Anesth Analg 2000;91:657-661
© 2000 International Anesthesia Research Society
REGIONAL ANESTHESIA AND PAIN MEDICINE
Aging Reduces the Efficacy of the Simulated Epidural Test Dose in Anesthetized Adults
Makoto Tanaka, MD, and
Toshiaki Nishikawa, MD
Department of Anesthesia, Akita University School of Medicine, Akita, Japan
Address correspondence and reprint requests to Makoto Tanaka, MD, Department of Anesthesia, Akita University, School of Medicine, Hondo 1-1-1, Akita-shi, Akita-ken 010-8543, Japan. Address e-mail to mtanaka{at}med.akita-u.ac.jp
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Abstract
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Aging is associated with reduced ß-adrenergic responsiveness. However, the age-related effects on hemodynamic changes and effectiveness of a simulated epidural IV test dose have not been defined during general anesthesia. We studied 20 (140 total) consecutive patients (ASA physical status I) assigned in each of the following age groups after endotracheal intubation and during stable end-tidal sevoflurane 2% and 67% nitrous oxide anesthesia (in yr): 10s, 20s, 30s, 40s, 50s, 60s, and 70s. Each group first received normal saline 3 mL IV, followed 4 min later by 1.5% lidocaine 3 mL plus 15 µg epinephrine (1:200,000) IV for 5 s. Heart rate (HR) and systolic blood pressure (SBP) were continuously monitored for 4 min after saline administration and the test dose injections. None receiving IV saline and all patients receiving IV test dose in age groups 10s to 50s developed HR increases 
10 bpm, whereas 17 and 13 patients met this HR criterion in age groups 60s and 70s (85% and 65% sensitivities), respectively. There was a significant inverse correlation between the maximum HR increase and the age (P < 0.001 by Spearman’s rank correlation). However, none receiving saline and all patients receiving IV test dose in all age groups developed SBP increases of 15 mm Hg, resulting in 100% efficacy based on the SBP criterion. We conclude that during stable sevoflurane anesthesia administration (a) the efficacy based on the HR criterion for detecting accidental intravascular injection of the epidural test dose is age-dependent, (b) the HR criterion may be clinically applicable only in patients <60 yr of age, and (c) the SBP criterion is effective for all age groups studied.
Implications: To determine whether an epidurally administered local anesthetic has been unintentionally injected into a blood vessel, a small dose of epinephrine is often added to a local anesthetic. We found that an increase in systolic blood pressure 15 mm Hg is a more useful indicator than an increase in heart rate 10 bpm in the patients 60 yr old during stable sevoflurane anesthesia administration.
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Introduction
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Because of the increasing use of combined epidural-general anesthesia for surgery, criteria for detecting unintentional intravascular injection of local anesthetic solution during general anesthesia have been developed (1,2). In young, healthy surgical patients anesthetized with isoflurane, a modified heart rate (HR) criterion (positive if 10 bpm increase) has been derived from 95% confidence interval of maximum HR increases after simulated IV test dose containing 15 µg epinephrine. An increase in systolic blood pressure (SBP) 15 mm Hg was also found to be a reliable indicator for both awake and anesthetized patients (1,3). In the awake elderly patients, hemodynamic responses to IV epinephrine test dose may be unreliable (4,5). More recently, elderly patients (65 yr old) lightly anesthetized with sevoflurane and fentanyl revealed 70% sensitivity and 77% negative predictive value after simulated IV test dose based on the modified HR criterion, suggesting limited usefulness of the peak HR change in this population (6). Although depressed HR responses to IV epinephrine may be considered, at least in part, caused by age-related diminished ß-adrenergic responsiveness to epinephrine (7), the effect of patient age on hemodynamic responses to, and efficacy for, detecting accidental intravascular injection of the epinephrine test dose has not been defined in anesthetized patients.
Accordingly, the current study was designed to determine blood pressure (BP) and HR changes, and effectiveness of the epinephrine test dose based on hemodynamic criteria in healthy adult patients of various age groups during stable sevoflurane anesthesia administration. The goal of the study is to estimate the "cut-off" age above which the modified HR criterion may not be clinically applicable.
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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. We studied 20 consecutive patients (140 total) assigned in each of the following age groups (in yr): 10s, 20s, 30s, 40s, 50s, 60s, and 70s. All patients were ASA physical status I and were scheduled to undergo general anesthesia for elective surgeries. None was pregnant, and none was taking cardiovascular medications.
All patients arrived at the operating room after an 8- to 10-h fast and without premedication. Preinduction BP and HR were obtained noninvasively, and standard lead-II electrocardiography was continuously monitored throughout the study. A radial arterial catheter was placed after local anesthesia infiltration for preinjection and subsequent BP measurements after saline administration and test dose injections. Lactated Ringer’s solution was infused at a constant rate of approximately 15 mL · kg-1 · h-1 throughout the study. After the induction of general anesthesia with thiopental 5 mg/kg IV, endotracheal intubation was facilitated with vecuronium 0.1 mg/kg IV. Then, anesthesia was maintained at end-tidal sevoflurane 2% and 67% nitrous oxide in oxygen, while ventilation was controlled by using a tidal volume 10 mL/kg and a respiratory rate of 7–9 breaths/min to obtain an end-tidal carbon dioxide tension of 30–35 mm Hg. When hypertension, i.e., SBP > 130% of the preinduction value, occurred after endotracheal intubation, inspiratory sevoflurane concentration was transiently increased up to 4%–5% until resolved. If hypotension, i.e., SBP < 70% of the preinduction value, persisted with end-tidal sevoflurane 2% with 67% nitrous oxide in oxygen, the patient was excluded from the study and was treated with ephedrine 5–10 mg IV and/or by decreasing the inspiratory sevoflurane concentration. When three measurements of SBP and HR determined at 1-min intervals were within 5% of the previous value, a steady end-tidal sevoflurane concentration was obtained for 5 min (end-tidal sevoflurane constantly showing 2% at a constant inspiratory concentration), and when at least 20 min had elapsed with end-tidal sevoflurane 2% after the induction of general anesthesia, each group of patients 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 line for 5 s. Continuous records of HR and SBP were obtained after saline administration 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. All hemodynamic measurements were made typically 30 min after the induction of general anesthesia with patients in the supine position before initiation of the scheduled surgery.
For power analysis, data from a previous study examining hemodynamic changes after IV injections of the epinephrine test dose in sevoflurane-anesthetized adults were used (8), and they revealed that >18 patients in each group would provide a significance (
) = 0.05 and a power (ß) > 0.8 for the detection of an approximately 20% difference in maximum hemodynamic changes between two groups (9). Positive HR and SBP responses to the IV test dose were prospectively defined from previous studies: HR increase 10 bpm and a SBP increase 15 mm Hg occurring within 2 min of the study drug administration (1–3). We determined 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]).
All values were presented as mean ± SD. Statistical analysis was performed by using two-way analysis of variance to compare changes in hemodynamic variables among groups. When a significant difference was identified, this was followed by unpaired Student’s t-tests with Bonferroni’s correction. Intergroup differences in demographic data were also compared with unpaired Student’s t-tests with Bonferroni’s correction or 
2 test. Changes in hemodynamic variables over time within each age group were analyzed by using repeated measures analysis of variance, followed by paired Student’s t-tests. Correlations between age, age group versus maximum changes in HR, were examined by using Pearson’s correlation coefficient and Spearman’s correlation coefficient by rank, respectively. P < 0.05 was considered the minimum level of statistical significance.
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Results
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There were no significant differences in the patients’ weight and sex distribution (Table 1). Patients in the 10s were significantly taller than the rest of the age groups, while those of the 20s and 30s were significantly taller than those of the 60s and 70s. Resting SBP and diastolic BP of the 70s were significantly higher than those in the 10s through 50s, and than those of the 10s and 20s, respectively, but SBP and diastolic BP of the other age groups and resting HR values of all groups were similar. However, after the induction of general anesthesia with sevoflurane and nitrous oxide at steady state, there were no significant differences in BP and HR among groups.
The IV injection of saline produced virtually no hemodynamic effects, and thus none elicited positive responses on either the modified HR or the SBP criterion (data not shown). IV injection of the test dose containing 15 µg epinephrine produced biphasic changes in HR, i.e., an increase followed by a decrease compared with baseline (preinjection) values in the age groups from the 10s to the 60s, but no significant decrease in HR was seen in patients of the 70s (Fig. 1). Maximum increase in HR of the 10s was significantly greater than those of the 30s and older groups, whereas those of the 20s and 30s were significantly greater than those of the 60s and 70s (Table 1). These HR changes occurred at 51 ± 3, 52 ± 8, 51 ± 10, 53 ± 8, 49 ± 7, 58 ± 11, and 59 ± 17 s after the test dose injections in the 10s, 20s, 30s, 40s, 50s, 60s, and 70s, respectively. There were significant negative correlations between the patient’s age and the peak HR value attained (R = 0.6 by Pearson’s correlation coefficient) and between the age group and the peak HR value (P < 0.001 by Spearman’s correlation coefficient by rank). However, maximum increases in SBP were similar in all age groups, and occurred at 80 ± 17, 78 ± 14, 84 ± 9, 95 ± 20, 95 ± 21, 105 ± 23, and 113 ± 19 s after test dose injections in the 10s, 20s, 30s, 40s, 50s, 60s, and 70s, respectively (Table 1 and Fig. 2). These changes in SBP of the 10s, 20s, and 30s occurred significantly earlier than those of the 60s and 70s (P < 0.05).
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Figure 1. Changes in heart rate after the IV injections of the test dose consisting of 1.5% lidocaine 3 mL plus 15 µg epinephrine during stable 2% end-tidal sevoflurane and 67% nitrous oxide in oxygen (n = 20 for each age group). Because heart rate was essentially unchanged after saline injections, these data are not presented. Values are mean ± SD. *P < 0.05 versus preinjection values.
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Figure 2. Changes in systolic blood pressure after the IV injections of the test dose consisting of 1.5% lidocaine 3 mL plus 15 µg epinephrine during stable 2% end-tidal sevoflurane and 67% nitrous oxide in oxygen (n = 20 for each age group). Because systolic blood pressure was essentially unchanged after saline injections, these data are not presented. Values are mean ± SD. *P < 0.05 versus preinjection values.
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The numbers of patients who developed maximum increases in HR of 10 bpm in response to the IV test doses were 20 in the age groups of 10s to 50s, but were 17 and 13 in the 60s and 70s, respectively. Because no false positive responses were seen after IV saline administration, sensitivity, specificity, positive predictive value, and negative predictive value of the HR criterion were 100% in all age groups except the 60s and 70s (Table 2). However, all patients receiving the IV test dose and none receiving IV saline developed SBP increases 15 mm Hg, resulting in sensitivity, specificity, positive predictive value, and negative predictive value of 100% based on the SBP criterion. Maximum absolute values of SBP 180 mm Hg were obtained in 1, 1, 1, 1, 2, 4, and 3 patients in the 10s, 20s, 30s, 40s, 50s, 60s, and 70s, respectively, but no ventricular or supraventricular arrhythmia was observed in any patient receiving saline or the test dose throughout the study period.
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Table 2. Sensitivity, Specificity, and Positive and Negative Predictive Values of an Epidural Test Dose Containing Epinephrine
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Discussion
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Our major findings were that the HR response to, and the efficacy of, the epinephrine test dose for detecting intravascular injection according to the modified HR criterion were age-dependent during stable sevoflurane anesthesia administration. This is in accordance with a previous finding by Guinard et al. (10), who demonstrated that increasing age was associated with smaller increases in HR, but not SBP, after the IV injection of 10 µg epinephrine in awake surgical patients. Our study also confirmed the results of our recent observation, in which the modified HR criterion did not reliably detect IV injection of the test dose of identical components in lightly anesthetized patients >65 years of age (6). Although the possibility of improving the efficacy and HR responses by using larger doses of epinephrine has never been addressed in anesthetized elderly patients, simply increasing the dose of epinephrine has resulted in dose-dependent augmentation of SBP response, but not HR response, in healthy young patients anesthetized with isoflurane (1), possibly caused by a greater degree of baroreflex-mediated slowing of HR with a larger dose of epinephrine. Based on these considerations as well as our present findings, careful attention should be paid to SBP changes in addition to HR in anesthetized patients 60 years of age to maximize the detectability of accidental intravascular injection of the epinephrine test dose.
Because maximum increases in SBP were similar in all age groups in our study, and baroreflex-mediated slowing of HR in response to increased BP is inversely correlated with age (11), depressed HR responses in the anesthetized elderly patients compared with younger patients after the IV test dose may be largely attributed to the impaired ß1-receptor-mediated responsiveness, per se. Indeed, a previous report demonstrated that the dose of isoproterenol required to increase HR by 25 bpm at the age of 80 years is 10 times that at the age of 20 years (7), and aging is associated with reduced receptor affinity for ß-agonists rather than reduced ß-receptor density (12,13). Furthermore, volatile anesthetics, including halothane and isoflurane, depress normal electromechanical activity of human atrial fibers as well as the maximum sinus rate response to epinephrine by using a guinea pig in vitro preparation (14,15). Therefore, profoundly depressed HR response in sevoflurane-anesthetized elderly patients is most probably a result of the combination of both factors, i.e., reduced ß-receptor affinity to agonists caused by aging as well as direct depression of the SA node by sevoflurane.
The importance and clinical usefulness of the SBP criterion have been emphasized in patients taking ß-adrenergic blockers (3), healthy adult patients under a deep level of isoflurane anesthesia (1), and awake and anesthetized elderly patients (6,10). An anecdotal case report also showed, in two patients at 76 and 62 years old, that no noticeable HR, but marked BP increases, occurred after unintentional intravascular administrations of test doses containing 15 and 10 µg epinephrine, respectively (5). In our study, the duration of SBP increases seems to last long enough, especially in patients 60 years old, thus enabling us to detect those clinically significant SBP changes by an automated BP cuff used possibly at the most frequent measurement interval. However, the reliability of noninvasive BP measurements for detecting intravascular injection of the test dose was not substantiated in a previous clinical trial. More importantly, one must consider that the inherent error for a single determination of SBP with an automated BP cuff may well exceed the threshold of SBP criterion (16). Because placing an arterial line in all patients 60 years old undergoing combined epidural-general anesthesia is neither practical nor economical, whether noninvasive BP measurements are sensitive enough to detect transient SBP changes after the IV test dose remains to be determined in the anesthetized elderly patient.
Our results must be interpreted with some caution. First, even though the present study demonstrated 100% sensitivity and specificity based on the modified HR criterion in patients <60 years old, previous studies revealed controversial results during sevoflurane anesthesia administration (8,17). This may be explained by the small number of patients assigned in each group (type II error) (18). Second, interpretation of our data should be confined to a situation when a full dose of epinephrine was injected IV. In actual clinical practice, however, only a fractional dose may be inadvertently injected IV. This may occur if only the tip of the multi-orifice epidural catheter migrates into the intravascular space. Therefore, a further dose-response study by using a small dose of epinephrine may be warranted. Third, more contemporary T wave criteria have not been examined in our study. In healthy adult patients anesthetized with sevoflurane and nitrous oxide, absolute decrease in T wave amplitude 0.1 mV and a percent decrease 25% were as reliable as the SBP and more reliable than the modified HR criterion (8). Whether changes in T wave morphology could be used as a clinically useful marker in elderly patients remains to be determined. Fourth, when a high thoracic epidural blockade is present in combination with general anesthesia, the HR response to an IV test dose is attenuated compared with that with a low thoracic epidural blockade or in the awake state (19). Moreover, when the epidural blockade is wearing off and a reinforcing dose is required, concomitant surgical stimulation may adversely increase the false-positive responses and, thus, influence the efficacy. Therefore, ultimate validation of our results requires trials under combined epidural-general anesthesia during surgery. Lastly, because minimum alveolar anesthetic concentration of sevoflurane decreases with aging (20), it is likely that our elderly patients were relatively overdosed compared with younger patients, which may partially explain more depressed HR response to the IV test dose in this population.
In conclusion, the modified HR criterion (positive if there was a 10-bpm increase) was a reliable indicator for detecting inadvertent intravascular injection of the test dose containing 15 µg epinephrine in healthy adult patients <60 years old, but not in those 60 years old, during stable sevoflurane and nitrous oxide anesthesia administration. However, the SBP criterion (positive if there was a 15-mm Hg change) was 100% sensitive and specific in all age groups in our study.
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Accepted for publication May 4, 2000.
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Abstract
Introduction
