Background
The aim of this study was to investigate the incidence and predictors of neuropsychiatric (NP) symptoms during 24 hours after dobutamine-atropine stress testing (DST).
Methods
Consecutive outpatients undergoing DST were asked to return a questionnaire regarding symptoms during the following 24 hours. Trained registered nurses administered the Delirium Observation Screening Scale before and after DST. To assess baseline symptoms in a control group, consecutive patients referred for DST completed the questionnaire regarding their symptoms during the 24 hours before DST.
Results
A total of 1,006 patients were included (mean age, 67 ± 12 years; 462 [46%] women). Of the 750 patients who returned questionnaires, 53 patients (7.1%) reported NP symptoms. Among the 199 controls, three patients (1.5%) reported NP symptoms. Symptoms were usually mild and resolved spontaneously. Independent predictors of NP symptoms were atropine dose ≥ 1 mg (odds ratio [OR], 7.69; 95% confidence interval [CI], 4.13–14.81), prior NP disorder (OR, 2.11; 95% CI, 1.11–4.02), positive Delirium Observation Screening Scale result (OR, 4.89; 95% CI, 1.21–18.09), and body mass index < 24 kg/m 2 (OR, 2.37; 95% CI, 1.10–4.90).
Conclusions
Although usually mild, NP symptoms were nearly fivefold more common after DST ( P < .001). Patients who had received ≥ 1 mg atropine and those with underlying NP disease, positive Delirium Observation Screening Scale results, or lower body mass indexes are at increased risk.
Dobutamine-atropine stress testing (DST) is widely accepted as a standard diagnostic stress test for coronary artery disease and is used with multiple cardiac imaging modalities, including stress echocardiography, nuclear perfusion imaging, and cardiac magnetic resonance imaging. Major complications such as death, myocardial infarction, and life-threatening cardiac arrhythmias are rare.
We have occasionally received reports from our patients regarding the occurrence of neuropsychiatric (NP) symptoms, such as confusion, amnesia, and disorientation, following DST. These symptoms have previously been reported as rare noncardiac complications during DST. Atropine, commonly used in conjunction with dobutamine to further augment the heart rate during DST, has been implicated as a cause of these complications because of its anticholinergic effects. However, NP symptoms after DST have also been reported in patients who did not receive atropine. Until now, no systematic study has been undertaken to evaluate patients’ symptoms during 24 hours after DST.
In this study, we sought to determine the incidence of NP symptoms during the first 24 hours after DST. Additionally, we evaluated the predictors of these symptoms and the utility of two well validated screening questionnaires, the Short Portable Mental Status Questionnaire (SPMSQ) and the Delirium Observation Screening Scale (DOSS), to identify patients at risk.
Methods
Patients
Consecutive outpatients referred for clinically indicated dobutamine stress echocardiography at our institution were considered for participation. We excluded patients who had difficulty communicating and hearing, including patients with aphasia or deafness, non-English-speaking patients, and patients who were unwilling or unable to participate in the study. Written informed consent was obtained.
Study Design
The study was approved by the institutional review board. Trained registered nurses administered the two screening questionnaires before and after DST. At the conclusion of testing, patients were provided with a one-page questionnaire regarding their symptoms during the 24 hours following DST and asked to return this by mail. To assess baseline symptoms in a control group, 200 consecutive patients referred for DST completed the one-page questionnaire regarding their symptoms during the 24 hours before their scheduled DST; additionally, their medical records were reviewed to determine if any sought medical attention at our institution for NP symptoms during the subsequent 24 hours. One of these did not complete a Health Insurance Portability and Accountability Act authorization form; data from the remaining 199 patients were included. Patients’ symptoms during DST and clinical data, including comorbidities and medications, were prospectively recorded at the time of DST. Underlying NP disorders, including history of delirium, depression, other mental illness, migraine, and cognitive dysfunction, were recorded from review of the medical records. Anticholinergic Risk Scale score, a ranking of anticholinergic potential of commonly prescribed medications that has been reported to relate to anticholinergic symptoms including confusion, was also determined.
Dobutamine Stress Testing
DST was performed according to a standard protocol using a graded dobutamine infusion starting at 5 μg/kg/min and increasing in 3-minute intervals to 10, 20, 30, and 40 μg/kg/min. Atropine, in divided doses of 0.25 to 0.5 mg to a total of 2.0 mg, was used as needed to achieve target heart rate. Standard test end points included the achievement of 85% of the age-predicted maximal heart rate, new or worsening wall motion abnormalities of moderate degree, significant arrhythmias, hypotension, severe hypertension, and intolerable symptoms.
Short Mental Status Assessments
The SPMSQ is a 10-item questionnaire for the assessment of cognitive function, including acute confusional state (delirium), dementia, and memory deficit. It is adjusted by patient’s education and has good validity and reliability. This test is considered to be quick and easy to administer and is commonly administered by nurses. SPMSQ score > 2 was considered to be a positive test indicating impaired cognitive function.
The DOSS is a well-validated screening test for delirium with previously reported sensitivity of 89% to 94% and specificity of 76% to 86%. The sensitivity and specificity are comparable with those of other well-known screening scales, but the DOSS is easier and quicker to administer. The 13-item test was applied in our study and administered by a nurse after the SPMSQ. A score ≥ 3 points indicates acute confusional state.
24-Hour Follow-Up Questionnaire
This included questions about the occurrence and details of NP symptoms as well as minor complications, such as headache, dizziness, nausea, vomiting, dry mouth, and difficulty with urination, during the first 24 hours after DST. Patients were provided with a self-addressed, stamped envelope in which to return the questionnaire at the end of the 24-hour time period.
Definition of NP Symptoms
NP symptoms included amnesic symptoms (memory impairment or forgetfulness), confusion, disorientation, restlessness, difficulty speaking, including dysarthria and incoherence of speech, disequilibrium, falls, and symptoms consistent with transient ischemic attack or stroke.
Statistical Analysis
All analyses were carried out using JMP version 7.01 for windows (SAS Institute Inc., Cary, NC). Data are presented as mean ± SD for continuous variables and as frequency (percentage) for categorical variables. Patients who did not return the questionnaires were compared with those who did using two-sample t tests for continuous variables and χ 2 tests for categorical variables. Clinical characteristics and self-reported NP symptoms were compared for the control group and for the patients who completed the study. The association of potential predictors with NP symptoms was assessed using univariate logistic regression models. Variables showing significant univariate associations ( P < .05) with NP symptoms were then included in a multivariate logistic regression model. In the case of closely related variables such as peak dobutamine dose (micrograms per kilogram per minute) and total dobutamine use (milligrams), only one variable (the most significant univariate association) was included in multivariate modeling to avoid multicollinearity. Results are reported as odds ratios (ORs) with 95% confidence intervals (CIs).
Results
One thousand two hundred sixty-six consecutive patients were considered for participation in our study. Of these, 191 patients declined participation, and 69 were not eligible because they had difficulty in communicating. The remaining 1,006 patients participated in the study. The mean age of the study population was 67 ± 12 years, and 462 (46%) were women. The peak dose of dobutamine was 35 ± 7 μg/kg/min, and 627 (62%) patients received atropine. The 199 patients in the control group had a mean age of 66 ± 12 years and included 87 women (44%). Demographic and clinical data of patients and controls are given in Table 1 . None developed major cardiovascular complications such as death, myocardial infarction, or life-threatening cardiac arrhythmias.
| Variable | Patients | Controls ∗ | P |
|---|---|---|---|
| Age (y) | 67 ± 12 | 66 ± 12 | .29 |
| Women | 462 (46%) | 87 (44%) | .54 |
| BMI (kg/m 2 ) | 30.4 ± 6.4 | 31.7 ± 6.9 | .02 |
| Peak dobutamine dose (μg/kg/min) | 35 ± 7 | 36 ± 7 | |
| Atropine administration | 627 (62%) | 111 (58%) | .21 |
| Education | |||
| Less than high school | 66 (7%) | 15 (8%) | |
| High school | 394 (39%) | 64 (35%) | |
| More than high school | 546 (54%) | 104 (57%) | |
| Indication for DST | <.001 | ||
| Evaluation of suspected CAD | 359 (36%) | 60 (30%) | |
| Evaluation of known CAD | 30 (3%) | 28 (14%) | |
| Preoperative evaluation | 615 (61%) | 111 (56%) | |
| Valvular heart disease | 2 (0.2%) | 0 (0%) | |
| Risk factors | |||
| Diabetes mellitus | 375 (37%) | 72 (37%) | .95 |
| Hypertension | 770 (77%) | 154 (80%) | .27 |
| Dyslipidemia | 690 (69%) | 139 (72%) | .30 |
| Current or past smoker | 611 (61%) | 117 (61%) | .96 |
| Family history of CAD | 535 (53%) | 60 (31%) | <.001 |
| Prior CAD | 288 (29%) | 53 (28%) | .80 |
| Medications | |||
| Aspirin | 543 (54%) | 109 (57%) | .48 |
| β-blocker | 538 (53%) | 113 (59%) | .17 |
| Calcium channel blocker | 270 (27%) | 59 (31%) | .27 |
| ACE inhibitors or ARBs | 448 (45%) | 79 (41%) | .39 |
| Statins | 492 (49%) | 114 (59%) | .01 |
| Symptoms during DST | |||
| Chest pain | 112 (11%) | 22 (11%) | .88 |
| Dyspnea | 54 (5%) | 10 (5%) | .94 |
| Headache | 91 (9%) | 14 (7%) | .44 |
| Lightheadedness | 50 (5%) | 15 (8%) | .11 |
| Nausea or vomiting | 69 (7%) | 16 (8%) | .45 |
∗ DST was completed in 193 controls and canceled or deferred in six because of abnormal findings on the rest images in four patients, reluctance to perform the test in one patient, and tachycardia in one patient.
Of these, 720 patients (72%) completed mental status assessments and returned the 24-hour follow-up questionnaires, 30 patients (3%) returned the questionnaires but did not complete the mental status assessments, and 256 (25%) patients completed mental status assessment but did not return the questionnaires. There were no significant differences in age, sex, indication for DST, peak dobutamine dose, and atropine use between the patients who did and did not complete the mental status assessment. The patients who returned the questionnaires ( n = 750) were older (mean age, 68 ± 11 vs 64 ± 14 years; P < .05), more often women (49% vs 37%, P < .05), and had a lower frequency of atropine use during DST (60% vs 68%, P < .05) compared with those who did not return the questionnaires ( n = 256).
Incidence of NP Symptoms
Of 750 patients who returned the follow-up questionnaires, 53 patients (7.1%) experienced NP symptoms. In patients with NP symptoms, the mean age was 69 ± 11 years (range, 38–89 years), 28 (53%) were women, and 42 (79%) had received atropine. NP symptoms included confusion in 45 patients, amnesia in three, restlessness in seven, difficulty in speaking in five, and disequilibrium in seven, including one patient who fell in the bathroom and another who sought evaluation at an emergency department and was diagnosed as having a transient ischemic attack. One patient experienced three of the above symptoms, 12 patients experienced two symptoms, and 40 patients experienced one symptom. Five patients (0.7%) sought medical attention for their NP symptoms. Of the 53 patents, 45 (84%) reported resolution within 24 hours after DST; eight patients did not specify the time of resolution of symptoms.
Comparison with Controls
Among the 199 controls, three patients (1.5%) reported NP symptoms (confusion in two and restlessness in one) during the 24 hours before DST. Thus, NP symptoms were nearly fivefold more common after DST ( P < .001). None of the controls sought medical attention at the Mayo Clinic for NP symptoms during the 24 hours after the scheduled DST.
Predictors of NP Symptoms
We analyzed the predictors of NP symptoms for 720 patients who had completed both the SPMSQ and the DOSS and also returned the follow-up questionnaire. Univariate associations with NP symptoms are shown in Table 2 . Body mass index (BMI) < 24 kg/m 2 , underlying NP disorders, β-blocker therapy, peak dobutamine dose, total dobutamine dose, use of atropine, atropine dose ≥ 1 mg, resting and peak stress heart rate, headache or lightheadedness during DST, duration of DST, and positive DOSS result before and after DST were univariately associated with the occurrence of NP symptoms after DST. Atropine use was associated with NP symptoms ( P = .002), but rates of NP symptoms in patients receiving a low dose of atropine (<1 mg) compared with patients receiving no atropine and compared with controls were similar ( P = .50 and P = .36, respectively). Patients receiving ≥1 mg, however, had a significantly higher rate of NP symptoms (19.54%) compared with those receiving low doses of atropine (2.78%, P < .0001), those not receiving atropine (3.83%, P < .0001), and controls (1.50%, P < .0001) ( Figure 1 ). Neither the use of anticholinergic drugs nor an Anticholinergic Risk Scale score ≥ 3 was associated with NP symptoms.
| Variable | Patients with NP symptoms ( n = 53) | Patients without NP symptoms ( n = 667) | OR (95% CI) | P ∗ |
|---|---|---|---|---|
| Age (y) | 68 ± 11 | 68 ± 12 | 1.01 (0.99–1.04) | .42 |
| Women | 52.8% | 49.2% | 1.16 (0.66–2.04) | .61 |
| Weight (kg) | 84.0 ± 19.1 | 88.6 ± 21.4 | 0.99 (0.98–1.00) | .13 |
| BMI (kg/m 2 ) | 29.0 ± 5.4 | 30.6 ± 6.5 | 0.96 (0.91–1.00) | .06 |
| BMI <24 kg/m 2 | 24.5% | 13.5% | 2.08 (1.04–3.95) | .04 † |
| Comorbidities | ||||
| Diabetes mellitus | 35.9% | 35.8% | 1.00 (0.55–1.77) | .99 |
| Hypertension | 75.5% | 77.2% | 0.91 (0.49–1.81) | .77 |
| Dyslipidemia | 69.8% | 67.3% | 1.12 (0.62–2.12) | .71 |
| Prior CAD | 24.5% | 27.4% | 0.86 (0.43–1.60) | .65 |
| History of TIA or stroke | 17.0% | 10.6% | 1.72 (0.76–3.51) | .18 |
| Atrial fibrillation | 15.1% | 9.2% | 1.77 (0.74–3.73) | .18 |
| Renal insufficiency | 32.1% | 24.0% | 1.50 (0.80–2.70) | .20 |
| Chronic liver disease | 7.6% | 4.4% | 1.80 (0.52–4.80) | .32 |
| NP disease | 43.4% | 28.0% | 1.97 (1.10–3.47) | .02 † |
| Medications | ||||
| Anticholinergic drugs | 30.2% | 26.5% | 1.20 (0.63–2.17) | .57 |
| Anticholinergic Risk Scale score ≥3 | 9.4% | 9.3% | 1.02 (0.34–2.42) | .97 |
| Insulin | 22.6% | 15.1% | 1.64 (0.80–3.14) | .17 |
| Statins | 54.7% | 48.4% | 1.29 (0.73–2.27) | .38 |
| β-blockers | 67.9% | 50.8% | 2.05 (1.15–3.81) | .02 † |
| Total number of medications | 8.4 ± 4.0 | 7.8 ± 4.0 | 1.04 (0.96–1.11) | .28 |
| DST parameters | ||||
| Peak dobutamine dose (μg/kg/min) | 37 ± 6 | 35 ± 7 | 1.07 (1.02–1.13) | .005 † |
| Total dobutamine use (mg) | 27 ± 11 | 23 ± 10 | 1.03 (1.01–1.06) | .015 † |
| Atropine use | 79.3% | 58.6% | 2.70 (1.41–5.59) | .002 † |
| Atropine dose ≥ 1 mg | 66.0% | 21.9% | 6.94 (3.87–12.86) | <.001 † |
| Contrast agent | 37.7% | 48.7% | 0.64 (0.35–1.12) | .12 |
| Resting HR (beats/min) | 64 ± 11 | 69 ± 12 | 0.96 (0.93–0.98) | .001 † |
| Stress HR (beats/min) | 123 ± 15 | 132 ± 13 | 0.96 (0.94–0.98) | <.001 † |
| Rest SBP (mm Hg) | 135 ± 22 | 137 ± 22 | 0.99 (0.98–1.01) | .43 |
| Stress SBP (mm Hg) | 144 ± 30 | 145 ± 32 | 1.00 (0.99–1.01) | .77 |
| Ejection fraction (%) | 60 ± 9 | 60 ± 8 | 1.00 (0.97–1.04) | .98 |
| Symptoms of headache or lightheadedness | 24.5% | 11.8% | 2.42 (1.20–4.61) | .02 † |
| DST positive for ischemia | 24.5% | 21.9% | 1.15 (0.58–2.17) | .66 |
| Duration of DST (min) | 15 ± 3 | 14 ± 3 | 1.12 (1.04–1.21) | .004 † |
| Mental status tests | ||||
| SPMSQ (before DST) | 7.6% | 4.8% | 1.62 (0.47–4.29) | .41 |
| SPMSQ (after DST) | 7.6% | 4.2% | 1.86 (0.54–4.99) | .29 |
| DOSS (before DST) | 7.6% | 1.2% | 6.72 (1.74–22.15) | .008 † |
| DOSS (after DST) | 9.4% | 1.4% | 7.62 (2.26–22.96) | .002 † |
∗ From logistic regression analysis.
Atropine dose ≥ 1 mg, BMI < 24 kg/m 2 , underlying NP disorder, and positive DOSS result after DST were independently associated with the occurrence of NP symptoms during first 24 hours after DST, but β-blocker therapy, peak dobutamine dose, peak stress heart rate, and duration of DST were not. Symptoms of headache and lightheadedness during DST showed a trend toward significance. The final model ( Table 3 ) included age and gender as adjustment variables. The area under the receiver operating characteristic curve for this model was 0.803.
