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Abstract |
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Recent studies have shown that an epidural test dose containing 15 µg of epinephrine has a sensitivity and specificity of 100% for detecting intravascular injection based on the systolic blood pressure (SBP) (positive if
15-mm Hg increase) and the T wave criteria (positive if 0.1 mV and 25% decrease in amplitude), whereas the modified heart rate (HR) criterion (positive if 10-bpm increase) produced uncertain results in sevoflurane-anesthetized adults. Because a fractional dose of the test dose may be injected intravascularly in actual clinical situations, we designed this study to determine, in a dose-related manner, the efficacy and minimum effective dose of epinephrine based on those hemodynamic and the T wave criteria. Eighty healthy adult patients were randomly assigned to one of four groups according to a simulated IV test dose under 2% end-tidal sevoflurane and nitrous oxide anesthesia after endotracheal intubation (n = 20 each). The saline group received 3 mL of normal saline IV; the epinephrine-15 group received 3 mL of 1.5% lidocaine containing 15 µg of epinephrine (1); and the epinephrine-10 and -5 groups received 2 and 1 mL of the test dose of the identical components, respectively. HR, SBP, and lead II of the electrocardiograph were recorded continuously for 5 min after the IV injection of the study drug. Sensitivities and specificities of 100% were obtained based on the HR and the SBP criteria only if 15 µg of epinephrine was injected IV, whereas sensitivities and specificities of 100% were obtained based on both T wave criteria after 15 and 10 µg of epinephrine was injected IV. Two blinded observers were able to detect all T wave changes in patients who received 15, 10, and 5 µg of epinephrine IV, resulting in 100% efficacy (P < 0.05 versus HR and SBP criteria). We conclude that minimum effective epinephrine doses for detecting accidental intravascular injection are 15 µg on the HR and the SBP criteria, and 10 µg on both T wave criteria, and that observing T wave changes may detect even smaller (5 µg) doses of epinephrine injected IV in adult patients anesthetized with sevoflurane and nitrous oxide.
Implications: To determine whether an epidural catheter is in a blood vessel, an epidural test dose containing 15 µg of epinephrine is used. We found that a decrease in T wave amplitude appears to be more sensitive than heart rate and systolic blood pressure change for detecting accidental intravascular injection of a small dose of epinephrine-containing test dose in sevoflurane-anesthetized patients.
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Introduction |
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Epidural anesthesia is increasingly used in combination with general anesthesia. Although the inability to aspirate blood from an epidural catheter does not ensure extravascular placement, and the efficacy of repeated injections of a test dose has not been substantiated in a previous study (1), objective hemodynamic and electrocardiographic changes have been reported to indicate intravascular migration of the epidural catheter (2,3). An inadvertent IV injection of a large amount of local anesthetic-containing epinephrine solution could result in potentially life-threatening cardiovascular or central nervous system complications during general anesthesia (4).
Previous studies have shown that the systolic blood pressure (SBP) (positive if 15-mm Hg increase) criterion was 100% sensitive and specific for detecting intravascular injection of the test dose containing 15 µg of epinephrine over wide end-tidal concentrations of isoflurane and sevoflurane in anesthetized adults (2,3), whereas the modified heart rate (HR) (positive if 10-bpm increase) criterion revealed controversial results (3,5). Meanwhile, a recent study demonstrated that decreases in T wave amplitude on lead II of the electrocardiograph by 25% and 0.1 mV were 100% sensitive and specific over 0.5% to 2% end-tidal sevoflurane, with an IV test dose containing 15 µg of epinephrine (3). In actual clinical situations, however, only a part of the local anesthetic solution may be injected intravascularly when the tip of the catheter with multiple side orifices migrates into the intravascular space. Hence, it is clinically important to define the minimum effective dose of epinephrine required to elicit 100% efficacy based on those hemodynamic and T wave criteria. However, there are no reports examining the efficacy of simulated intravascular test doses in sevoflurane-anesthetized patients in a dose-related manner.
Accordingly, our prospective, randomized, dose-response study was designed to determine hemodynamic and T wave changes to, and effectiveness of, simulated IV test doses containing 5, 10, and 15 µg of epinephrine based on hemodynamic and the more contemporary T wave criteria in sevoflurane-anesthetized patients. In addition, we sought to determine whether a 25% decrease in T wave amplitude could be detected on a strip chart by observers blinded to the study drug and hemodynamic alterations.
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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. Eighty nonpregnant, ASA physical status I patients, 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-h fast and without premedication. They were subsequently randomized to one of four groups (n = 20 each) according to computed random numbers: a saline group, an epinephrine-15-µg group, an epinephrine-10-µg group, and an epinephrine-5-µg group. Preinduction blood pressure (BP) and HR were obtained noninvasively. Standard lead II electrocardiography was monitored continuously throughout the study. A radial arterial cannula was placed for preinjection and subsequent BP measurements after injections. Lactated Ringer’s solution was maintained at a constant rate of approximately 15 mL · kg-1 · h-1 throughout the study. After induction of general anesthesia with thiopental 5 mg/kg IV, endotracheal intubation was facilitated with vecuronium 0.1 mg/kg IV. Anesthesia was then maintained with end-tidal sevoflurane 2% and 67% nitrous oxide in oxygen (Capnomac Ultima; Datex, Helsinki, Finland), whereas ventilation was controlled to maintain end-tidal carbon dioxide tension at 30–35 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 induction of general anesthesia, either normal saline or one of three simulated epidural test doses was injected IV into a peripheral vein over 5 s, and HR and SBP were analyzed at 20-s intervals for 5 min. In addition, maximal HR and SBP responses were noted. The saline group received 3 mL of normal saline, the epinephrine-15 group received 3 mL of 1.5% lidocaine containing 15 µg of epinephrine (1:200,000), and the epinephrine-10 and -5 groups received 2 and 1 mL of the test dose of the identical components, respectively. Typically, we began hemodynamic measurements 25–30 min after anesthesia induction. All hemodynamic measurements were performed before initiation of the patient’s scheduled surgery in the supine position.
Continuous records (strip chart) of HR, SBP, and lead II of electrocardiography (Life Scope; Nihon Koden, Tokyo, Japan) were obtained after injection of the study drug. The high- and low-frequency filters of electrocardiography 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. All measurements of T wave amplitude were made at its maximal deflection and at 60-s intervals for 5 min by another observer blinded to the treatment group of the patient and the hemodynamic changes. The study solutions were prepared and coded by the hospital pharmacy, and injected by one of the investigators. Upon completion of the study and all the data collection, these codes were broken by the author (MT). In addition, continuous records of strip-chart electrocardiography were analyzed at random orders and at separate occasions by two observers (TG and TK), who were informed of a 25% decrease in T wave amplitude as a positive threshold, but remained blinded to the treatment group of patients as well as to hemodynamic alterations upon study drug injections.
A power analysis based on a previous report revealed that more than 16 and 20 patients would provide a power >0.8 (P = 0.05) for detection of a 25% difference in paired hemodynamic responses and changes in T wave amplitudes, respectively (3,6,7). Positive HR, SBP, and T wave changes to the IV test dose were prospectively defined from previous reports: positive if an HR increase was 10 bpm (2), an SBP increase was 15 mm Hg (6), and a decrease in T wave amplitude was 0.1 mV or 25% (3), occurring within 2 min of study-drug administrations. 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 two-way analysis of variance to compare changes in hemodynamic variables and T wave amplitude (normally distributed data) among groups, and when a significant difference was identified, was followed by unpaired Student’s t-tests with Bonferroni’s correction. Intergroup differences in demographic data and test-dose effectiveness were also compared using unpaired Student’s t-tests with Bonferroni’s correction, and 
2 or Fisher’s exact probability test as appropriate. Changes in hemodynamic variables and T wave amplitudes over time within each group were analyzed by repeated-measures analysis of variance followed by paired Student’s t-tests. P < 0.05 was considered to be statistical significance.
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Results |
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There were no significant differences among the four groups in terms of age, weight, height, and sex distribution (Table 1). After induction of general anesthesia using sevoflurane and nitrous oxide at steady state, BP and HR decreased significantly compared with resting (preinduction) values in all groups, whereas T wave amplitude slightly, but significantly, decreased in the epinephrine-15 and -5 groups. However, no significant differences were seen in resting and preinjection (immediately before study-drug injections) values of BP, HR, and T wave amplitude among the four groups.
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Compared with preinjection values, IV injection of the epinephrine test dose produced significant increases in HR between 40–80 s in the epinephrine-15 and -10 groups, and between 60–80 s in the epinephrine-5 group, whereas significant decreases in HR were seen between 160–280, 120–300, and 140–300 s in the epinephrine-15, -10, and -5 groups, respectively (Figure 1). Mean maximal increases in HR in the epinephrine-15, -10, and -5 groups were 26 ± 8, 16 ± 6, and 12 ± 6 bpm (P < 0.05, epinephrine-15 group versus epinephrine-10 and -5 groups), occurring at 50 ± 6, 56 ± 10, and 67 ± 17 s after test dose injections, respectively. However, significant, monophasic increases in SBP were seen between 20–240, 40–240, and 40–200 s in the epinephrine-15, -10, and -5 groups, respectively (Figure 2). Mean maximal increases in SBP were dose related, and were 42 ± 14, 28 ± 9, and 16 ± 8 mm Hg (P < 0.05, between any two groups), occurring at 85 ± 13, 98 ± 15, and 103 ± 25 s after test-dose injections, respectively. All patients who received test doses, but none who received saline, developed decreases in T wave amplitude within 60 s of injections (Figure 3). Compared with preinjection values, significant decreases in T wave amplitudes were seen until 180, 180, and 120 s after test-dose injections in the epinephrine-15, -10, and -5 groups, respectively (Figure 4). Mean maximal absolute decreases in T wave amplitudes were similar, and were 0.25 ± 0.10, 0.27 ± 0.10, and 0.21 ± 0.12 mV, occurring at 36 ± 11, 42 ± 7, and 56 ± 14 s, in the epinephrine-15, -10, and -5 groups, respectively. There were also no significant differences in the mean maximal percent decreases in T wave amplitudes (Figure 4). The range of the greatest percent change in T wave amplitudes after IV saline was from -9% to 10%, including all patients during the entire study. Coefficients of variations of all T waves determined beat-by-beat during the first 60 s within each individual patient who received saline were <3%.
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In the epinephrine-15, -10, and -5 groups, 20, 17, and 12 patients developed maximal HR increases
10 bpm in response to IV test doses, respectively. Because no patients who received saline developed HR 10 bpm, sensitivity/specificity/positive predictive value/negative predictive value on the HR criterion were 100%/100%/100%/100%, 85%/100%/100%/87%, and 60%/100%/100%/71%, respectively (Table 2). Similarly, 100% sensitivity and specificity were obtained based on the SBP criterion only if 15 µg of epinephrine was injected IV, whereas 100% efficacy was obtained based on the combination of HR or SBP criterion (positive if either HR or SBP criterion was met) if more than 10 µg of epinephrine was injected. However, all patients in the epinephrine-15 and -10 groups and none receiving saline developed maximal absolute decreases in T wave amplitude 0.1 mV, and maximal percent decreases in T wave amplitude 25% of preinjection values, resulting in sensitivity/specificity/positive predictive value/negative predictive value of all 100% based on both T wave criteria. Two patients in the epinephrine-5 group developed 0.08 and 0.09 mV decreases, and one developed 23% decrease in T wave amplitude. Two blinded observers, however, were able to identify visually all the T wave changes in those receiving IV test doses, resulting in 100% effectiveness in all epinephrine groups.
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Four patients in the epinephrine-15 group and one the epinephrine-10 group developed a negative T wave, which resolved within 2 min of the test-dose administrations. No ventricular or supraventricular arrhythmia was observed in any patient throughout the study.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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One major finding of our study is that the efficacy of hemodynamic criteria for detecting intravascular injection of the test dose depends on the dose of epinephrine injected IV in sevoflurane-anesthetized adult patients. Both the HR and the SBP criteria were reliable only when a full dose of the test dose containing 15 µg of epinephrine was injected intravascularly. However, when a tip of an epidural catheter with multiple side orifices migrates into the intravascular space and a fractional dose is injected intravascularly, false negatives may result based on either HR, SBP, or their combination criteria. This is in accordance with a previous study, in which the HR and the SBP responses to, and effectiveness of, a smaller dose of the epinephrine test dose were depressed during stable 1% end-tidal isoflurane anesthesia (2). Therefore, one should consider that using a multi-orifice epidural catheter may be associated with an increased likelihood of developing false-negative responses based on the hemodynamic thresholds. In actual clinical situations, when hemodynamic responses were marginal after the test-dose injection, either a larger dose or repeated administrations of the test dose may be necessary.
Although reliability of these interventions has not been validated in a larger clinical trial (1), our results imply that, when the initial test-dose injection through a multi-orifice catheter failed to produce any significant hemodynamic alterations, a larger dose may augment hemodynamic changes and the detectability of accidental intravascular injection. In contrast, both T wave criteria were 100% sensitive and specific after IV injection of 10 µg of epinephrine, and were more sensitive than hemodynamic criteria after 5 µg of epinephrine. T wave morphology can be monitored noninvasively and continuously, and its magnitude of change determined either as an absolute change or as a percent change did not depend on the wide range of sevoflurane concentrations studied (3), as opposed to the hemodynamic changes (2). A larger study would be required to determine the usefulness of the T wave criterion under variable clinical circumstances.
Two blinded observers in our study were able to detect all the decreases in T wave amplitudes of more than 25%, as well as a T wave decrease of 23% in one patient who received five micrograms of epinephrine, but none of the 20 patients who received IV saline was considered as a positive response, i.e., no false positives. This may be attributed to extremely small T wave variations in individual patients receiving saline during stable sevoflurane anesthesia. However, we cannot exclude a possibility that small, but progressive, changes in R-R interval and/or T wave morphology on the electrocardiograph in a strip chart may have affected a judgment, rather than T wave amplitude, per se
Although most of the patients who received an IV test dose developed maximal T wave reductions in 30–90 seconds, 60%, 60%, and 95% of those in the epinephrine-15, -10, and -5 groups, respectively, retained decreases in T wave amplitudes less than 25% two minutes after test-dose injections. These results indicate that the reduction of the T wave amplitude is a transient finding. Because making a continuous record of electrocardiography every time the test dose is injected is neither practical nor cost effective, whether a 25% decrease in T wave amplitude can be detected on the oscilloscope should be addressed in a future study by using a blinded, prospective approach before T wave alterations can be considered as a viable criterion.
Whether the reduction of the T wave amplitude is caused by epinephrine, lidocaine, or their combination, and what the mechanism of changes in T wave morphology is, have not been elucidated. Our preliminary (unpublished) data showed that IV isoproterenol produced inconsistent changes in T wave amplitudes, whereas the combination of epinephrine and bupivacaine produced consistent reductions of T wave amplitudes. These results suggest that alteration in T wave amplitude is not simply a manifestation of a ß-adrenoceptor-mediated response, and that local anesthetic may not be a primary determinant of T wave alterations. Epinephrine reduces serum potassium concentrations via ß2-adrenoceptor stimulation (8,9). However, the influence of serum potassium changes in a transient reduction of T wave amplitude would be difficult to determine. More recently, an increase, rather than a decrease, in T wave amplitude was reported to occur consistently after an IV test dose containing 0.5 µg/kg epinephrine in sevoflurane-anesthetized children (10). In this study, a significant inverse correlation between the age and the degree of T wave augmentation had been demonstrated. However, the "cut-off" age at which T wave conversion occurs after an IV test dose is undetermined. More importantly, flattening of the T wave or T wave inversion was reported with various physical and mental stresses (11–13). The usefulness of the T wave criteria ultimately requires validation in a large clinical trial during surgery when an epidural block from local anesthetic is wearing off, and also whether simultaneous surgical stimulation produces false-positive responses remains to be studied.
Our study must be interpreted with some caution. First, preexisting T wave abnormalities, such as in patients taking digoxin, those with left ventricular hypertrophy, or those with a history of myocardial infarction, precludes using the T wave criteria (14). Second, T wave amplitude of lead II was used as a testing threshold, but other leads of the electrocardiograph were not studied. Although changes in T wave morphology of other leads have not been reported after IV test doses in adults, similar electrocardiographic alterations were reported in leads I and II in anesthetized children (15). Finally, whereas we used the monitor mode, by using the diagnostic mode, i.e., bandwidth of 0.05 to 100 Hz, detectability of T wave changes may have been augmented. However, this level of low-frequency filter is often associated with respiratory movement of electrocardiography lead wires and wandering baselines (16).
In conclusion, our results indicate that a minimal effective epinephrine dose for detecting unintentional intravascular injection of the test dose was 15 µg based on the HR (positive if 10 bpm increase) and the SBP (positive if 15 mm Hg increase) criteria, and 10 µg based on both T wave criteria (positive if 0.1 mV and 25% decrease in T wave amplitude in lead II), whereas observing T wave changes may detect even smaller (5 µg) doses of epinephrine-containing test dose injected intravascularly in adult patients anesthetized with sevoflurane and nitrous oxide.
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Footnotes |
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Presented in part at the annual meeting of the American Society of Anesthesiologists, October 9–13, 1999, Dallas, TX.
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References |
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- Mulroy MF, Norris MC, Liu SS. Safety steps for epidural injection of local anesthetics: review of the literature and recommendations. Anesth Analg 1997; 85: 1346–56.[Web of Science][Medline]
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Tanaka M, Nishikawa T. A comparative study of hemodynamic and T-wave criteria for detecting intravascular injection of the test dose (epinephrine) in sevoflurane-anesthetized adults. Anesth Analg 1999; 89: 32–6.
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Kubota Y, Toyoda Y, Kubota H, Asada A. Epinephrine in local anesthetics does indeed produce hypokalemia and ECG changes [letter]. Anesth Analg 1993; 77: 867.
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[Abstract/Free Full Text] - Guazzi M, Fiorentini C, Polese A, et al. Stress-induced and sympathetically mediated electrocardiographic and circulatory variations in the primary hyperkinetic heart syndrome. Cardiovasc Res 1975; 9: 342–54.[Web of Science][Medline]
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- Verrier RL, Nearing BD. T-wave alternans as a harbinger of ischemia-induced sudden cardiac death. In: Zipes DP, Jalife J, eds. Cardiac electrophysiology: from cell to bedside. Philadelphia: WB Saunders, 1995: 467–77.
- Fisher QA, Shaffner DH, Yaster M. Detection of intravascular injection of regional anaesthetics in children. Can J Anaesth 1997; 44: 592–8.[Web of Science][Medline]
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