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PEDIATRIC ANESTHESIA

Evaluating Hemodynamic and T Wave Criteria of Simulated Intravascular Test Doses Using Bupivacaine or Isoproterenol in Anesthetized Children

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

	Abstract

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An increase in T wave amplitude 25% is a reliable indicator for detecting intravascular injection of lidocaine-epinephrine test dose in anesthetized children. We examined whether a simulated IV test dose containing bupivacaine instead of lidocaine, and isoproterenol instead of epinephrine, produces reliable changes in heart rate (HR) and T wave morphology. One hundred healthy infants and children (6–72 mo) were randomized to one of five groups (n = 20 each) during 1.0 minimum alveolar anesthetic concentration sevoflurane and 67% nitrous oxide in oxygen: atropine pretreatment (0.01 mg/kg IV) followed by 0.25% bupivacaine containing epinephrine 0.5 µg/kg IV, atropine followed by normal saline, atropine followed by 1% lidocaine containing isoproterenol 0.1 µg/kg, saline pretreatment followed by the lidocaine-isoproterenol test dose, and saline followed by saline. HR was recorded every 20 s and T wave amplitude of lead II was continuously recorded. All patients receiving the bupivacaine-epinephrine test dose and none receiving saline met the HR (positive if 10 bpm increase) and T wave criteria (positive if 25% increase in amplitude). The isoproterenol-containing test dose produced positive responses based only on the HR criterion with or without atropine pretreatment. Our results indicate that HR and T wave changes are useful if a bupivacaine-epinephrine test dose is used and that HR is the only useful indicator if an isoproterenol-containing test dose is used in sevoflurane-anesthetized children.

Implications: To determine if an epidurally administered local anesthetic has been unintentionally injected into a blood vessel, a small dose of epinephrine or isoproterenol may be added to a local anesthetic. We found that an increase in heart rate 10 bpm and an increase in T wave amplitude of lead II 25% are useful indicators for detecting accidental intravascular injection of an epinephrine-containing test dose in sevoflurane-anesthetized children, whereas only a heart rate change is a reliable diagnostic tool if an isoproterenol-containing test dose is used.

	Introduction

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Epidural anesthesia in combination with general anesthesia is increasingly used in pediatric patients. In infants and children, epidural anesthesia is usually initiated after the induction of general anesthesia. Since inadvertent intravascular injection of a large amount of local anesthetic and epinephrine solution could result in potentially life-threatening cardiovascular and central nervous system toxicity (1), optimal subjective symptoms and testing criteria for intravascular injection of such solution have been investigated in anesthetized children (2–7).

Previous studies have shown that simulated IV test doses containing lidocaine and epinephrine (0.5 µg/kg) produce 100% sensitivity and specificity in sevoflurane-anesthetized, atropine-treated children according to the heart rate (HR; positive if 10 bpm increase) and T wave criteria (positive if 25% increase in amplitude) (6–8). However, the systolic blood pressure (SBP) criterion (positive if 15 mm Hg increase) revealed controversial results (6–8). The efficacy of a test dose containing bupivacaine, instead of lidocaine, has not been determined based on these hemodynamic and T wave criteria. Meanwhile, isoproterenol alone or in combination with bupivacaine has also been tested as a chronotropic marker, and was found to be as sensitive as epinephrine for detecting unintentional intravascular injection in both awake and anesthetized children (3–5). Whether the isoproterenol-containing test dose produces characteristic changes in the T wave morphology, as seen with an epinephrine-containing test dose, has never been examined.

Accordingly, this randomized, double-blinded study was designed to determine hemodynamic responses to, and efficacy of, simulated intravascular test doses containing bupivacaine or isoproterenol for detecting accidental intravascular injection. We also tested a hypothesis that bupivacaine instead of lidocaine and isoproterenol instead of epinephrine also produce similar changes in T wave morphology to those after the IV test dose containing lidocaine and epinephrine in healthy infants and children anesthetized with sevo-flurane and nitrous oxide.

	Methods

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After institutional review board approval and informed, parental consent, 100 ASA physical status I children, aged 6–72 mo, with a normal sinus rhythm (determined by preoperative electrocardiography) and 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 of clear liquid 4 h before the estimated time of general anesthesia induction. They also received midazolam 1 mg/kg rectally 10 min before the induction of general anesthesia.

Standard monitors, including an automated blood pressure cuff, electrocardiography (lead II), and a pulse oximeter, were applied. The right arm electrode was placed below the right clavicle between the midclavicular and anterior axillary lines, the left arm electrode was placed below the left clavicle between the midclavicular and anterior axillary lines, and the leg electrode was placed at the epigastrium in all patients. 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 · kg^-1 · h^-1. Ventilation was first assisted and then controlled to obtain end-tidal CO₂ tensions between 30 and 35 mm Hg. A Jackson-Rees circuit was used with a fresh gas flow approximately 3 times the minute ventilation for children <15 kg or a semiclosed circle system was used with a fresh gas flow 6 L/min for children 15 kg throughout the study. Anesthesia was maintained with alveolar concentration of 1 minimum alveolar concentration of sevoflurane adjusted for age (9), and 67% nitrous oxide in oxygen. When hemodynamic variables and end-tidal concentrations were stable for at least 10 min after induction, all patients were randomly assigned to one of five groups (n = 20 each) according to the pretreatment and a simulated IV test dose by using the computer-generated random numbers: an atropine-bupivacaine-epinephrine (Atr-Bup-Epi) group first received IV atropine 0.01 mg/kg followed 5 min later by an IV test dose consisting of 0.25% bupivacaine with 1:200,000 epinephrine solution 0.1 mL/kg (epinephrine 0.5 µg/kg), an atropine-saline (Atr-Sal) group received the same dose of IV atropine followed by normal saline 0.1 mL/kg IV, an atropine-lidocaine-isoproterenol (Atr-Lido-Iso) group received IV atropine followed by an IV test dose containing 1% lidocaine 0.1 mL/kg and isoproterenol 0.1 µg/kg, a saline-lidocaine-isoproterenol (Sal-Lido-Iso) group received IV saline followed by the same isoproterenol-containing test dose IV, and a saline-saline (Sal-Sal) group received IV saline followed by the same dose of IV saline. The study solutions were prepared and coded by the hospital pharmacy, and injected by a blinded observer (MT) over 5 s into a peripheral vein before initiation of the surgery in the supine position. Measurements of HR and SBP were made 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 IV atropine, and at 20-s (HR) and 30-s (SBP) intervals for 4 min after IV injections of the bupivacaine-epinephrine test dose, lidocaine-isoproterenol test dose, or saline. Lead II electrocardiography was continuously recorded in a strip chart, and subsequently analyzed for changes in T wave amplitude before and after atropine administration, at its maximum change, and at 1-min intervals for 4 min after the test dose or saline injections. In addition, maximum HR and SBP responses, and arrhythmia, if present, were noted. HR was computed by using the mean of consecutive three R-R intervals from electrocardiography. BP was measured noninvasively throughout the study. The high- and low-frequency filters of electrocardiography were 0.3 and 40 Hz, respectively. The calibration of the recorder was set at 0.5 mV/cm, whereas the chart speed was set at 25 mm/s. T wave amplitudes were measured by an observer blinded to the treatment group of the patient, as well as the hemodynamic changes and subsequently analyzed by two blinded, separate observers who had only been informed of the testing threshold of the T wave criterion as being positive if 25% increase.

A power analysis based on a previous report revealed that more than 16 patients would provide a power greater than 0.8 (P = 0.05) for detecting a 25% difference in paired hemodynamic responses (10). Positive HR, SBP, and T wave changes to IV test doses were prospectively defined from previous reports: positive if a HR increase 10 bpm, a SBP increase 15 mm Hg, or a T wave increase 25% occurred within 2 min of the study drug administration (2,6,11). 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 the means ± SD. Statistical analysis was performed by two-way analysis of variance to compare changes in hemodynamic variables and T wave amplitude between groups. When a significant difference was identified, it was followed by unpaired Student’s t-test with Bonferroni’s correction. Intergroup differences in demographic data were also compared using unpaired Student’s t-test with Bonferroni’s correction or 2 test. 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-test. Proportions of patients with positive responses were compared with Fisher’s exact probability test. A P value less than 0.05 was considered to be statistically significant.

	Results

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There were no significant differences in the patients’ age, weight, height, and sex distribution among groups (Table 1). After the induction of general anesthesia with sevoflurane and nitrous oxide (postinduction), SBP and diastolic blood pressure decreased significantly compared with preinduction (after premedication) values in all groups, whereas a significant decrease in T wave amplitude was seen only in the Atr-Bup-Epi group (Table 1). In the Atr-Bup-Epi, Atr-Sal, and Atr-Lido-Iso groups, preinjection (after IV atropine) HR values were significantly greater than postinduction (before atropine) values, and were significantly greater than those of the Sal-Lido-Iso and Sal-Sal groups at the corresponding interval (Table 1). Oxygen saturation was 97% in all patients during the entire study period.

View larger version (28K): [in this window] [in a new window]   Figure 1. Changes in heart rate after the IV injection of the test dose containing 0.25% bupivacaine 0.1 mL/kg + epinephrine 0.5 µg/kg with prior atropine 0.01 mg/kg (Atr-Bup-Epi group, n = 20), and 1% lidocaine 0.1 mL/kg + isoproterenol 0.1 µg/kg with (Atr-Lido-Iso group, n = 20) and without (Sal-Lido-Iso group, n = 20) prior atropine 0.01 mg/kg in sevoflurane-anesthetized children. Since heart rate was essentially unchanged after saline injections of the other groups, these data are not presented. Data are the means ± SD. *P < 0.05 versus preinjection values.

View larger version (18K): [in this window] [in a new window]   Figure 3. (Top) A typical response of T wave amplitudes (96% increase) in lead II of a 25-mo-old boy before (A) and after (B) the patient received an IV test dose containing 0.5 µg/kg epinephrine in 0.25% bupivacaine. (Bottom) Alteration of T wave amplitudes (27% increase) in lead II of a 51-mo-old boy before (A) and after (B) the patient received an IV test dose containing 0.5 µg/kg epinephrine in 0.25% bupivacaine.

View larger version (23K): [in this window] [in a new window]   Figure 4. Percent changes in T wave amplitude (lead II electrocardiography) after the IV injection of the test dose containing 0.25% bupivacaine 0.1 mL/kg + epinephrine 0.5 µg/kg with prior atropine 0.01 mg/kg (Atr-Bup-Epi group, n = 20), and 1% lidocaine 0.1 mL/kg + isoproterenol 0.1 µg/kg with (Atr-Lido-Iso group, n = 20) and without (Sal-Lido-Iso group, n = 20) prior atropine 0.01 mg/kg in sevoflurane-anesthetized children. Since T wave amplitude was essentially unchanged after saline injections of the other groups, these data are not presented. Data are the means ± SD. *P < 0.05 versus preinjection values. The label "MAX" indicates the time when the maximum T wave occurred in each patient after the bupivacaine-epinephrine test dose injection.

View larger version (28K): [in this window] [in a new window]   Figure 2. Changes in systolic blood pressure after the IV injection of the test dose containing 0.25% bupivacaine 0.1 mL/kg + epinephrine 0.5 µg/kg with prior atropine 0.01 mg/kg (Atr-Bup-Epi group, n = 20), and 1% lidocaine 0.1 mL/kg + isoproterenol 0.1 µg/kg with (Atr-Lido-Iso group, n = 20) and without (Sal-Lido-Iso group, n = 20) prior atropine 0.01 mg/kg in sevoflurane-anesthetized children. Since systolic blood pressure was essentially unchanged after saline injections of the other groups, these data are not presented. Data are the means ± SD. *P < 0.05 versus preinjection values.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
One of the major findings of our study is that the bupivacaine-epinephrine test dose produced 100% efficacy based on the HR and the T wave criteria. Hemodynamic and T wave alterations in response to the bupivacaine-epinephrine test dose were similar to our previous observation using lidocaine-epinephrine test dose (7). In this study, the HR and T wave criteria were clinically useful in sevoflurane-anesthetized children if more than 0.25 µg/kg epinephrine was used as a test dose component. In addition, mean maximum increases in HR and T wave of the current study were of similar magnitudes to those observed in that study. These results imply that epinephrine and its dose, rather than local anesthetics, play a major role in determining HR and T wave responses to IV test dose. In contrast to epinephrine-containing test doses, our study also demonstrated that changes in T wave amplitude were not reliable for detecting unintentional intravascular injection of the isoproterenol-containing test dose with or without prior atropine. These findings suggest that the characteristic change in T wave morphology is not simply a manifestation of a ß-adrenoceptor-mediated response.

Two blinded observers identified all the positive responses in T wave amplitude in patients receiving the epinephrine test dose. Absence of false-positives may be attributed to small T wave variations after IV saline (i.e., less than 5% coefficient of variation in individual patients). These results suggest potential clinical applicability of the T wave criterion for diagnosing accidental intravascular injection of the test dose in anesthetized children. Our observers were blinded only to patients’ treatment and hemodynamic alterations after the IV test dose. Therefore, we cannot exclude a possibility that small but progressive changes in the R-R interval and/or T wave morphology may have affected a judgment, rather than T wave amplitude, per se. In addition, the limit of this observation remains to be determined in a larger study. More importantly, we did not determine whether the small but significant changes in T wave amplitude could be detected on the oscilloscopic monitor. Maximum changes in T wave amplitude occurred earlier than hemodynamic variables and were short-lived (Fig. 4). To maximize the detectability of an accidental intravascular injection of the epinephrine test dose, we recommend making a continuous record of electrocardiography, which should be started as soon as the test dose is injected.

A limitation of our study would be that lead II electrocardiography was continuously monitored and recorded, but no other leads were assessed. Nevertheless, a previous study by Fisher et al. (11) used either lead I or II, and found similar changes in T wave morphology after accidental intravascular injections of epinephrine test doses. Whether leads other than lead II produce more reliable T wave changes in response to the IV test dose remains to be determined. It may also be argued that preexisting ST-T segment abnormalities associated with bundle branch block or ventricular hypertrophy in some congenital cardiac anomalies, serum potassium abnormalities, and taking digoxin may preclude using the T wave criterion (12). Lastly, the test doses were injected via a peripheral vein to simulate a clinical situation, but not into an epidural vein. A similar time course of hemodynamic changes has been reported after an IV injection of a test dose into a peripheral arm vein and into an epidural vein (13).

In several previous reports, hemodynamic responses and efficacies of simulated IV test dose using isoproterenol compared favorably with epinephrine as a chronotropic marker (3–5). To date, however, toxicity of epidural and/or intrathecal administration of isoproterenol has not been fully investigated. The only published article regarding this issue studied spinal somatosensory-evoked potential after a single administration of epidural isoproterenol 50 µg in sheep, and showed unaffected latency and amplitude compared with preinjection values (14). Until screening for potential neurotoxicity of chronic exposure of isoproterenol in doses that far exceed the proposed clinical dose in at least two species, the use of isoproterenol as an epidural test drug should not be recommended in humans (15). Consequently, the efficacy of epidural isoproterenol may be clinically irrelevant at this time.

In conclusion, this randomized, double-blinded study showed that the IV injection of epidural test doses consisting of bupivacaine + epinephrine 0.5 µg/kg, and lidocaine + isoproterenol 0.1 µg/kg produced 100% efficacy based on the HR criterion (positive if 10 bpm increase) in sevoflurane-anesthetized infants and children. The epinephrine-containing test dose produced increases in T wave amplitude 25% in all children, but the isoproterenol-containing test dose resulted in inconsistent changes in T wave morphology. These results suggest that increases in T wave amplitude induced by IV epinephrine may not be simply a manifestation of ß-adrenoceptor-mediated response.

	References

Top Abstract Introduction Methods Results Discussion References

 

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999