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PEDIATRIC ANESTHESIA

The Influence of Anthracycline Therapy on Cardiac Function During Anesthesia

Egbert Huettemann, MD, DEAA^*, Thomas Junker, MD^*, Kyriasis P. Chatzinikolaou, MD, Gritta Petrat, MD^*, Samir G. Sakka, MD^*, Lothar Vogt, MD, and Konrad Reinhart, MD^* Section Editor

From the Departments of *Anesthesiology and Intensive Care Medicine and Pediatrics, University Hospital, Friedrich-Schiller-University, Jena, Germany; and Department of Intensive Care, Hippocration General Hospital, Thessaloniki, Greece

Address correspondence and reprint requests to Egbert Hüttemann, MD, DEAA, Department of Anesthesiology and Intensive Care Medicine, Friedrich-Schiller-University Jena, Bachstrasse 18, D-07740 Jena, Germany. Address email to egbert.huettemann{at}med.uni-jena.de

	Abstract

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Cardiotoxicity is a well recognized complication of anthracycline (AC) therapy. Subtle abnormalities in myocardial function that become apparent only after exercise may exist in survivors of childhood cancer who have previously received AC, yet have normal resting cardiac function. To evaluate if anesthesia-induced changes in cardiac function differ in pediatric patients with previous AC therapy from healthy children and adolescents, we evaluated in a prospective study 43 patients, of whom 42 were analyzed. Twenty-one patients (AC-group), mean age 9.6 yr (range, 3–16 yr), who had received 193 (30–490) mg/m² of AC as a mean cumulative dose with normal resting cardiac function (shortening fraction [SF] 0.34, normal value > 0.30) underwent removal of a Hickman catheter under general anesthesia. Twenty-one patients, mean age 10.9 yr (range, 4–17 yr), who underwent placement of a Hickman catheter before chemotherapy served as the control. All children were premedicated with midazolam 0.5 mg/kg orally. Anesthesia was induced by sodium thiopental (5 mg/kg), fentanyl (3 µg/kg), and rocuronium (0.6 mg/kg) and maintained with isoflurane (1 MAC) in N₂O/O₂ (70/30). Before induction (baseline), 5 and 20 min after intubation (T1 and T2), and 20 min after extubation (control), cardiac function was assessed by transthoracic (baseline, control) and transesophageal (T1, T2) echocardiography. Compared with baseline (SF: 34.9 ± 3.7 [AC], 34.1 ± 3.7 [C] [not significant]; stroke volume index [SVI] 36 ± 6 mL/m²[AC], 35 ± 4 mL/m²[C] [not significant]; cardiac index [CI] 3.6 ± 0.6 L/min/m²[AC], 3.2 ± 0.5 L/min/m²[C] [not significant]), we found a significant decrease in SF and SVI in both groups at T1 (SF: 26.2 ± 3.6 [AC] versus 28.6 ± 3.6 [C] [P < 0.05]; SVI: 26 ± 4 mL/m² [AC] versus 30 ± 46 mL/m² [C] [P < 0.05]) and T2 (SF: 24.1 ± 3.2 [AC] versus 28.2 ± 2.5 [C] [P < 0.01], SVI: 26 ± 6 mL/m² [AC] versus 31 ± 5 mL/m² [C] [P < 0.01]), which was significantly greater in the AC group. There were no significant changes of variables of diastolic function (E/A ratio, isovolumetric relaxation time) between both groups. Previous treatment with AC may enhance the myocardial depressive effect of anesthetics even in patients with normal resting cardiac function.

IMPLICATIONS: Previous treatment with anthracylines, a group of chemotherapeutic drugs in use for childhood cancer, may enhance the myocardial depressive effect of anesthetics even in children and adolescents with normal resting cardiac function.

	Introduction

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Cardiotoxicity is a well recognized complication of anthracycline (AC) and anthracenedione therapy. The most commonly used ACs are doxorubicin (adriamycin), idarubicin (idamycin), and daunorubicin (cerubidine). The exact mechanism of AC cardiotoxicity has not been definitely established. AC causes a cumulative loss of cardiac myocytes (1–3), probably mediated by toxic free radicals generated by an intracellular iron-AC complex (4,5), which are not as well metabolized by the heart as they are by other organs (6). In general, myocardial pathogenesis is related to the type of AC drug, the cumulative dose, and dosing schedule (2,6–9).

During the last decade, several studies have demonstrated that subtle cardiac abnormalities may exist in patients who have survived childhood cancer that become apparent only during or after exercise, yet have normal cardiac function at rest (10–12). To test the hypothesis that anesthetics may exert different or more pronounced effects on cardiac function, we studied the influence of previous AC therapy on cardiac function during general anesthesia in patients with normal resting function.

	Methods

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The study protocol was approved by the institutional ethics committee of the Friedrich-Schiller University Jena. All of the subjects (if applicable) and their parents were previously informed about the study and informed consent was obtained.

Forty-three consecutive children and adolescents undergoing placement or removal of a Hickman catheter with general anesthesia were enrolled in this study. One patient was excluded because it was impossible to obtain adequate echocardiographic or Doppler windows for analysis. Therefore 42 patients were analyzed (Table 1). The AC group comprised 21 children and adolescents (14 male, 7 female, mean age 9.6 [range, 4–16] yr) treated for cancer in the Children’s Hospital, University of Jena, who had received chemotherapy with AC for treatment of various forms of cancer, and underwent removal of a Hickman catheter under general anesthesia. All patients were in remission, clinically asymptomatic (i.e., dyspnea on exertion), euthyroid, and had a normal hemoglobin concentration. Four patients had received radiation to the skull but none of the mediastinum. Fourteen patients received cyclophosphamide (2–30 g/m²) as part of their chemotherapeutic regimen. The median cumulative dose of AC was 193 (range, 30–490) mg/m². The mean time period (interval) between the last chemotherapy and our study was 7 mo (range, 1–12 mo). Ten patients had received doxorubicin only, 7 patients doxorubicin and daunorubicin, 2 patients daunorubicin only, 1 patient daunorubicin and idarubicin and 1 patient epirubicin.

All children were premedicated with midazolam 0.5 mg/kg PO and were NPO for 4 -6 h preoperatively. Local cutaneous anesthesia for placement of a peripheral venous cannula was obtained with an anesthetic dressing (EMLA; Astra Chemicals, Plankstadt, Germany). Anesthesia was induced by sodium thiopental (5 mg/kg) and fentanyl (3 µg/kg), and tracheal intubation was facilitated by rocuronium (0.6 mg/kg) and maintained with isoflurane (1 MAC, end-tidal concentration 0.6%) in N₂O/O₂ (70/30). Neuromuscular block was monitored by transcutaneous nerve stimulation of the ulnar nerve (Stimulator NZ 252; Fisher and Paykel, New Zealand) as train-of-four. Repeated doses of rocuronium 0.1 mg/kg were given when a response to the third stimulus (75%–80% neuromuscular block) was detected. Surgery was performed in the supine position. All children underwent mechanical ventilation using a pressure-controlled mode (AS3; Datex-Engstrom, Helsinki, Finland). In all patients, the I:E ratio was 1:1 and end-expiratory pressure was maintained positive at 5 cm H₂O throughout the procedure.

Intraoperative monitors included noninvasive arterial blood pressure, heart rate (HR) by ECG, peripheral oxygen saturation (SaO₂), end-expiratory CO₂ concentration, and rectal temperature. End-expiratory concentration of isoflurane was measured by infrared gas analysers (Datex AS/3; Datex, Helsinki, Finland).

Echocardiographic measurements were performed before induction (T0), 5 min after intubation (T1), 20 min after intubation (T2), and 20 min after extubation (T4). Echocardiographic measurements consisted of left ventricular dimensions to allow calculation of fractional shortening (left ventricular end-diastolic dimension [LVEDD] - left ventricular end-systolic dimension [LVESD]/LVEDD x 100) and Doppler measurements of mitral and pulmonary artery blood flow. The view for measuring shortening fraction (SF) was the parasternal long axis view (transthoracic approach) and the transgastric short axis view (transesophageal approach). Doppler measurement of mitral flow evaluated diastolic function, i.e., the maximal velocity of the E wave of the mitral inflow Doppler signal (E_max), the maximal velocity of the A wave (A_max), the ratio E/A, and isovolumetric relaxation time (IVRT). Doppler measurement of pulmonary artery blood flow allowed calculating of stroke volume index (SVI) and cardiac index (CI). Before induction of anesthesia and after extubation (baseline and control, respectively), transthoracic echocardiographic (TEE) images of the subjects were obtained in the left decubitus position for the apical and parasternal windows. Measurements at T1 and T2 were performed by the transesophageal route. The echocardiographic equipment consisted of a Hewlett Packard (Palo Alto, CA) HP Sonos 1000 using a 2.5 MHz transducer with pulsed and continuous wave Doppler and a 5 MHz monoplane pediatric transesophageal probe. Transesophageal echocardiographic measurements were performed with patients in a supine position. Pulmonary artery diameter was measured immediately above the level of the semilunar valve. The sample volume axial dimension was kept to 3 mm, and the lateral width was constant at 1.5 mm. The sample volume was placed in the pulmonary artery immediately above the pulmonic valve, and positioning for maximal flow velocity was confirmed by both the intensity of the audio signal and the spectral display of the velocities obtained. Peak velocity was measured to the top with the most dense signal on the velocity curve and the beats of one respiratory cycle averaged. Continuously updated two-dimensional images, Doppler profiles, and simultaneous ECG tracings were displayed on a monitor and recorded on videotape. The Doppler determined time velocity integral of pulmonary artery blood flow and echocardiographically determined pulmonary artery diameter were used to calculate stroke volume and cardiac output (13,14). Preoperative echocardiographic studies were performed by L.V. and intraoperatively by E.H. and S.G. The analysis of the videotapes was performed by T.J. and K.C., who were blinded as to the study groups. In those patients undergoing placement of a Hickman catheter (control group), the exact positioning of the Hickman catheter was guided by TEE, allowing avoidance of radiograph controls for documentation of correct position. All patients were evaluated during the postanesthetic round for complaints related to TEE such as sore throat, difficulties in swallowing, and hoarseness.

Data are expressed as mean ± SD. Intergroup comparisons of single variable data were made using the Mann-Whitney U-test for nonparametric data. Data obtained after induction (T1, T2) were compared using a two-way analysis of variance for repeated measurements and the Bonferroni post hoc test. P < 0.05 was considered significant. Linear regression analysis was used to study the correlation between the echocardiographic variable (SF) of myocardial function and the cumulative AC dose.

	Results

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Patient demographic data are shown in Table 1. There were no significant differences for age or weight between the two groups (9.6 ± 4.1 versus 10.9 ± 3.4 yr and 27 ± 8 versus 31 ± 11 kg, P > 0.05). All patients underwent echocardiographic studies either during the previous chemotherapy (as surveillance for signs of a developing AC cardiomyopathy) or at least once as a baseline investigation before the start of treatment in the Children’s Hospital. The maximum interval between the latest echocardiographic study and our study was 2 mo. The variables of the most recent preoperative echocardiographic examination were all in the normal range (SF: 34.5 ± 5.5 (AC) versus 33.8 ± 4.7 (control); CI: 3.6 ± 0.8 (AC) versus 3.7 ± 1.1 (control) L/min/m²); HR: 93 ± 18.6 (AC) versus 91.7 ± 17.4 (control) bpm; E/A: 1.7 ± 0.42 (AC) versus 1.8 ± 0.41 (control)) and did not show differences reaching statistical significance.

No complications occurred intraoperatively. There were no difficulties associated with the placement of the TEE probe, regardless of the age of the subject. There were no more complaints of sore throat or difficulties in swallowing postoperatively than usually associated with general anesthesia and tracheal intubation.

Table 2 displays the results of the measured variables. Throughout the study, there were no significant differences in mean arterial blood pressure, heart rate, peripheral oxygen saturation, and end-tidal carbon dioxide tension between groups. All patients in both groups had normal resting SF (34.9 ± 3.7 [AC] versus 34.1 ± 3.7 [C], not significant) and SVI (35.7 ± 6.1 mL/m² [AC] versus 35.4 ± 3.9 mL/m² [C], not significant). Five and 20 min after intubation SF decreased to 26.2 ± 3.6 (AC) and 28.6 ± 3.6 (C) (P < 0.05) and 24.1 ± 3.2 (AC) and 28.2 ± 2.5 (C) (P < 0.01), respectively. In both groups SF decreased significantly compared with baseline values after induction and intubation (T1, T2). The decrease in SF in the AC group was significantly more than that in the control group (24.9% versus 16.1% (T1), 30.9% versus 17.3% (T2); P < 0.05). The values obtained 20 min after extubation (control) were not significantly different from the baseline values and there were no significant differences between the two groups.

Measurements of diastolic function (E/A ratio) and IVRT showed no significant differences between groups. There was no correlation between the cumulative AC dose and decrease in SF.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Our study indicates that a previous treatment of AC therapy may enhance the cardiodepressive effects of anesthetics. The investigation compared children and adolescents who had survived childhood cancer and had in previous treatments received a median cumulative AC dose of 193 (30–490) mg/m² yet showed normal cardiac function at rest and children newly diagnosed with cancer. The AC patients exhibited a significantly greater decrease in SF and SVI after induction and during maintenance of general anesthesia with isoflurane compared with the control group.

Clinical cardiotoxicity after AC treatment for childhood cancer comprises both an early cardiotoxicity (during therapy or in the first year after therapy) and a late cardiotoxicity. In both children and adults, the risk of cardiotoxicity increases with the cumulative dose of AC (8). The risk of congestive heart failure for children who receive a cumulative dose of 100 to 399 mg/m² is 1.7% as compared with a risk of 9% at cumulative doses more than 500 mg/m² (15). Other possible risk factors for early clinical cardiotoxicity include radiation therapy to the fields that involve the heart, female sex, and younger age (8,16). Despite attempts to reduce cardiotoxicity by limiting the cumulative dose of AC, abnormalities in cardiac structure and function were noted in 65% of survivors of childhood acute lymphoblastic leukemia 6 years after completion of AC therapy (17). Early congestive heart failure in this population is the strongest risk factor for perioperative cardiovascular complications with subsequent surgical procedures (18). Investigations in oncology patients who have received AC showed a significantly smaller increase in SF after exercise compared with patients who had not received AC as part of their medical regimen (11,12). Thus, in survivors of childhood cancer, subtle abnormalities in cardiac function may exist even in patients with normal resting cardiac function that become apparent only after exercise.

No data exist concerning whether the cardiodepressive effects of anesthetics differ in patients with previous exposure to AC from that in healthy children. The cardiac effects of the most widely used anesthetics in pediatric anesthesia, thiopental and the inhaled anesthetics halothane and isoflurane, have previously been investigated by echocardiography by several groups (19–21). Induction of anesthesia by inhaled halothane has been associated with a decrease in SF by 24.6% and SVI by 21% in premedicated children (21). Thiopental (7.5–8.5 mg/kg) has been shown to decrease SF by 31.6% (range, 38%–26.1%) and SVI by 35.3% during induction (preintubation) and by 27.5% after intubation compared with preinduction values (20). In infants and small children, 1.0 MAC of isoflurane caused a 16% decrease in SVI and a decrease in left ventricular ejection fraction (LVEF) of 23% (19). The decrease in SF (-16.1% and -17.2%) and SVI (-16.3% and -13.4%) 5 and 20 minutes after intubation compared with baseline, measured in our control group, conforms well with these published data. With respect to premedication and fasting period, the patients described in the investigations mentioned above did not differ significantly from ours.

Our study concept was different from those studies investigating the cardiovascular effects of anesthetics. First, our study was not designed to differentiate between the effects of an IV induction drug (thiopental) and inhaled anesthetics (isoflurane). The primary objective of our study was to investigate whether the cardiovascular response of children who had previously received AC to a standard anesthetic regimen—balanced anesthesia with an IV induction agent (thiopental), opioids, and an inhaled anesthetic (isoflurane) for maintenance—is different. Thus, the cardiovascular effects of thiopental and isoflurane can not be differentiated. The second difference from previous studies using echocardiography for hemodynamic assessment is that we used TEE intraoperatively. There were three major reasons for this approach. First, sterile draping of the operation field makes an intraoperative transthoracic echocardiographic study intraoperatively almost impossible. Second, the image quality by TEE is far superior to that transthoracically, especially if a left lateral decubitus position is not possible intraoperatively. And third, TEE allows accurate positioning of central venous catheters and thus avoids the need for radiograph control.

Contrary to most previous investigations on AC cardiotoxicity, almost no correlation was found in our investigation between the accumulative dose of AC and abnormalities of cardiac function during anesthesia. However, in one study that found a significantly lesser increase in SF after supine bicycle exercise in the AC group compared with the control group, all but one patient received relatively small doses of AC (19–439 mg/m²) (12). This is in concordance with previous observations that at the smaller range of doses no discernible relationship between the dosage and cardiac abnormality could be detected and that individual patients may have a lower threshold and develop toxicity at a significantly smaller dosage (12,22,23).

Contrary to our findings regarding systolic function, we did not find significant differences between groups with respect to diastolic function. Several reasons may account for this: the small groups, the fact that diastolic function indices are influenced by several factors such as HR and loading conditions, and that anesthetics may exert differently pronounced effects on systolic and diastolic function. Moreover, a prospective study on left ventricular diastolic filling patterns associated with AC-induced myocardial damage found that diastolic abnormalities were not strongly predictive of reduced SF (24).

Echocardiography has been widely used to monitor cardiac function during and after AC treatment. The indices chosen for the echocardiographic assessment vary significantly among different centers. Measurement of SF and EF are the most widely used methods, though both may fail to detect early toxicity and are confounded by variables such as left ventricular loading conditions, anemia, and fever. In our study we used the pulmonary artery Doppler flow for the calculation of stroke volume and cardiac output. The accuracy of this approach has been investigated extensively in clinical studies. In a validation study, Savino et al. (13) found excellent agreement between pulmonary artery Doppler flow-derived cardiac output and the current standard (i.e., the pulmonary artery thermodilution technique). Furthermore, Vanzetto et al. (14) compared pulmonary artery Doppler flow-derived cardiac output values with those obtained from aortic and mitral valve Doppler in 100 consecutive patients and reported good agreement (r = 0.96).

Our study has several limitations. First, the mean age (9.6 ± 4.1 versus 10.9 ± 3.4 years) was slightly younger and body surface area was slightly lower in the AC group than in the control group, without reaching statistical significance. Although younger children are generally considered to be more prone to develop AC cardiomyopathy, an age dependency was not found in our study. Individual varying susceptibility to the toxic effects of AC may account for this. Second, children underwent mechanical ventilation using a pressure-controlled mode of ventilation with an I:E ratio of 1:1. The increase in intrathoracic pressure and decreased venous return resulting from the long inspiratory time and decelerating flow may have exacerbated the cardiac dysfunction and more readily unmasked the cardiac dysfunction in the AC group. Third, we combined transthoracic echocardiography and TEE. Although there are several investigations demonstrating that left ventricular diameters and derived indices such as SF obtained by each method are comparable (25,26), there is no investigation comparing pulmonary artery flow measurements by each method. However, an investigation comparing transthoracic Doppler echocardiographic measurements of pulmonary venous flow with transesophageal measurements showed good correspondence (27). Fourth, our patients received four different AC types (doxorubicin, daunorubicin, epirubicin, idarubicin) alone or in combination. One study addressing the issue of equipotency of cardiotoxicity of three ACs (doxorubicin, daunorubicin, and epirubicin) found no differences in the incidence of cardiotoxicity and in absolute SF between the different AC types (28). Thus, it is rather unlikely that our results are confounded by varying cardiotoxicity of the drugs used. Fifth, 14 patients received cyclophosphamide (2–30 g/m²) as part of their chemotherapeutic regimen. However, a recent detailed study on large-dose cyclophosphamide monotherapy and cardiac function (including measurement of cardiac troponin levels, ventricular repolarization indices and echocardiography) found that cyclophosphamide is safe with respect to cardiotoxicity (29). This supports an earlier study on clinical cardiotoxicity after AC treatment for childhood cancer that cyclophosphamide did not increase the risk of cardiotoxicity beyond that noted for AC alone (30). Thus, is it rather unlikely that co-treatment with cyclophosphamide may have confounded the effects of AC on cardiac function in our study. Sixth, we have compared patients with untreated cancer and patients in remission. There was no evidence in the echocardiographic studies that untreated cancer as such compromised cardiac function. However, notable were the differences in HR between the AC and control group, which were most likely related to the fact that the standardized premedication had a lesser effect in the AC group as a result of previous medical experience ("hospitalization").

The main finding of our study is that children who have previously received AC with normal myocardial function at rest may exhibit a more pronounced cardiodepressive effect of anesthetics as evidence of a subclinical AC cardiotoxicity. When assessing the clinical relevance of our findings, it is important to pay attention to the fact that although CI was consistently lower in the AC than in the control group during anesthesia (AC group versus control group: T1 2.9 ± 0.5 versus 3.2 ± 0.5 L/min/m²; T2 2.4 ± 0.5 versus 2.6 ± 0.5 L/min/m²), there were no differences in CI during anesthesia reaching statistical significance, although this was probably attributable to our small study groups. Given the absolute levels of CI, we feel that the decrease in CI by 34% as such does not necessarily pose a risk to the AC patients because there was no clinical evidence of a critical decrease in global oxygen delivery. However, as variables of global or regional perfusion and metabolism (e.g., mixed or central venous oxygen saturation, gastric mucosal carbon dioxide tension) were not measured, this remains speculative. Data from investigations on the cardiac effects of anesthetics in pediatric anesthesia (in healthy patients) mentioned above demonstrated decreases in SVI in a similar range than that found in our study. Thus, in general, we do not propose, particularly in minor surgery, a change in anesthetic strategy. However, in consideration of the increased susceptibility of patients with previous AC therapy to cardiodepressive drugs, increasing intravascular volume, use of inotropic drugs, and extended monitoring (central venous oxygen saturation) may be valuable options in case of major surgery (i.e., with anticipated major fluid shifts) and/or additional cardiodepressive factors such as sepsis.

	Footnotes

 
Presented, in part, at the annual meeting of the American Society of Anesthesiologists, Dallas, October 10–13, 1999.

	References

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