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Divisions of *Pediatric Cardiology, Pediatric Cardiovascular Anesthesiology, and Congential Heart Surgery, Texas Children’s Hospital and Baylor College of Medicine, Houston; and Division of Pediatric Cardiology, Children’s Hospital and Regional Medical Center and the University of Washington School of Medicine, Seattle, Washington
Address correspondence and reprint requests to Dean B. Andropoulos, MD, Division of Pediatric Cardiovascular Anesthesiology, Texas Children’s Hospital, 6621 Fannin, WT 19345H, Houston, TX 77030-2399. Address e-mail to dra{at}bcm.tmc.edu
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Abstract |
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IMPLICATIONS: Sevoflurane, halothane, isoflurane, and fentanyl/midazolam do not change pulmonary-to-systemic blood flow ratio in children with atrial and ventricular septal defects when administered at standard anesthetic doses with 100% oxygen.
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Introduction |
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The purpose of this study was to compare pulmonary and systemic hemodynamics as well as the effects on myocardial contractility of these four anesthetic regimens in patients undergoing surgery for ASD or VSD using transthoracic echocardiography. Change in Qp:Qs was our primary outcome variable, and we hypothesized that there would be a significant increase in Qp:Qs when these anesthetics were administered with 100% oxygen.
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Methods |
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Patients were randomized to one of four groups by selecting the first of a lot of prelabeled cards representing each group. They were thoroughly mixed to ensure randomization and maintained so that the group assignment of the next patient was not known until the card was actually drawn. The four groups were halothane, isoflurane, sevoflurane, or fentanyl/midazolam. All patients received premedication with oral midazolam 0.75 mg/kg or IV midazolam 0.05–0.2 mg/kg to achieve a sedated but responsive state. After the application of standard monitors and recording of heart rate (HR), oscillometric blood pressure, and SpO2, a baseline transthoracic echocardiogram was performed with the patient breathing room air. Anesthesia was then induced with either an inhaled anesthetic using calibrated vaporizers, with 10 L/min of oxygen, or a fentanyl/midazolam infusion for 1 min. Muscle relaxation was facilitated with vecuronium 0.3–0.4 mg/kg, and the trachea was intubated. Fractional inspired oxygen was maintained at 1.0 and the ETCO2 at 30–40 mm Hg. The lowest possible mean airway pressure was maintained, and peak inspiratory pressure remained <25 cm H2O; a positive end-expiratory pressure of 2 cm H2O and an I:E ratio of 1:2 to 1:3 were used. In random order (according to the second to last digit of the seven-digit medical record number, with even numbered patients receiving 1 mean alveolar anesthetic concentration [MAC] first and odd numbers 1.5 MAC first), an age-adjusted MAC of 1 or 1.5 was achieved for the inhaled anesthetics (9–11) using the technique of overpressure (12) to achieve the target end-tidal concentration as rapidly as possible. The randomization scheme, both for anesthetic and MAC level, was known only to the single investigator (DBA) actually administering the anesthetic. ETCO2 and fraction of inspired O2 concentrations (FIO2) were measured at a side port on the elbow connector attached to the patient’s endotracheal tube with an infrared sidestream device calibrated weekly with standard gas mixtures. For patients randomized to fentanyl/midazolam infusion and maintenance, infusion rates were calculated based on published pediatric pharmacokinetic data to predict two different plasma levels: 4 and 6 ng/mL for fentanyl and 100 and 200 ng/mL for midazolam (see Appendix for doses). These levels are associated with sedation, hypnosis, and analgesia for surgery and approximate 1 and 1.5 MAC levels of the volatile anesthetics (13–18). The order of predicted plasma levels was always 1 MAC first because of the lack of time available to allow for the plasma levels of the drugs to decrease if the 1.5 MAC level were achieved first. The inhaled anesthetics or the fentanyl/midazolam infusion were maintained at a constant end-tidal concentration or infusion rate for 10 min. A second echocardiogram was performed, and vital signs were again recorded. The inhaled anesthetics were then adjusted to the second MAC level and allowed to equilibrate for 10 min; the fentanyl/midazolam patients were given a second infusion equal to 50% of the first, and the maintenance rate was increased by 50% for 10 min. A final echocardiogram was performed, and vital signs were repeated.
All patients either received maintenance IV fluids until the time of the induction or if no IV catheter was present, were allowed to ingest clear liquids until 2 h before the induction. Only maintenance IV fluids were administered during the study period. No vasoactive drugs were given aside from the anesthetics. Each patient had a right internal jugular vein catheter inserted immediately after tracheal intubation to measure central venous pressure for calculation of systemic vascular resistance (SVR). A radial artery catheter was placed as soon as possible, and an arterial blood gas was sampled during steady-state ventilation and hemodynamics. Any hemodynamic response perceived to be due to these procedures was allowed to subside before echocardiographic assessment; all measurements were made during periods of steady-state hemodynamics.
Two-dimensional and pulsed Doppler transthoracic echocardiography was performed by a pediatric cardiologist using an Acuson 128XP/10 or Acuson Sequoia ultrasonic imaging system. The pediatric echocardiographer was blinded to the type of anesthetic administered and to the MAC randomization. Studies at baseline, 1 MAC, and 1.5 MAC were each obtained over 3–5 min during a period of unchanging HR and blood pressure. Each study was performed in the same manner, according to the recommendations of the American Society of Echocardiography Committee on Standards (19), and all analyses were performed offline. All measurements were obtained over three consecutive cardiac cycles, and the average of the values was recorded. Orthogonal left ventricular end-diastolic volume and left ventricular end-systolic volume were traced; ejection fraction (EF) was calculated according to the modified Simpson’s biplane method. Aortic and pulmonary artery velocity time integrals were traced, and the aortic and pulmonary valve annuli were measured. The following variables were measured or calculated at the three time periods: HR, mean arterial blood pressure, EF, stroke volume index, left ventricular end-diastolic volume index, Qs (equal to the systemic cardiac output), Qp, and SVR index (20,21). The anesthetic and MAC order was unknown to the echocardiographers during the analyses. See Appendix for hemodynamic and echocardiographic calculations.
Data are reported as mean ± SD. Statistical calculations and analyses were performed using Sigma Stat version 2.03 (SPSS Inc, Chicago, IL). Analysis of variance for repeated measures was used to compare variables at the three MAC levels within the same group. To compare variables between the four groups at each MAC level, a two-way analysis of variance with repeated measures was used. The Tukey test was used for post hoc pair-wise comparisons of the mean responses to the different treatment groups. 
2 analysis was used to compare the number of patients in each group with an increase in Qp:Qs at the 1.5 MAC level of more than 50% from baseline. P < 0.05 was considered significant for all tests.
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Results |
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Qp decreased at both 1 and 1.5 MAC with halothane, but there was no change in the other groups. Qs (systemic cardiac index) decreased at 1.5 MAC with halothane and at both 1 and 1.5 MAC with sevoflurane and fentanyl/midazolam. Qp:Qs did not change statistically from baseline within any of the four anesthetic groups, nor was there a difference between groups. The 32% increase in Qp:Qs from baseline with fentanyl/midazolam at the 1.5 MAC equivalent did not reach statistical significance (P = 0.069). Three of 9 fentanyl/midazolam patients had an increase in Qp:Qs of more than 50% from baseline at 1.5 MAC. One of 10 patients in the isoflurane and halothane groups and none of the 11 patients in the sevoflurane group increased Qp:Qs by more than 50% from baseline at 1.5 MAC. This difference between groups was also not significant (P = 0.28; 2 analysis). In addition, when Qp + Qs, representing total volume of blood pumped through the heart per minute, was assessed, this also reflected no change from baseline with any regimen at either concentration. The Qp:Qs for each individual patient is presented in Figure 1.
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Discussion |
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An FIO2 of 1.0 was chosen for this study to replicate common clinical conditions and would be expected to increase Qp and thus Qp:Qs (8). In patients with reactive pulmonary vasculature, oxygen relaxes tone in the pulmonary arterial system. This decreased tone will lower PVR and lead to an increased Qp in patients with intracardiac shunting. However, we did not observe increased Qp from oxygen therapy. One possible explanation is that positive-pressure ventilation decreased Qp. In this study, the peak and mean airway pressures were maintained as low as possible; however, this pressure is transmitted to the pulmonary capillary bed, increasing resistance in the pulmonary vasculature and possibly offsetting the vasodilating effect of oxygen.
Direct studies of Qp:Qs changes in response to these anesthetic regimens in children with unrepaired CHD have not been reported. Glenski et al. (6) reported that fentanyl, halothane, and isoflurane did not change right ventricular preejection period, an indirect echocardiographic M-mode measure that estimates PVR. They studied a group of 48 infants and children with CHD, most of whom had left-to-right intracardiac shunt like the patients in our study. Hickey et al. (7) reported that 25 µg/kg of fentanyl did not change cardiac index or SVR or PVR in the immediate postoperative period in 12 patients with repaired CHD, of which 10 previously had left-to-right cardiac shunts. This study was performed using thermodilution measurement of cardiac index, with direct measurements of left atrial, right atrial, and pulmonary artery pressures.
It is common practice to reduce the oxygen concentration in patients with left-to-right shunts to avoid overcirculation of blood to the lungs and steal from the systemic circulation. Data from this study would indicate that such a practice is unnecessary because the four anesthetic regimens evaluated did not significantly change the Qp:Qs, despite the use of 100% oxygen and positive-pressure ventilation. We do not know how Qp:Qs might be affected by anesthetics in patients with left-to-right shunts if FIO2 was maintained at 0.21; it is certainly possible that changes in Qp, Qs, or Qp:Qs might in this case be elicited.
The results of this study cannot be applied to all patients with CHD or to all patients with left-to-right shunting. We studied only patients with two ventricles and isolated VSD or ASD as the source of intracardiac shunting. Patients with a more critical dependence on relative SVR and PVR and blood flows, such as single ventricle patients with a large patent ductus arteriosus or systemic-to-pulmonary artery shunt as their major source of communication between pulmonary and systemic circulations (22), or patients with unrepaired truncus arteriosus (23), were not studied. Also, only three infants younger than six months were studied. These patients demonstrate more profound myocardial depressant responses to the volatile anesthetics and increased hemodynamic compromise with large concentrations of inspired oxygen, as relatively more blood is shunted into their reactive pulmonary vascular bed (24). We also did not study patients with right-to-left intracardiac shunting and cyanosis.
With only 9–11 patients in each group, the statistical power of the negative findings, with a type I error protection of 0.05, was less than the desired level of 0.80 for most tests. This is of particular importance for the main outcome variable Qp:Qs, which is subject to a type II statistical error, i.e., a falsely negative statistical outcome.
In conclusion, sevoflurane, halothane, isoflurane, or fentanyl/midazolam in 1 or 1.5 MAC concentrations or their equivalent do not change Qp:Qs in patients with isolated ASD or VSD when positive-pressure ventilation and FIO2 of 1.0 are used.
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Appendix |
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where Vd = volume of distribution
Infusion rate (µg · kg-1 · h-1) = desired plasma level (ng/mL) x CL (L · kg-1 · min-1) x 60,
where CL = drug clearance
Appendix
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Midazolam. Because of the reported variability in pharmacokinetic data of midazolam in children, the same initial and maintenance infusion was chosen for all ages (20–22). Calculations were based on a CL of 0.009 L · kg · -1min-1, and a Vd of 1.9 L/kg. A dose of 0.29 mg/kg was followed by an infusion of 139 µg · kg · -1h-1. The second dose was 0.15 mg/kg followed by an infusion of 208 µg · kg · -1h-1.
Echocardiographic Calculations (19–23)
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EF = ejection fraction; LVEDV = left ventricular end-diastolic volume; LVESV = left ventricular end-systolic volume
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CO = systemic cardiac output; Da = aortic diameter; VTIa = aortic velocity time integral.
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SV = stroke volume, HR = heart rate
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SVR = systemic vascular resistance, MAP = mean arterial blood pressure, CVP = central venous pressure. SV, LVEDV, and CO were divided by the patient’s body surface area to calculate an index to account for the different patient sizes. The SVR was multiplied by the body surface area to calculate an SVR index.
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Acknowledgments |
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The authors thank Barbara Skjonsby, R.N. for technical assistance, and Anna Frolov, M.S. for statistical consultation.
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Footnotes |
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References |
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