Epidural anesthesia is often used as an adjunct to general anesthesia and for postoperative analgesia. Most commonly, epidural anesthesia is initiated under general anesthesia for infants and children. To avoid life-threatening central nervous system (CNS) and cardiac sequelae associated with the accidental intravascular injection of large amounts of local anesthetic solution , a variety of strategies to reliably detect intravascular injection have evolved [2,3]. In awake adult patients, assessment of sensory analgesia, subjective symptoms indicating minor CNS toxicity and objective hemodynamic changes after a small dose of local anesthetic plus epinephrine, help to elucidate the catheter location in most cases [4,5]. In anesthetized children, however, only objective signs can indicate or rule out the intravascular placement of the catheter.
An epinephrine-containing test dose reliably causes an increase in heart rate (HR) >20 bpm in awake adult patients when it is accidentally given IV . During general anesthesia, however, HR changes are remarkably depressed in both adult and pediatric patients, possibly because of the direct effect of general anesthetics on sinoatrial nodal activity. Hence, the accuracy of the test dose, according to the adult HR criterion, is clinically unacceptable [3,6-8]. In addition, the effect of a small dose of epinephrine on HR depends on the arterial baroreflex sensitivity, which is also affected to a differing extent by each volatile anesthetic . Furthermore, positioning of the patient and needle insertion may provoke adrenergic responses and result in false-positive observations, which may prompt unnecessary abandonment of an otherwise effective epidural technique. These considerations urged us to look for an indicator that could provide more reliable accuracy than simple hemodynamic alterations, that would not be influenced by adrenergic cardiovascular responses, and that would be clinically feasible in lightly anesthetized children.
Previous reports suggest that the accidental intravascular injection of a small dose of local anesthetic plus epinephrine solution produced changes in T-wave morphology in anesthetized children, i.e., increases in T-wave amplitude [10,11]. However, the clinical applicability of such observations is limited by the retrospective nature of the reports, the use of different local anesthetics, and the nonuniform dose of epinephrine. Accordingly, we designed the present study to prospectively determine the efficacy of a simulated IV test dose using changes in T-wave amplitude as a criterion to detect intravascular injection in sevoflurane-anesthetized children.
After institutional review board approval and informed, parental consent, 32 ASA physical status I children, aged 6-72 mo, with a normal sinus rhythm (determined by the preoperative electrocardiography), undergoing elective minor surgeries under general anesthesia were enrolled. All patients were allowed ad libitum food 8 h before, and a maximum of 10 mL/kg clear liquid 4 h before the anticipated time of general anesthesia induction. They also received midazolam 1 mg/kg rectally 10-15 min before the induction of general anesthesia. A Jackson-Rees circuit was used with a fresh gas flow approximately 3 times the minute ventilation for children <15 kg or semi-closed circle system with a fresh gas flow of 6 L/min for children >or=to15 kg throughout the study. Standard monitors including automated blood pressure (BP) cuff, electrocardiography (lead II), and pulse oximeter were applied. After mask induction with sevoflurane and 67% nitrous oxide in oxygen, a forearm peripheral vein was cannulated, and lactated Ringer's solution containing 2% dextrose was administered at a rate of 5 mL [center dot] kg-1 [center dot] h-1. Ventilation was first assisted, then controlled to obtain end-tidal CO2 tensions of 30-35 mm Hg. Anesthesia was maintained with alveolar concentration of 1 minimum alveolar anesthetic concentration of sevoflurane adjusted for age  and 67% nitrous oxide in oxygen. When hemodynamic variables and end-tidal concentrations were stable for at least 10 min after induction, IV atropine 0.01 mg/kg was administered in all patients. Another 5 min was allowed to obtain a stable HR and systolic BP (SBP) before patients were randomly assigned to one of the following groups according to the computer-generated random numbers: the test dose group received a test dose consisting of 1% lidocaine with 1:200,000 epinephrine solution 0.1 mL/kg (0.5 [micro sign]g/kg epinephrine, n = 16), and the saline group received isotonic sodium chloride solution 0.1 mL/kg (n = 16). The study solutions were prepared and coded by the hospital pharmacy and injected by a blinded observer (MT) over 5 s into a peripheral IV line before the initiation of surgery with patients in the supine position. HR and SBP were measured at rest, after premedication with midazolam, at least 10 min after the induction of general anesthesia before atropine administration when stable hemodynamic variables and end-tidal concentrations were maintained, 5 min after the IV administration of atropine, and at 20-s (HR) and 30-s (SBP) intervals for 5 min after IV injections of the test dose or saline. Lead II was continuously recorded in a strip chart and subsequently analyzed for changes in T-wave amplitude before and after atropine administration, at its maximal amplitude, at the peak HR, and at 1-min intervals for 5 min after the test dose or saline injections. If present, arrhythmia was also noted. HR was computed using the mean of consecutive three RR intervals from the electrocardiography. BP was measured noninvasively throughout the study. T-wave amplitude was measured by another observer blinded to the treatment group of the patient and the hemodynamic changes.
A power analysis based on a previous report revealed that >16 patients would provide a power >0.8 (P = 0.05) for detection of a 25% difference in paired hemodynamic responses . Positive HR and SBP responses to the IV test dose were prospectively defined from previous reports: positive if a HR increase >or=to10 bpm and a SBP increase >or=to15 mm Hg occurred within 2 min of administration [2,13]. 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 are presented as mean +/- SD. Statistical analysis was performed by using two-way analysis of variance to compare changes in hemodynamic variables and T-wave amplitude between groups. When a significant difference was identified, this was followed by an unpaired Student's t-test. Intergroup differences in demographic data were also compared by using a Student's t-test or chi squared test. Changes in hemodynamic variables and T-wave amplitudes over time within each group were analyzed by using repeated-measures analysis of variance followed by a paired Student's t-test. Correlations between patients' age and maximal HR increases versus maximal percent increases in T-wave amplitudes were analyzed using Pearson's correlation coefficient. A P value <0.05 was considered statistically significant.
Mean (range) age, weight, and height of all patients were 41 +/- 20 (6-72) mo, 16.0 +/- 5.0 (7.6-25.0) kg, and 98.3 +/- 16.0 (66.7-123.0) cm, respectively, and no significant differences were found in these demographic data between groups. There were nine male and seven female patients in each group. After the induction of general anesthesia with sevoflurane and nitrous oxide, SBP and diastolic BP (DBP) decreased significantly compared with resting values after rectal midazolam in both groups (Table 1). IV atropine produced significant increases in HR compared with those before atropine in both groups, whereas SBP, DBP, and T-wave amplitude were unchanged (Table 1). There were no significant differences between groups in terms of SBP, DBP, HR, and T-wave amplitudes at rest, 10-15 min after premedication, and before and 5 min after atropine administration (Table 1). T-wave amplitudes were also unchanged over time in both groups before the study drug injections. Oxygen saturation was >or=to97% in all patients during the entire course of the study.
The IV injection of the test dose produced significant increases in HR between 20 and 60 s and significant decreases between 120 and 300 s compared with preinjection values (Figure 1), whereas SBP showed monophasic significant increases 30-180 s after injections. Essentially no changes in these variables were found in the saline group (data not shown). Mean maximal increases (95% confidence interval) in HR and SBP in the test dose group were 21 +/- 7 (17-23) bpm and 31 +/- 15 (23-39) mm Hg, occurring at 30 +/- 7 and 70 +/- 31 s, respectively. T-wave amplitude consistently increased compared with preinjection values in all patients receiving the IV test dose, and it was significantly increased until 2 min after the injections (Figure 2). Mean maximal percent increase in T-wave amplitude in the test dose group was 121.1% +/- 59.9% (80.8%-161.4%), which occurred 20 +/- 5 s after injections.
All children in the test dose group, but none in the saline group, developed HR increases >10 bpm, resulting in sensitivity, specificity, a positive predictive value, and a negative predictive value of 100%. Of 16 children, 13 developed SBP increases >15 mm Hg, whereas none in the saline group met the SBP criterion. Therefore, sensitivity, specificity, and positive and negative predictive values based on the SBP criterion were 81%, 100%, 100%, and 84%, respectively. However, all children in the test dose group and none in the saline group developed a maximal percent increase in T-wave amplitude >25%, resulting in sensitivity, specificity, and positive and negative predictive values of 100%.
Significant negative linear correlation was demonstrated between the patients' age and the maximal percent increase in T-wave amplitude (Figure 3) (P = 0.03, R = 0.61), whereas no significant correlation was seen between the maximal increase in HR and the maximal percent increase in T-wave amplitude (R = 0.07). No arrhythmia was observed throughout the entire course of the study.
The major finding of our study is that a simulated IV test dose produced reliable increases in T-wave amplitude in monitor lead II electrocardiography when a 25% increase was considered as a threshold of a positive response. Although 25% could be considered an arbitrary number, it was chosen as a threshold in a previous study . The 25% increase could also be easily detected visually on a strip chart, as in our study. However, a more appropriate criterion should be determined using the 95% or 99% confidence interval obtained in a larger study. Moreover, the potential usefulness of the T wave as a novel marker should be evaluated and compared with other hemodynamic criteria using smaller doses of epinephrine, because only a fraction of the test dose may be administered intravascularly in clinical practice.
The present study and our previous studies demonstrated 100% efficacy based on the pediatric HR criterion (positive if >or=to10 bpm increase) in sevoflurane-anesthetized children pretreated with IV atropine . However, Desparmet et al.  found, in halothane-anesthetized children, that HR did not increase >10 bpm in 39% of children not pretreated with atropine and in 5% of those pretreated with atropine. Similarly, Fisher et al.  showed that a HR increase >10 bpm failed to detect an intravascular injection in 17% of children using various anesthetic techniques. In addition, adrenergic responses associated with epidural needle insertion and postural changes may lead to increased false-positive responses, which may precipitate termination of an effective epidural technique. These previous results suggest that HR responses, as well as the efficacy based on the peak HR, may differ considerably depending on the primary anesthetic used. Further studies are therefore warranted to determine whether similar changes in T-wave morphology could be elicited by an IV test dose using other volatile and local anesthetics. However, the efficacy based on the SBP criterion produced controversial results; although a previous study demonstrated 100% sensitivity and specificity only after atropine treatment in sevoflurane-anesthetized children , the marginal efficacy seen in the present study may be explained by the differences in errors inherent in noninvasive BP monitoring . Lack of power may also explain the discrepancy, and a larger study that involves more patients may be warranted.
Our study does not clarify the mechanism of increased T-wave amplitude after a simulated IV test dose in children. Changes in T-wave amplitude were first reported by Freid et al.  and were originally considered to be due to an amide local anesthetic. However, epinephrine alone was shown to alter T-wave morphology . In adult patients, flattening or inversion of the T-wave occurs in association with various physical and mental stresses and with IV epinephrine [15-17]. Although epinephrine causes a reduction of serum potassium concentration via beta2-adrenoceptors [18,19], the influence of such mechanism on transient changes in T-wave morphology in anesthetized children is unclear. In our study, the increase in the T-wave amplitude did not seem to be related to an increase in HR per se, because IV atropine had no effect on the T-wave amplitude and the increase in HR was not correlated with that in T-wave amplitude. Significant negative correlation between the patients' age and the increase in the T-wave amplitude in our study, as well as a T-wave flattening effect in adult patients reported previously, suggest an age-specific effect of IV epinephrine on T-wave morphology. Because older children may receive epidural anesthesia, it would be of value to determine the cutoff age above which the criterion using the T-wave amplitude cannot be used. Furthermore, whether isoproterenol, another effective chronotropic marker in anesthetized children, produces similar T-wave changes remains to be determined.
In our study, the peak change of the T-wave occurred almost within a circulation time, approximately 10 and 50 s earlier than those of HR and SBP, respectively. Although a significant increase in the T-wave amplitude was seen until 2 min after the test dose injections, 3 (19%), 10 (63%), and 12 (75%) of 16 children showed percent increases in the T-wave amplitudes <25% at the peak HR and 1 and 2 min after the injections, respectively. To successfully detect the maximal T wave in response to the IV test dose, continuously recording of electrocardiography data on a strip chart is highly recommended and should be started as soon as the test dose is administered.
A possible criticism of our study might be that lead II electrocardiography was monitored in our study, whereas changes in T-wave morphology in other leads were not assessed. A previous study by Freid et al.  did not specify which lead was being investigated, whereas the study by Fisher et al.  used either lead I or II and found similar changes in T-wave morphology. Whether leads other than lead II produce more reliable T-wave changes in association with the IV test dose remains to be determined. One might also argue that atropine is no longer routinely administered to pediatric patients undergoing general anesthesia. However, the administration of atropine 10 [micro sign]g/kg IV immediately before the test dose injection improves the reliability for detecting an intravascular injection of the epinephrine-containing test dose based on the HR  and SBP  criteria. Without atropine pretreatment, however, decreases (rather than increases) in T-wave amplitude have been reported in sevoflurane-anesthetized children .
In conclusion, 1% lidocaine with 1:200,000 epinephrine solution 0.1 mL/kg (0.5 [micro sign]g/kg epinephrine) is a reliable indicator of the intravascular injection of the test dose based on the peak T-wave amplitude (positive if >or=to25% increase) from lead II and the pediatric HR threshold (positive if >or=to10 bpm increase), but not on the SBP criterion (positive if >or=to15 mm Hg increase), in children anesthetized with sevoflurane and nitrous oxide. Further studies are warranted to determine whether this novel criterion is still applicable under different anesthetic techniques, with different local anesthetics, or with smaller doses of epinephrine.
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