Cardiac stress testing is a keystone in the evaluation of patients with increased cardiac risk undergoing non-cardiac surgery. Dobutamine stress echocardiography is one of the recommended tests for this purpose [1,2]. The diagnostic power of dobutamine stress echocardiography has been demonstrated , and its safety has been shown in awake  and anaesthetized patients [5,6]. Detection of ischaemia by dobutamine stress echocardiography is based on echocardiographic analysis of new segmental wall motion abnormalities (SWMA) that provides a sensitivity rate of 75-95% [7,8] compared with the sensitivity rate of 42-67% [7,9] for ST-segment analysis by 12-lead electrocardiography (ECG). However, analysis of SWMA also has important limitations: (a) it is not quantitative, thereby reducing its reproducibility; (b) multiple views have to be analysed for accurate evaluation , making this a time-consuming process; (c) minor ischaemic areas may be missed even if multiple cross-sections are monitored ; and (d) regional wall motion abnormalities may have a non-ischaemic aetiology .
In contrast, Doppler studies of diastolic transmitral flow velocity can be easily performed in a quantitative manner using a single echocardiographic view. Changes in these indices have been shown to be highly sensitive for detection of myocardial ischaemia in awake patients both during coronary angioplasty  and dobutamine stress echocardiography . However, these findings have been questioned by two recent studies [14,15], and the diagnostic accuracy of these indices in the intraoperative setting is completely unknown.
The relative diagnostic value of Doppler studies of diastolic transmitral flow velocity compared with monitoring of segmental wall motion and ECG has not been evaluated during dobutamine stress echocardiography in anaesthetized patients. The diagnostic value of these Doppler variables might differ between awake and anaesthetized patients because general anaesthesia affects the integrative circulatory control of the organism and markedly alters the circulatory response to sympathomimetic drugs . The purpose of the present study was to evaluate the diagnostic value of diastolic transmitral flow velocity for detection of myocardial ischaemia in anaesthetized patients during dobutamine stress echocardiography.
The study protocol was approved by the Institutional Review Board of the Basel University Hospital, and written informed consent was obtained from each of the 72 study patients. All patients had severe (≥70% stenosis) coronary artery disease (CAD) and subsequently underwent coronary artery bypass graft (CABG) surgery. All patients had preserved left ventricular function (ejection fraction > 40%) and no valvular heart disease. Anti-ischaemic medication (Table 1) was not discontinued.
Dobutamine stress echocardiography
Each dobutamine stress echocardiogram was performed immediately before surgery during general anaesthesia as soon as central venous access had been achieved. Anaesthesia was induced with thiopental (3-5 mg kg−1) or etomidate (0.2-0.3 mg kg−1), fentanyl (2-4 μg kg−1), and muscle relaxation facilitated by pancuronium (0.1 mg kg−1). Anaesthesia was maintained with flunitrazepam (0.02-0.06 mg kg−1) and isoflurane (0.4-0.6% end-expiratory concentration), and additional boluses of fentanyl (1-4 μg kg−1), as needed. Controlled mechanical ventilation of the lungs with 50% oxygen in air was provided to achieve normocapnia as indicated by continuous end-tidal CO2 monitoring and intermittent arterial blood-gas studies.
We previously described the details of the standardized dobutamine stress protocol . Briefly, dobutamine was infused for 3 min each at 10, 20 and 40 μg kg−1 min−1. Atropine 1 mg intravenously (i.v.) was given if dobutamine alone did not increase the heart rate to the age-adjusted maximum or induce >0.1 mV ST-segment depression or new segmental wall-motion abnormalities.
Synchronized recordings of 12-lead ECG, two-dimensional transoesophageal echocardiography (TOE) and haemodynamic variables were performed immediately before dobutamine administration (baseline), at the end of each infusion rate, and at 5 and 10 min after discontinuation of dobutamine administration. TOE (Sonos 2500® and biplane or omniplane 5 MHz probe; Hewlett Packard, Andover, MA, USA) included transgastric mid-papillary short-axis and mid-oesophageal four- and two-chamber views. The images were registered at end-expiration. However, a small number of loops were acquired during inspiration because of inadequate image quality during expiration. Haemodynamic recordings (PCMS Workstation 19845-15-03®; Spacelabs, Inc, Chatsworth, CA, USA) included systemic arterial and central venous pressures.
The pulsed-wave Doppler studies of diastolic transmitral flow velocity were performed immediately before dobutamine infusion, at peak infusion rate, and 10 min after discontinuation of dobutamine administration, and were recorded on S-VHS tape at end-expiration. The sampling volume was placed at the tips of the opened mitral leaflets.
Off-line analyses of both ECG and two-dimensional TOE recordings were performed by two independent investigators who were blinded to all other patient data during each analysis. Discrepancies between the two readers were handled by consensus reading, and consensus readings were either confirmed by an independent third reader or excluded from the analysis. The analysis system and reproducibility of the wall-motion readings by the two readers have been described in detail [6,17]. In short, echocardiographic evidence of myocardial ischaemia was defined as a worsening in segmental motion and thickening by at least one class on a five-grade scale  during increasing dobutamine dose or as a biphasic response [6,19]. Electrocardiographic evidence of ischaemia was defined as >0.1 mV horizontal or downsloping ST-segment depression or horizontal ST-segment elevation at 60 ms after the J-point. Echocardiographic and/or ECG evidence of ischaemia were used to define the dobutamine stress echocardiographic study as positive or negative.
Based on the mid-papillary short-axis cross-section, end-diastolic and -systolic areas, as well as fractional area change, were determined as described .
Pulsed-wave Doppler recordings of diastolic transmitral flow velocity were evaluated off-line by an experienced reader who used a Sonos 2500® computer (Hewlett Packard). For determination of interobserver variability, a second reader evaluated 26% of the Doppler recordings. At each study point, the maximal velocity envelopes of three consecutive cardiac cycles were traced and the results averaged. The following Doppler-derived indices of LV filling were measured: peak early filling velocity (E), peak atrial filling velocity (A), E/A ratio, average E wave acceleration rate (Eacc, determined by dividing peak E by the time from onset of the flow to peak E), average E wave deceleration rate (Edec, determined by dividing peak E by the time from onset of the flow to an extrapolation of the deceleration slope to the baseline), and total diastolic time-velocity integral (TVID).
Subsequently, these Doppler derived indices of transmitral flow velocity were evaluated for their diagnostic power of detecting myocardial ischaemia in anaesthetized patients during dobutamine stress echocardiography. According to El Said and colleagues , the changes of the following variables from baseline to peak dobutamine were regarded as suggestive for detecting ischaemia: decreases in E, in E/A ratio, in Eacc and in TVID.
All statistical analyses were performed by using StatView 5.0® computer package (SAS Institute, Inc, Cary, NC, USA). Fisher's exact test analysed dichotomous variables. The Wilcoxon signed rank sum test analysed paired continuous variables, and the U-test analysed unpaired continuous variables. P < 0.05 was considered as significant. Continuous variables are reported as median ± SD.
Sixty-five of the 72 patients showed evidence of ischaemia during dobutamine stress echocardiography by standard echocardiographic or ECG criteria, or both, and seven patients did not. Patients with positive dobutamine stress echocardiography were slightly older than those with negative results. All other patient characteristics (Table 1), and the type and dosage of anaesthetics used were similar.
Wall motion analysis and ST-segment changes
In seven patients, dobutamine stress echocardiography was considered negative because neither new SWMA nor ST-segment changes were observed. In 65 patients, dobutamine stress echocardiography was considered positive: 49 patients had new SWMA and 43 had ST-segment changes. In 22 patients, new SWMA were observed in the absence of ST-segment changes, and in 16 patients ST-segment changes in the absence of new SWMA. In 27 patients, both ST-segment changes and new SWMA were observed.
In all patients, heart rate and blood pressure increased significantly from baseline to peak dobutamine stress, and right atrial pressure remained unchanged (Table 2).
Doppler transmitral flow variables
Fusion of E and A waves occurred during peak dobutamine administration in eight patients, making analysis of transmitral flow variables unfeasible. Three of these patients had new SWMA, two had ST-segment changes and three patients had both. Medians of the Doppler indices of the remaining 64 patients are given in Table 3. Independent of whether dobutamine stress echocardiography was found to be positive or negative by standard criteria, the Doppler indices changed similarly and in the same direction in both groups: A, Eacc and Edec increased, and the E/A ratio decreased significantly, whereas, TVID remained unchanged, and E had only slight tendency to increase. Accordingly, there was no statistically significant difference between the patients with positive or negative dobutamine stress echocardiography. Analyses of Doppler variables within each patient are shown in Figure 1.
The interobserver variability ranged from 6% for peak velocity measurements to 16% for Edec measurements at peak dobutamine dose. Inter-reader agreement for increase or decrease of the analysed Doppler indices was 100%.
Our study, performed with anaesthetized patients during intermittent positive pressure ventilation of the lungs, questioned the diagnostic value of transmitral Doppler flow velocity indices that were previously suggested to be highly sensitive for detecting ischaemia during dobutamine stress echocardiography in awake patients . A previous study  had used a similar dobutamine stress echocardiography protocol in 23 patients with documented coronary artery disease and in 10 healthy control subjects. In all patients with coronary artery disease, E and Eacc decreased during dobutamine stress echocardiography, and in all control subjects, E and Eacc increased. TVID decreased in 21 of 23 (91%) of patients and increased in six of 10 (69%) of the control subjects .
Our findings in anaesthetized patients were completely different: in the 57 patients with standard evidence of ischaemia during dobutamine stress echocardiography and without fusion of E and A waves, E decreased in only 25 (44%), Eacc decreased in 13 (23%) and TVID decreased in 30 (53%) of our patients. Similar changes in these indices were found at a comparable incidence in the seven patients with documented coronary atrery disease but without any standard evidence of ischaemia during dobutamine stress echocardiography (Fig. 1).
The potential reasons for the different findings in our study and in El Said and colleagues  are a failure to induce ischaemia in the present study, different degrees of coronary artery disease, specific effects of β-adrenoceptor-blocking drugs, specific effects of general anaesthesia or intermittent positive-pressure ventilation, a biphasic response of the Doppler criteria to ischaemia or the unreliability of changes in transmitral Doppler flow velocity indices as indicators of myocardial ischaemia during dobutamine stress echocardiography.
Failure to induce ischaemia in our study might have occurred because our patients were anaesthetized with isoflurane, which has been shown to provide some protection from myocardial ischaemia [20,21]. However, most patients (90%) fulfilled established echocardiographic or ECG criteria for ischaemia, confirming the presence of myocardial ischaemia. The different degree of coronary artery disease in the previous  and the present study also is an unlikely explanation because our patients had more severe multivessel disease compared with single-vessel disease. Another factor that may have influenced the findings in the present study is ongoing medication with β-adrenoceptor-blocking drugs. However, such medication does not explain the difference between the two studies because nearly half of the patients in the previous study were also treated with these drugs .
The use of general anaesthesia might explain the difference in the findings of the two studies. General anaesthesia markedly alters the circulatory response to dobutamine , and was only used in the patients of the present study. This might explain why diastolic transmitral flow velocity in the present study were completely different during dobutamine stress echocardiography from those previously observed by El Said and colleagues in awake patients . The use of intermittent positive-pressure ventilation of the lungs is another difference between this study and previous investigations. This fact may have caused some differences in the baseline findings between the present study and previous studies. However, an effect of ventilation on our findings is unlikely because baseline measurements and measurements during dobutamine administration were both obtained during stable intermittent positive pressure ventilation in patients who were each their own control (Fig. 1). A biphasic response of transmitral Doppler flow velocity indices, i.e. typical changes in the indices occurring at low dobutamine doses but disappearing at high dose, cannot be completely ruled out from our data. However, such a phenomenon that lasts for only a short period and disappears despite ongoingischaemia would not be clinically useful.
The general value of transmitral Doppler flow velocity indices for detection of ischaemia during dobutamine stress echocardiography was also questioned by two recent studies [14,15] that failed to confirm the findings of El Said and colleagues . Taking all of the above into consideration, the present study in anaesthetized patients and the recent studies in awake patients do not support the usefulness of transmitral flow velocity indices as indicators of ischaemia during dobutamine stress echocardiography, regardless of whether the patients are anaesthetized or awake. Likely reasons are that dobutamine directly influences diastolic relaxation  and alters factors that determine diastolic transmitral flow velocity, such as preload , afterload  and heart rate .
Other Doppler echocardiographic indicators of diastolic function have been suggested to be less dependent on loading conditions and heart rate, e.g. tissue-Doppler imaging of the mitral annulus , or colour-Doppler M-mode propagation of mitral inflow . Because changes in loading conditions and heart rate commonly occur during major surgery, these parameters might be more useful and their diagnostic value for detecting myocardial ischaemia during surgery and dobutamine stress echocardiography should be evaluated in patients at high cardiac risk.
However, it should be noted that the findings of the present study may not apply to situations with supply ischaemia because only demand ischaemia (dobutamine-induced rise in myocardial oxygen consumption) was studied. Accordingly, it is unknown whether the investigated indices are sensitive to ischaemia in anaesthetized patients when dobutamine is administered at clinically used doses (≤10 μg kg−1 min−1), or in the absence of dobutamine administration.
In conclusion, the present study questions whether Doppler-derived indices of diastolic transmitral flow velocity, previously suggested as diagnostic of ischaemia in awake patients, are of diagnostic value in anaesthetized patients who undergo dobutamine stress echocardiography during intermittent positive-pressure ventilation of the lungs. The present results most likely reflect effects of dobutamine both directly on diastolic relaxation and indirectly on factors that determine transmitral flow velocity, such as preload, afterload and heart rate.
Supported in part by a grant from the International Anesthesia Research Society. The authors thank Joan Etlinger for editorial assistance.
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