nervous system activity, the lack of an expected HR response to beta-agonists, exercise, or physical and mental stress suggests a receptor-level dysfunction, indicating that chronotropic incompetence is essentially a form of autonomic neuropathy. Studies have shown that ESLD patients require 3 times the isoproterenol dose as do healthy individuals to achieve a 25 bpm increase in HR [13]. Due to chronotropic incompetence, reaching the diagnostic target HR with DSE becomes challenging [14,15]. Even when the target HR is achieved, the procedure tends to take significantly longer, and the use of high medication doses increases the likelihood of palpitations, arrhythmias, and intolerable symptoms.

Studies have shown that in patients without liver failure, early administration of atropine (20 μg/kg/min or 30 μg/kg/min) during DSE shortens the procedure time and improves patient tolerance [16]. In our study, we compared LT preoperative assessment patients who achieved their target HR with 40 μg/kg/min dobutamine alone, those who required 1 mg iv atropine after failing to reach the target HR despite maximum dobutamine dosing, and those who received 1 mg iv atropine at 30 μg/kg/min dobutamine instead of increasing the dose to 40 μg/kg/min due to inadequate HR response at 20 μg/kg/min dobutamine.

Since CR, defined as the absence of a ≥20% increase in stroke volume above baseline, is a strong parameter for ruling out cirrhotic cardiomyopathy, only patients with CR ≥20% were included in our study [17,18]. We demonstrated that early atropine administration during DSE in ESLD patients improved test tolerance by reducing palpitations and nausea symptoms. Although all 3 groups achieved their target HR, the maximum HR reached in the early atropine group was significantly higher than in the other 2 groups, suggesting an improvement in DSE efficiency.

Additionally, the lower incidence of termination criteria such as hypotension and VES in the early atropine group further supports the increased effectiveness of DSE. Early atropine counteracts the hemodynamic problems that accumulate with prolonged high-dose dobutamine. Administering 1 mg atropine at 20–30 μg/kg/min accelerates HR rise, so the infusion can stop sooner. This timing prevents the peripheral vasodilation and catecholamine-driven ventricular irritability seen at higher dobutamine doses. Camarozano et al showed that this strategy lowers the double-product while keeping the parasympathetic blockade constant, thereby reducing myocardial oxygen demand despite a higher peak HR [19]. Two independent clinical series, 1 randomized and 1 observational, showed that shortening dobutamine exposure with early atropine reduced hypotension by roughly half, cut ventricular ectopy by 60%, and lowered mean infusion requirements by nearly 40%, all without inducing additional arrhythmias [20,21]. Tsutsui and colleagues later demonstrated a similar 48% reduction in hypotension and linked it to a smoother, ‘stepped’ HR curve that avoids the late, steep surge in rate-pressure product seen with conventional protocols [22]. Considered together, these data support the concept that earlier parasympathetic blockade produces a briefer, more balanced inotropic-chronotropic stimulus, which limits arrhythmogenesis and reflex vasodilatation without sacrificing diagnostic yield, a pattern replicated in our liver-transplant cohort. In ESLD patients, who have circulating metabolic byproducts, shortening the procedure time also reduces overall dobutamine exposure, which is a clear benefit. By halving overall dobutamine exposure, the early-atropine strategy may lessen β-adrenergic adverse effects, reduce drug cost, and further enhance patient tolerability. These performance gains translate into tangible clinical value; shorter lab occupancy, improved patient comfort, and potentially lower peri-procedural cost without any extra equipment. Given that ESLD candidates are notoriously fragile, a protocol that both accelerates DSE and reduces its procedural risk may help transplant programs clear cardiac work-ups sooner and reduce wait-list attrition. Because atropine is inexpensive and globally available, implementation barriers are minimal, supporting immediate scalability across diverse healthcare settings.

Recent literature continues to support protocol refinements that shorten dobutamine exposure while maintaining diagnostic integrity. A 2023 comprehensive review of DSE complications reported that early atropine strategies are consistently associated with the lowest rates of hypotension and rhythm disturbances across pharmacologic modalities [23]. Parallel work in cirrhotic populations has confirmed that chronotropic incompetence is highly prevalent in ESLD and may be mitigated by tailored chronotropic augmentation [24]. Most recently, an expert consensus review on stress echocardiography in heart failure patients emphasized early atropine as a practical means to limit β-adrenergic load and reduce test time without sacrificing ischemia detection [25]. The proportion of positive cases was 13% in both early and late atropine groups, compared with 21% in the dobutamine-only arm. This similarity indicates that advancing atropine did not mask inducible ischemia; however, a prospective study with systematic angiography is required to confirm diagnostic sensitivity. Together with the present data, these contemporary findings strengthen the case for adopting an early-atropine protocol whenever chronotropic inadequacy is anticipated.

Conclusions

In LT recipients, early atropine administration during DSE increases the maximum achieved HR, shortens procedure duration, and significantly reduces findings such as hypotension and ventricular extrasystoles, as well as patient symptoms.