Epidural anesthesia is increasingly used in combination with general anesthesia. The inability to aspirate blood from an epidural catheter does not ensure extravascular placement (1), and thus some authors have advocated the routine use of an epidural test dose containing epinephrine. Although the efficacy of repeated injections of a test dose has not been substantiated (2), objective hemodynamic and electrocardiographic alterations have been reported to indicate intravascular injection of an epinephrine-containing test dose (3–5). An accidental intravascular injection of large amounts of local anesthetic solution can result in potentially life-threatening cardiovascular or central nervous system toxicity during general anesthesia.
Several lines of evidence suggest the clinical usefulness of T-wave amplitude changes for detecting intravascular injection of local anesthetic solution in adult and pediatric patients (4–6). In sevoflurane-anesthetized adults, the efficacy of the T-wave criteria (positive if ≥25% and ≥0.1 mV decrease in amplitude) was reported to be superior to that of heart rate (HR) (positive if ≥10 bpm increase), systolic blood pressure (SBP) (positive if ≥15 mm Hg increase), and their combination criteria, when a fractional dose of the test dose was injected intravascularly (5). However, the usefulness of the T-wave criteria has been verified only during sevoflurane anesthesia. In anesthetized children, the direction and extent of T-wave alterations, and hence efficacies for detecting intravascular injection based on the peak T-wave change, depend on the anesthetic used (7). Therefore, we designed this dose-response study to determine minimal effective doses of the epinephrine test dose for detecting intravascular injection based on the hemodynamic and electrocardiographic T-wave criteria in propofol-anesthetized adults.
After obtaining approval from our institutional research committee and informed consent from each patient, we studied 80 nonpregnant, ASA physical status I adult patients scheduled to undergo general anesthesia for elective surgeries. None of the patients was taking β-blockers, calcium channel blockers, or angiotensin-converting enzyme inhibitors.
After fasting 8–10 h, all patients were premedicated with ranitidine 150 mg orally 90 min before the induction of general anesthesia. Patients were subsequently assigned randomly, according to the computer-generated random numbers, into one of four groups according to the simulated epidural test-dose injection IV (n = 20 each): a Saline group received 3 mL of normal saline IV, an Epinephrine-15 group received a test dose consisting of 1.5% lidocaine 3 mL plus 5 μg epinephrine/mL IV, and Epinephrine-10 and -5 groups received 2 and 1 mL of the test dose of identical components IV, respectively. The anesthetic technique was standardized as follows: on arrival in the operation room, control blood pressure (BP) and HR values were obtained noninvasively. After local anesthesia infiltration, arterial cannula with which subsequent BP measurements were made, was inserted in the radial artery in all patients. Lactated Ringer’s solution was administered and maintained at a constant rate approximately 15 mL · kg−1 · h−1 throughout the study period. After the induction of general anesthesia with propofol 2 mg/kg IV, tracheal intubation was facilitated with vecuronium 0.2 mg/kg IV. Anesthesia was maintained with propofol 133 μg · kg−1 · min−1 and 67% nitrous oxide in oxygen. The patients’ lungs were mechanically ventilated using a tidal volume of 10 mL/kg and respiratory rate of 8–10 breaths/min to maintain end-tidal carbon dioxide tension at 35–40 mm Hg. When three measurements of SBP and HR determined at 1-min intervals were within 5% of previous values and at least 10 min had elapsed after the induction of general anesthesia, either saline or a simulated epidural test dose was injected IV into a peripheral vein over 3 s. SBP and HR were observed at 20-s intervals for 5 min after the IV injection of the study drug. Lead II was continuously recorded on a strip chart, and subsequently analyzed for changes in T-wave amplitude at maximal deflection, and at 1-min intervals for 5 min after test dose or saline injections. Also, arrhythmia, if present, was noted. High- and low-frequency filters of the electrocardiogram were 0.3 and 40 Hz, respectively (monitor mode). The calibration of the recorder was set at 0.5 mV/cm, whereas the chart speed was set at 25 mm/s. An anesthesiologist who observed all hemodynamic changes was blinded to the group of patients. All hemodynamic measurements were performed before the initiation of the patients’ scheduled surgery in the supine position. Another observer blinded to the groups and hemodynamic changes made all measurements of T-wave amplitudes.
Positive HR, SBP, and T-wave changes to the IV test dose were prospectively defined from previous reports: positive if an HR increase ≥10 bpm (3), an SBP increase ≥15 mm Hg (8), and a T-wave decrease ≥0.1 mV or ≥25% in amplitude occurred within 2 min of administration (4). We determined sensitivity, specificity, and positive (+PV) and negative predictive values (−PV) based on those criteria. Sensitivity was calculated as the number of true positives divided by the number of true positives plus false negatives. Specificity was the number of true negatives divided by the number of true negative plus false positives. +PV was the number of true positives divided by the number of true positives plus false positives. −PV was the number of true negatives divided by the number of true negatives plus false negatives.
A power analysis based on a previous study revealed that >16 patients would provide a power >0.8 (P = 0.05) to detect a 25% difference in paired hemodynamic responses (8). All data were expressed as mean ± sd. Patients’ demographic and hemodynamic data, and T-wave amplitudes were compared by using the χ2 test or unpaired Student’s t-test. Pairwise hemodynamic data and T-wave amplitudes in each group were analyzed by using repeated-measures analysis of variance, followed by a paired Student’s t-test with Bonferroni’s correction. Fisher’s exact probability test was used to compare sensitivities among the groups. Correlations among patients’ demographic data, epinephrine dose per kilogram, and baseline HR versus hemodynamic changes were examined by using Pearson’s correlation coefficient. A P value < 0.05 was considered the minimal level of statistical significance.
There were no significant differences among the four groups in terms of age, weight, height, and gender distribution (Table 1). No significant difference was seen in BP, HR, and T-wave amplitude among the four groups before and after the induction of general anesthesia with propofol. Oxygen saturation was more than 97% in all patients during the entire course of the study.
The IV injection of the test dose containing epinephrine produced biphasic changes in HR, i.e., initial increases followed by subsequent decreases, whereas IV saline produced essentially no hemodynamic alteration (Fig. 1). Significant increases in HR compared with the baseline values were seen at 40–80 s after test-dose injections in all Epinephrine groups, whereas statistically significant HR decreases were seen at 160–300 s, 120–300 s, and 140–300 s in the Epinephrine-15, -10, and -5 groups, respectively. Mean maximal increases (range, 95% confidence interval) in HR in the Epinephrine-15, -10, and -5 groups were 43 ± 16 bpm (16–68, 35–50), 36 ± 11 bpm (19–53, 31–41), and 25 ± 8 bpm (12–38, 21–28), occurring at 53 ± 6 s (46–66, 50–56), 53 ± 7 s (42–64, 50–56), and 60 ± 11 s (46–85, 55–65) after test-dose injections, respectively. However, SBP changes were monophasic and significant increases from preinjection values were observed within 40–240 s and 40–220 s after test-dose injections in the Epinephrine-15 and -10 groups, respectively (Fig. 2). In the Epinephrine-5 group, however, SBP increased significantly at 40 s, returned to the preinjection level, and again increased significantly at 80–220 s after test-dose injections. No significant change in SBP was found at any interval in the Saline group (data not shown). Mean maximal increases (range, 95% confidence interval) in SBP in the Epinephrine-15, -10, and -5 groups were 75 ± 27 mm Hg (23–134, 63–88), 46 ± 16 mm Hg (17–71, 38–53), and 24 ± 11 mm Hg (2–49, 19–30), occurring at 84 ± 10 s (72–144, 79–89), 88 ± 11 s (69–116, 83–93), and 99 ± 18 s (73–140, 90–107) after test-dose injections, respectively. All patients developed decreases, but not increases, in T-wave amplitude within 1 min of the test-dose injection (Fig. 3). Compared with preinjection values, significant decreases in T-wave amplitude were seen until 5, 5, and 3 min after test-dose injections in the Epinephrine-15, -10, and -5 groups, respectively. In the saline group, no significant changes were observed until 5 min after injection (data not shown). Mean largest absolute decreases (range, 95% confidence interval) in T-wave amplitudes were 0.25 ± 0.14 mV (0.10–0.59, 0.18–0.32), 0.31 ± 0.13 mV (0.14–0.60, 0.25–0.37), and 0.30 ± 0.11 mV (0.06–0.46, 0.25–0.35), occurring at 46 ± 17 s (25–100, 38–54), 47 ± 10 s (28–60, 42–52), 56 ± 13 s (40–90, 50–62) in the epinephrine-15, -10, and -5 groups, respectively. In all patients receiving IV saline, the largest absolute change in T-wave amplitude was from 0.0 to 0.03 mV. The mean largest percent decreases in T-wave amplitudes were 63% ± 22% (30–100, 57–73), 69% ± 16% (43–113, 62–77), and 77% ± 31% (29–175, 62–92) in the Epinephrine-15, -10, and –5 groups, respectively. The largest percent changes in T-wave amplitudes after IV saline decreased within 0% to 9% during the observation period.
The numbers of patients who developed maximal increases in SBP ≥15 mm Hg in response to the IV test dose were 20, 20, and 16 in the Epinephrine-15, -10, and -5 groups, respectively. Because no patient receiving IV saline developed an SBP increase ≥15 mm Hg after injection, sensitivity/specificity/+PV/−PV based on the SBP criterion were 100%/100%/100%/100%, 100%/100%/100%/100%, and 80%/100%/100%/83% after IV injections of test doses containing epinephrine 15, 10, and 5 μg, respectively. However, all patients receiving IV test doses containing epinephrine, and none receiving IV saline, developed an HR increase ≥10 bpm, resulting in sensitivity/specificity/+PV/−PV of 100% based on the modified HR criterion. All patients in Epinephrine-15 and -10 groups, and none receiving saline developed maximal absolute decreases in T-wave amplitude by ≥0.1 mV, and maximal percent decreases in T-wave amplitude by ≥25% compared with preinjection values, resulting in 100% sensitivity and specificity based on both T-wave criteria. One patient in the epinephrine-5 group developed a 0.06 mV (29%) decrease in T-wave amplitude, resulting in sensitivity/specificity/+PV/−PV of 95%/100%/100%/95% according to the absolute T-wave change, but were 100%/100%/100%/100% based on the T-wave criterion using percent changes.
Two patients in the Epinephrine-10 group developed ventricular ectopic beats, which resolved within a few minutes. One patient in each of the epinephrine-5 and -15 groups developed bradycardia (HR <45 bpm) at 2 min after test-dose injections. Two patients in the Epinephrine-5 group and one in each of the Epinephrine-10 and -15 groups developed a negative T-wave, which resolved within 2 min of the test-dose injections. No significant correlations were demonstrated between the maximal changes in HR and body weight, age, epinephrine dose in milligram per kilogram, or baseline HR within each group.
The major objective of the present study was to define the dose-response relationship between the epinephrine doses versus hemodynamic and T-wave changes. The results showed that the efficacy of hemodynamic criteria for detecting intravascular injection depends on the dose of epinephrine injected intravascularly. If only the tip of a multiorificed catheter was placed in a blood vessel, a fractional dose of the test dose may have been injected IV. In actual clinical circumstances, therefore, closer attention should be given to HR and T-wave alterations rather than SBP changes during propofol anesthesia, because the modified HR and T-wave criteria were associated with 100% efficacy with the least dose of epinephrine used in our study. This is in clear contrast with previous studies in which the SBP criterion consistently showed equal or superior efficacy to the modified HR criterion at various concentrations of isoflurane and sevoflurane anesthesia (3,4). Concentration-dependent depression of the HR response to the IV test dose during general anesthesia with a potent volatile anesthetic is in agreement with previous in vitro studies in which volatile anesthetics reduced the normal electromechanical activity of human atrial fibers as well as the maximal sinus rate response to epinephrine in a noncompetitive manner in guinea pig hearts (9,10). Propofol, however, produces virtually no electrophysiologic effect on the human heart conducting system and the sinoatrial node (11,12). Indeed, the mean maximal HR increase after an IV test dose containing 15 μg of epinephrine in propofol-anesthetized patients was considerably more than that in sevoflurane-anesthetized patients (43 versus 26 bpm), but was comparable to that of awake volunteers (50 bpm) (5,13,14).
In contrast to hemodynamic responses to the IV test dose, neither absolute nor percent change in T-wave amplitude demonstrated a clear dose-response relationship (Fig. 3). The fact that a larger dose of epinephrine does not necessarily produce a greater change in T-wave amplitude may reflect that alterations of T-wave morphology were not simply a manifestation of β-adrenoceptor-mediated response (15). Although the mechanism of changes in T-wave morphology has not been completely elucidated, flattening or inversion of the T wave has been reported with various physical and mental stresses in adults (16,17), which suggests that false-positive responses may result from surgical procedures, per se. Therefore, the clinical usefulness of the T-wave criteria has to be ultimately validated in a large clinical trial during surgery. In addition, because the smallest dose of epinephrine was associated with 100% efficacy based on the HR and T-wave criteria in our study, further study is warranted to determine the minimal effective dose of the epinephrine-containing test dose during propofol anesthesia.
It is not clear from our study whether a steady-state concentration of propofol was obtained at the time of study drug injections. However, based on a pharmacokinetic model proposed by Marsh et al. (18), the simulated propofol concentration was approximately 3 μg/mL and was maintained constant after a 10-min stabilization period using our dosing regimen. The dose of propofol, 133 μg · kg−1 · min−1 after the induction of anesthesia, was used in our study to approximate actual clinical practice, because a plasma concentration ≥2.5 μg/mL would be required to achieve hypnosis during combined regional-general anesthesia with propofol (19).
After the IV test-dose injection, six patients in the Epinephrine-15 group and none in the other three groups developed absolute SBP ≥180 mm Hg. In addition, two patients in the Epinephrine-10 group developed transient ventricular ectopic beats. Because the modified HR and T-wave criteria (positive if ≥25% decrease) were associated with 100% sensitivity and specificity after the IV test dose containing 5 μg of epinephrine, these results suggest that the test dose containing 5 μg of epinephrine should be used in patients during propofol and nitrous oxide anesthesia. Furthermore, caution should be exercised in cardiac patients, because hypertension and tachycardia caused by the IV injection of the epinephrine-containing test dose may put these patients at risk for developing myocardial ischemic and/or heart failure.
Possible limitations of this study deserve mention. First, we used T-wave amplitude of lead II, whereas changes in T-wave morphology in other leads were not examined. Whether other leads produce more reliable T-wave changes than lead II in association with the IV test dose is unclear. Second, preexisting T-wave abnormalities, such as in patients taking digoxin, with ventricular hypertrophy or with a history of myocardial infarction, precludes use of the T-wave criteria. Third, when the high thoracic epidural blockade is present in combination with isoflurane anesthesia, the HR response to an IV test dose is attenuated compared with the HR response with low thoracic epidural or in the awake state (20). Moreover, when the epidural block is wearing off, and the test-dose injection is required before the reinforcing dose, concomitant surgical stimulation may increase the false-positive responses based on any criterion, and may adversely affect efficacy. Finally, T-wave morphology was evaluated using a strip-chart in our study. Because making a continuous record of the electrocardiogram every time the test dose is injected is neither practical nor economical, real-time analysis of the electrocardiogram needs to be performed on the oscilloscope in actual clinical practice. Whether a 25% decrease in T-wave amplitude can be detected on the oscilloscope should be addressed in a future study by a blinded, prospective approach.
We conclude that the minimal effective dose of epinephrine associated with 100% sensitivity and specificity was 10 μg based on the SBP criterion, and was 5 μg based on the HR and T-wave criteria.
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