Anesth Analg 2001;93:1332-1337
© 2001 International Anesthesia Research Society
REGIONAL ANESTHESIA
T-Wave Amplitude as an Indicator for Detecting Intravascular Injection of Epinephrine Test Dose in Awake and Anesthetized Elderly Patients
Makoto Tanaka, MD, and
Toshiaki Nishikawa, MD
Department of Anesthesia, Akita University School of Medicine, Akita-city, Japan
Address correspondence and reprint requests to Makoto Tanaka, MD, Department of Anesthesia, Akita University School of Medicine, Hondo 1-1-1, Akita-city 010-8543, Japan. Address email to mtanaka{at}med.akita-u.ac.jp
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Abstract
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Aging is associated with reduced heart rate (HR) responsiveness to a simulated IV test dose containing epinephrine. We tested the hypothesis that a more contemporary T-wave criterion (positive if there was a 
25% decrease in T-wave amplitude) was applicable in both awake and anesthetized older patients. Sixteen healthy patients 65 yr old first received 3 mL of normal saline IV, followed 4 min later by 1.5% lidocaine 3 mL containing 15 µg epinephrine (1:200,000) IV in the supine position when awake, and they were anesthetized with stable 2% end-tidal sevoflurane and 67% nitrous oxide. HR, systolic blood pressure (SBP) determined invasively, and lead II of the electrocardiogram were continuously recorded for 4 min after the IV injections of saline and the test dose. A sensitivity of 88% and a negative predictive value of 89% were obtained in awake patients on the basis of the conventional HR criterion (positive if there was a 20 bpm increase), whereas a sensitivity of 81% and a negative predictive value of 84% were obtained during sevoflurane anesthesia on the basis of the modified HR criterion (positive if there was a 10 bpm increase). However, sen-sitivities, specificities, and positive and negative predictive values were all 100% on the basis of the SBP (positive if a 15 mm Hg increase was recorded with an arterial line) and the T-wave criteria for both awake and anesthetized conditions. These results suggest that the SBP and T-wave criteria should be applied in awake and anesthetized elderly patients for detecting accidental intravascular injection of the epinephrine-containing test dose.
IMPLICATIONS: To determine whether an epidural catheter is in a blood vessel, an epidural test dose containing 15 µg epinephrine is often used. We found that an increase in systolic blood pressure and a decrease in T-wave amplitude, but not an increase in heart rate, seem to be reliable indicators for detecting accidental intravascular injection in both awake and sevoflurane-anesthetized patients 65 yr old.
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Introduction
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Epidural anesthesia, alone or in combination with general anesthesia, is increasingly used. To avoid potentially life-threatening cardiovascular or central nervous system toxicity associated with accidental intravascular injection of large amounts of local anesthetic solution, an epidural test dose containing 15 µg epinephrine is used (1,2). In unmedicated, young, healthy subjects, an increase in heart rate (HR) 20 bpm after the test dose injection through an epidural catheter is regarded as a highly sensitive and specific testing threshold (conventional HR criterion), whereas an HR increase 10 bpm has been generally accepted as a positive diagnostic threshold during general anesthesia (modified HR criterion) (2–4). However, several lines of evidence suggest that those conventional and modified HR criteria were unreliable in awake and anesthetized elderly patients, respectively, presumably as a result of depressed ß-adrenoceptor responsiveness to IV epinephrine in this population (5–8).
Meanwhile, one study demonstrated that a decrease in T-wave amplitude on lead II of the electrocardiogram by 25% was 100% sensitive and specific over 0.5% to 2% end-tidal sevoflurane for detecting an intravascular test dose containing 15 µg epinephrine (9). In addition, the T-wave criterion was more sensitive than hemodynamic criteria when a fractional dose of the epinephrine test dose was injected intravascularly during sevoflurane anesthesia (10). However, these findings were based on data obtained from young and healthy patients (9,10) or an anecdotal case report (11), and whether the T-wave criterion was applicable in awake and anesthetized elderly patients has never been addressed. Monitoring the T-wave morphology can be achieved noninvasively and continuously and thus would be of clinical value if the T-wave criterion were found to be reliable in this population.
Accordingly, this study was designed to test the hypothesis that the characteristic T-wave alterations also occur as a result of a simulated IV test dose in awake and anesthetized elderly subjects and that the T-wave criterion previously derived from young, healthy subjects is applicable in this population.
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Methods
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The study protocol was approved by our institutional research committee, and informed consent was obtained from each patient. Sixteen ASA physical status I or II patients 65 yr old, scheduled to undergo general anesthesia for elective surgeries, were enrolled. None of the patients was taking ß-adrenergic blockers, calcium channel blockers, or angiotensin-converting enzyme inhibitors.
All patients arrived at the operating room after an 8- to 10-h fast and without premedication. After local anesthetic infiltration, a peripheral IV cannula was placed, and lactated Ringer’s solution was maintained at a constant rate of approximately 15 mL · kg-1 · h-1 throughout the study. A radial arterial cannula was also inserted, with which subsequent blood pressure measurements were made. The standard lead II of the electrocardiogram (EKG) and the oxyhemoglobin saturation were monitored continuously. After 10 min of stabilization, all subjects first received normal saline 3 mL IV, followed 4 min later by 1.5% lidocaine 3 mL containing 15 µg epinephrine (1:200,000) IV as a simulated intravascular test dose via a peripheral venous line over 5 s. Continuous records (strip-chart) of HR, systolic blood pressure (SBP), and lead II of the EKG were obtained after saline and the test dose injections, from which HR and SBP were analyzed at 20-s intervals for 4 min. In addition, maximum HR and SBP responses were noted. Measurements of T-wave amplitude were made at its minimum amplitude within the first 60 s and at 60-s intervals for 4 min.
Then, general anesthesia was induced with thiopental 5 mg/kg, and endotracheal intubation was facilitated with vecuronium 0.1 mg/kg. Anesthesia was maintained with end-tidal sevoflurane 2% and 67% nitrous oxide in oxygen while the patient’s lungs were mechanically ventilated to maintain end-tidal carbon dioxide tension between 30 and 35 mm Hg. When three measurements of SBP and HR determined at 1-min intervals were within ±5% of the previous value, steady end-tidal sevoflurane concentration was obtained for 5 min (end-tidal sevoflurane constantly showing 2% at constant inspiratory concentration), and at least 20 min had elapsed after the induction of general anesthesia, all patients received IV injections of normal saline 3 mL, followed 4 min later by 3 mL of the identical test dose. Measurements of HR, SBP, and T-wave amplitude were made similarly.
High- and low-frequency filters of the EKG were 0.3 and 40 Hz, respectively (monitor mode). The calibration of the recorder was set at 0.5 mV/cm, and the chart speed was set at 25 mm/s. Anesthesiologists and an investigator (MT) in charge of the patient’s care and injecting study drugs were not blinded. Patients were not informed of the timing of drug injections. After completion of the data collection, all measurements of T-wave amplitudes were made at random order by an observer blinded to the treatment group of the patients and the hemodynamic changes. Positive HR, SBP, and T-wave changes to the IV test dose were prospectively defined from previous reports: positive if an HR increase was 20 bpm in an awake and 10 bpm in an anesthetized patient (2,4), an SBP increase was 15 mm Hg (2,4), and a decrease in T-wave amplitude was 25% (9), occurring within 2 min of study drug administrations. We calculated sensitivity (true positives/[true positives + false negatives]), specificity (true negatives/[true negatives + false positives]), and positive (true positives/[true positives + false positives]) and negative predictive values (true negatives/[true negatives + false negatives]).
A power analysis based on a previous report revealed that more than 16 patients would provide a power >0.8 (P = 0.05) for detection of a 25% difference in paired hemodynamic and T-wave alterations (9,10). All values are presented as mean ± SD and 95% confidence interval, as indicated. Statistical analysis was performed by two-way analysis of variance for repeated measurements with respect to time and treatment (awake versus anesthetized), and when a significant difference was detected, this was followed by unpaired t-test with Bonferroni’s correction as appropriate. P < 0.05 was considered to be statistically significant.
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Results
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Seven men and nine women participated in the study. The mean age, weight, and height of the patients were 69 ± 4 yr, 51 ± 9 kg, and 154 ± 8 cm, respectively. Except for one obese patient (body mass index = 33), all participants belonged to ASA physical status I.
IV injection of the test dose produced significant increases in HR and SBP and significantdecreases in T-wave amplitude in both awake and anesthetized patients (Table 1 and Figs. 1–3), whereas IV injection of normal saline elicited no significant changes in these variables (data not shown in figures). While the patients were awake, maximum changes in HR, SBP, and T-wave morphology occurred at 56 ± 8, 94 ± 16, and 46 ± 13 s, respectively, after the test dose injection and at 62 ± 7, 103 ± 11, and 58 ± 12 s, respectively, during general anesthesia. Maximum and temporal changes in HR were greater when the patients were awake compared with being anesthetized (Table 1 and Fig. 1). When awake, 14 of 16 patients developed maximum HR increases 20 bpm in response to the IV test dose. Because none developed an HR increase 20 bpm after saline injection, sensitivity, specificity, positive predictive value, and negative predictive value on the basis of the conventional HR criterion were 88%, 100%, 100%, and 89% (Table 2). Similarly, 13 of 16 patients developed maximum HR increases 10 bpm in response to the IV test dose during general anesthesia, but none met this HR threshold after IV saline. As a result, sensitivity, specificity, positive predictive value, and negative predictive value according to the modified HR criterion were 81%, 100%, 100%, and 84% (Table 2). However, all subjects after the test dose and none after the saline injections developed the maximum increase in SBP of 15 mm Hg, the maximum percentage decrease in T-wave amplitude of 25%, and the maximum absolute decrease in T-wave amplitude of 0.1 mV, resulting in 100% sensitivity and specificity on the basis of the SBP and the T-wave criteria while awake and during general anesthesia. Coefficients of variations of all the T waves determined beat by beat during the first 60 s within each subject after the saline injections were <3% in both conditions. None developed an inverted T wave or ventricular or supraventricular arrhythmia at any occasion during the study.
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Table 1. Preinjection Blood Pressure, Heart Rate, and T-Wave Amplitude and Their Maximum Changes After Saline and Test Dose Injections
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Table 2. Sensitivity, Specificity, and Positive and Negative Predictive Values Based on Hemodynamic and T-Wave Criteria
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Figure 2. Changes in systolic blood pressure after the IV injection of the test dose containing 15 µg of epinephrine in awake and sevoflurane-anesthetized patients 65 yr old (n = 16). Because systolic blood pressure was virtually unchanged after saline injections, these data are not presented. Data are mean ± SD. *P < 0.05 versus preinjection values. No significant difference was detected between awake and anesthetized values.
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Figure 3. Percentage change in T-wave amplitude after the IV injection of the test dose containing 15 µg of epinephrine in awake and sevoflurane-anesthetized patients 65 yr old (n = 16). Because T-wave amplitude was virtually unchanged after saline injections, these data are not presented. Data are mean ± SD. *P < 0.05 versus preinjection values. The label, at maximum change, indicates the time when the minimum T-wave occurred in each patient after the test dose injection. No significant difference was detected between awake and anesthetized values.
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Discussion
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This study is the first to demonstrate that the testing threshold of the T-wave criterion derived from young, healthy patients in previous studies (9,10) also reliably detected intravascular injection of the epinephrine test dose in awake and anesthetized older patients 65 years old. In addition, the extent of T-wave depression did not depend on the concomitant administration of sevoflurane and nitrous oxide. This characteristic change in EKG morphology is in accordance with a previous study, in which maximum decreases and time-dependent changes in T-wave amplitude were not affected by end-tidal sevoflurane concentrations from 0.5% to 2% (9), but it is in clear contrast with the fact that HR and SBP changes after simulated IV test doses are influenced by volatile anesthetic concentrations (4,9). Because monitoring the T-wave morphology can be accomplished continuously and noninvasively, these considerations, together with our results, suggest a potential clinical usefulness of the T-wave criterion. Furthermore, our previous study and a recent case report suggest that the characteristic T-wave change may occur with a fractional dose of the test dose, which is insufficient to cause positive HR and SBP responses during general anesthesia (10,11). Therefore, further study is warranted to determine the minimum effective dose of epinephrine that can reliably produce the positive response in T-wave amplitude in awake and anesthetized older patients.
Our study also confirmed the effectiveness of the SBP criterion in older patients. In contrast with the depressed HR response to the IV test dose in the elderly, maximum SBP increases have been reported to be independent of the patients’ age from 10s to 70s, when the test dose containing 15 µg epinephrine was injected IV (7). In addition, general anesthetics did not seem to affect the SBP response in our study population. In comparison with the HR criterion, the importance and clinical usefulness of the SBP criterion have been emphasized in patients taking ß-adrenergic blockers (2), healthy adult patients under a deep level of isoflurane anesthesia (4), and patients sedated with midazolam and fentanyl (12). An anecdotal case report also showed that no noticeable HR, but marked SBP increases, occurred after unintentional intravascular administrations of test doses containing 15 and 10 µg epinephrine in two patients at the ages of 76 and 62 years, respectively (13). In our study, the duration of SBP increases seems to last long enough (Fig. 2), thus enabling us to detect those clinically significant SBP changes by an automated blood pressure cuff used at the most frequent measurement interval. Because noninvasive SBP and HR changes would be more useful and realistic indicators for detecting unintentional intravascular injection of the test dose, the reliability based on these variables, either alone or in combination, should be substantiated in a future clinical trial.
Significantly less of an increase in HR during sevoflurane anesthesia compared with the awake condition after the IV test dose, and 95% confidence intervals of the maximum HR responses to IV saline and the test dose, support the appropriateness of the modified HR threshold in the anesthetized elderly. However, failure to demonstrate 100% efficacy on the basis of this criterion indicates the limitation of HR response as a marker for detecting intravascular injection of the epinephrine test dose in this population. The considerably depressed chronotropic response to epinephrine seen in our anesthetized elderly subjects may be the result of a combination of a direct depressive effect of a volatile anesthetic on the sinoatrial node as well as the depressed ß-adrenoceptor responsiveness to ß-agonists in the elderly (8,14). However, this is the first report to demonstrate that SBP and T-wave responses to the IV test dose were similar to those determined in the same awake subjects, further confirming that the SBP and T-wave criteria need not be altered.
One may argue that the absence of false negatives based on the SBP and T-wave criteria may be attributed to a small number of patients involved in our study. In awake and anesthetized patients, differences between mean values of SBP increases and percentage T-wave changes and their corresponding testing thresholds are approximately 1.8–2.0 times the corresponding SDs (Table 1), suggesting that approximately 1 of 40 patients would lie below the testing thresholds of the SBP and the T-wave criteria. But it is more important that the actual usefulness (adjusted predictive values) needs to be determined by using the positive and negative predictive values according to Bayes’ theorem (15), which gives conditional probability adjusted for the observed prevalence of the phenomenon, i.e., intravascular catheterization in the context of our study. When such incidents are considered up to 9% and 0.7% in awake and anesthetized patients, according to previous reports (1,16), the actual positive/negative predictive values based on the conventional and modified HR criteria after application of Bayes’ theorem were found to be 99.9% and 98.8% and 99.9% and 99.8%, respectively. These results imply that positive test results should always be considered as indicating inadvertent systemic injection. However, low sensitivity associated with a high adjusted negative predictive value based on the peak HR change in awake and anesthetized states indicates the limited clinical value of the HR criteria if negative test results are obtained.
Possible shortcomings of our study are severalfold. First, preexisting T-wave abnormalities, such as in patients taking digoxin and those with left ventricular hypertrophy, may preclude using the T-wave criterion (17). Second, our protocol required repeated IV administrations of epinephrine in each patient, whereas the hemodynamic response to the second dose of the epinephrine test dose has not been defined. However, the residual effect of epinephrine had been minimized by a stabilization period of at least 20 min during general anesthesia before the second epinephrine test dose was administered. In fact, our patients typically received the second dose of the test dose 35 min after the first dose. Third, our study failed to demonstrate that the T-wave criterion was more effective than the HR criterion. This is because of the small number of patients assigned in our study (type II error). Retrospective power analysis of our data revealed that at least 56 and 64 patients would be required to provide a power >0.8 (P = 0.05) for detecting a statistical significance in sensitivities and negative predictive values, respectively, between the T-wave and HR criteria in awake patients (18). Fourth, whereas we used the monitor mode, by using the diagnostic mode, i.e., a bandwidth of 0.05 to 100 Hz, the detectability of significant T-wave changes may have been improved. However, this level of low-frequency filter is often associated with respiratory movement of the EKG lead wires and wandering baselines (19). Fifth, the blinded observer determined hemodynamic and T-wave alterations separately and in random orders. However, the observer also noted progressive decreases in R-R intervals in most of the cases receiving the IV test dose, and this may have introduced a certain bias in the measurement of T-wave amplitude.
In conclusion, the contemporary T-wave criterion (positive if there is a 25% decrease in T-wave amplitude in lead II) and the SBP criterion (positive if there is a 15 mm Hg increase) were reliable indicators, whereas the conventional and modified HR criteria (positive if there are 20 and 10 bpm increases, respectively) were imperfect markers for detecting intravascular injection of the test dose containing 15 µg epinephrine in awake and sevoflurane-anesthetized patients 65 years old.
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Accepted for publication July 5, 2001.
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Abstract
Introduction
P < 0.05 between groups.
