Large-dose synthetic opioid anesthesia with fentanyl 50–100 μg/kg is commonly used for neonates and infants undergoing congenital cardiac surgery, particularly if the patients have limited hemodynamic reserve, are at risk of pulmonary hypertension, or are expected to have a prolonged postoperative recovery. Neonates and infants undergoing cardiac surgery and deep hypothermic cardiopulmonary bypass (DHCPB) can generate a significant hormonal stress response (1). Sufentanil anesthesia attenuates this physiologic response and reduces the postoperative incidence of sepsis, metabolic acidosis, disseminated intravascular coagulation and death (2). However, while providing circulatory stability, particularly during the induction and intubation (3), complete suppression of responses during intense surgical stimulus and DHCPB cannot be guaranteed (4). No specific relationship between opioid dose and hormone or metabolic stress response has been established. Considering the advances in surgical techniques, including cardiopulmonary bypass (CPB) and perioperative management in the past decade that have lead to a significant improvement in patient outcome, a strategy of large-dose opioid anesthesia to blunt the stress response may be less critical.
Benzodiazepines are commonly used to ensure adequate hypnosis during opioid-based anesthesia. In a study of children with acyanotic heart disease undergoing cardiac surgery, the addition of diazepam to fentanyl-based anesthesia (75 μg/kg) resulted in a more stable hemodynamic profile without an increase in epinephrine levels when compared with an isoflurane-based anesthetic technique (5). In a study by Barankay et al. (6), of younger children (mean age, 28.5 ± 20.8 mo; mean weight, 10.9 ± 4.2 kg) undergoing correction of tetralogy of Fallot, the combined use of sufentanil and flunitrazepam provided a more stable hemodynamic profile and catecholamine response compared with a sufentanil-based technique alone. The potential benefit of benzodiazepines during cardiac surgery and effect on outcome have not been previously studied in infants.
This prospective, randomized, double-blinded study was undertaken to determine whether the currently used large-dose fentanyl anesthesia techniques, with or without midazolam, attenuate the stress response and influence subsequent outcome in infants undergoing corrective cardiac surgery.
After obtaining IRB approval and parental informed consent, 45 neonates and infants < 6 mo of age, who were undergoing DHCPB for complete biventricular repair of a congenital cardiac defect were enrolled in this prospective, randomized, double-blinded study. None of the children had undergone previous anesthesia or cardiac surgery. Children with neurologic, metabolic, endocrine, renal, or hepatic disorders were excluded.
Patients were randomized to one of three groups. Infants in Group 1 (fentanyl bolus, n = 15) received bolus fentanyl 25 μg/kg at the induction, before sternotomy, on initiation of CPB, and during the rewarming phase of CPB. Midazolam was not administered, and a continuous infusion of placebo (saline) at a rate of 1 mL · kg−1 · h−1 was started after the induction of anesthesia and continued throughout surgery. Infants in Group 2 (fentanyl infusion, n = 15) received a bolus of fentanyl 25 μg/kg at the induction of anesthesia, after which a fentanyl infusion (10 μg · kg−1 · h−1) was started and continued throughout surgery. On initiation of CPB, an additional fentanyl bolus of 25 μg/kg bolus was administered to the bypass circuit. Midazolam was not administered, and the fentanyl infusion rate (1 mL · kg−1 · h−1) was the same as the saline infusion in Group 1. Infants in Group 3 (fentanyl-midazolam, n = 15) received boluses of fentanyl 25 μg/kg and midazolam 200 μg/kg at the induction of anesthesia, after which an infusion of fentanyl (10 μg · kg−1 · h−1) and midazolam (100 μg · kg−1 · h−1) was started and continued throughout surgery at a rate of 1 mL · kg−1 · h−1. On initiation of CPB, additional boluses of fentanyl (25 μg/kg) and midazolam (100 μg/kg) were administered to the bypass circuit. We did not include a group randomized to small-dose fentanyl and inhaled anesthesia because we did not believe this would be a stable or suitable technique in all patients that could be randomized to the study. In all patients, neuromuscular blockade was achieved with bolus pancuronium (150–200 μg/kg) given at the induction of anesthesia and initiation of CPB. For infants in whom IV access was difficult, induction of anesthesia was achieved with halothane in 3 patients (1 patient from each group), which was then discontinued once access was obtained and before administering fentanyl, and in 2 patients, IM ketamine was used. Atropine or other hypnotic drugs were not administered IV at induction, and the bolus dose of fentanyl was administered via hand injection rather than as a timed infusion.
A randomization table was constructed by the operating room (OR) pharmacist, and once patients were enrolled in the study, they were assigned to a group according to the numerical sequence in the table. The anesthesiologists and investigators collecting data were blinded as to the randomization schedule, and the code was not broken until all 45 patients completed the study. Syringes for both bolus and infusion drug administration were prepared in equal volumes by the OR pharmacist, and the anesthesiologist was blinded as to the content of each syringe.
An identical perfusion protocol and bypass circuit prime was used for all patients. The circuit priming volume was between 350 and 400 mL, with plasmalyte and whole blood to achieve a hematocrit of 25%–30%. Methylprednisolone 30 mg/kg was administered into the bypass circuit for all patients within the first minute of bypass. No dextrose containing solutions were administered in the OR.
Arterial blood samples (6 mL each) for stress hormones, blood gas analysis, glucose, and lactate levels were obtained at five different time points: (T1) 15 min after the induction, (T2) 15 min after sternotomy, (T3) 15 min on CPB during cooling, (T4) on completion of surgery (skin closure), and (T5) at 24 h postoperative in the intensive care unit (ICU). Plasma fentanyl levels were also measured at the above time points except for T5. Plasma was separated immediately by centrifuge and then stored at −70°C before batch analysis. Norepinephrine and epinephrine were measured by single-isotope radioenzymatic assay (7), cortisol by chemiluminescence (Beckman Coulter Instruments, Inc., Brea, CA), and adrenocortical hormone (ACTH) by immunoradiometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA). The coefficient of variability within and between runs, and the sensitivity of each assay technique were, respectively, for epinephrine 14.6%, 29.2%, and 10 pg/mL; norepinephrine 4.7%, 11.2%, and 10 pg/mL; ACTH 1.0%, 2.5%, and 1 pg/mL; and cortisol 6.5%, 10.1%, and 0.26 μg/dl. Fentanyl was measured by using high-performance liquid chromatography with ultra-violet detection, and glucose and lactate levels by specific enzymatic methods (STAT PROFILE ULTRA Blood Gas and Electrolyte Analyzer; Nova Biomedical, Waltham, MA). The coefficient of variability for lactate was 6.0% and for glucose 5.0%.
The study protocol did not include control over management in the ICU after surgery. Infants were managed according to institutional clinical practice guidelines (CPGs) established within the Cardiovascular Program at Children’s Hospital, Boston. The infusions of fentanyl and midazolam were discontinued before transfer to the ICU. Analgesia and sedation were maintained according to usual ICU practices with bolus doses of morphine and midazolam at the discretion of the ICU nurse or physician, and patients received half-maintenance fluids with 5% dextrose and half-normal saline for the first 24 h after surgery according to the CPGs. The decision for vasoactive support for each patient was based on clinical assessment by the anesthesiologist, surgeon, and intensive care physician, and not according to study protocol.
Postoperative mortality was defined as death after cardiac surgery and before discharge from hospital. Postoperative complications specifically noted included the occurrence of cardiac arrest requiring cardiopulmonary resuscitation, ventricular or atrial arrhythmias causing hemodynamic disturbance and requiring treatment, sepsis, disseminated intravascular coagulation, and clinical evidence of seizures.
The total duration of mechanical ventilation and ICU and hospital stay were compared; however, because no specific times for tracheal extubation or ICU and hospital discharge were set by the study protocol, we also evaluated the number of patients in each group whose postoperative course was within or outside the CPG. Tracheal extubation was anticipated on the first postoperative day according to the CPG, but to account for the variable time of the day when surgery was performed, the postoperative time frame chosen for tracheal extubation in our study was 36 h. The expected day of discharge from the ICU from the CPG was postoperative Day 2, and for hospital discharge was postoperative Day 5.
In designing this randomized study, a power analysis revealed that 15 patients per group would provide 96% power for detecting an effect size of 0.5 standard deviations in each outcome variable among the three study groups based on analysis of variance (ANOVA) and post hoc testing. The final sample of 43 patients provided 94% statistical power for group comparisons (version 2.0, nQuery Advisor; Statistical Solutions, Boston, MA). The Kolmogorov-Smirnov goodness-of-fit test (8) indicated that each continuous variable followed a normal distribution. Therefore, parametric methods were used for all statistical analysis. One-way ANOVA followed by post hoc comparisons with the Bonferroni method was performed to compare the fentanyl-bolus, fentanyl-infusion, and fentanyl-midazolam groups with respect to demographic data and intraoperative and postoperative management variables. The number of patients in each group who were outside the CPG for the duration of mechanical ventilation and length of hospital stay were compared by using Fisher’s exact tests. For stress hormones, plasma fentanyl concentrations, and metabolic and hemodynamic data, two-way repeated-measures ANOVA was performed to test the effects of mode of delivery of anesthesia (between-group factor) and time (within-group factor). By using a profile analysis strategy, a mode by time interaction was included as a variable in the model to ascertain whether the three groups demonstrated similar or different patterns of change (9). A significant F-test for the interaction would reflect different slopes among the groups over the time course from after the induction to 24 h in the ICU. Differences in stress hormones, plasma fentanyl concentrations, and metabolic and hemodynamic variables over time with respect to after the induction were evaluated within each group by using repeated-measures ANOVA with a Greenhouse-Geisser F-test for small samples followed by multiple paired t-tests. A two-tailed Bonferroni-corrected P < 0.0125 was used to adjust the type I error inasmuch as four post hoc time point comparisons were made. For each group, multivariate repeated-measures ANOVA with the F-test from within-groups regression was used to determine whether there was a dose-response relationship between plasma fentanyl level, treated as a time varying covariate, and stress hormone levels across the 4 time points. Here, an uncorrected two-tailed P <0.05 was considered statistically significant because multiple comparisons were not required, and regression coefficients are provided for significant dose-response relationships. Stress hormone, demographic data, and fentanyl levels were expressed as mean ± sd. Statistical analysis was performed with the SPSS (version 9.0, SPSS Inc., Chicago, IL) and SAS (version 6.12, SAS Institute, Cary, NC) software packages.
Demographic data are presented in Table 1. One child was excluded from the analysis because the parents subsequently withdrew consent and another because of a protocol violation. Therefore, the results were derived from the 43 neonates and infants who completed the study. There were no hemodynamic complications during induction, and no patient required volume replacement or vasoactive drugs before CPB. There were no differences in intraoperative variables including CPB and surgical duration detected among the three groups. Changes in heart rate and mean arterial pressure among the groups at each measured time point are shown in Table 2.
The stress hormone data for each group from after the induction to 24 h in the ICU are shown in Figures 1 and 2. Repeated-measures ANOVA revealed no significant differences among the three study groups with respect to changes in epinephrine (P = 0.12), norepinephrine (P = 0.53), ACTH (P = 0.64), and cortisol (P = 0.60) levels over time. In addition, no significant group-by-time interactions were detected (P > 0.40 for each), indicating that the changes over time in epinephrine, norepinephrine, ACTH, and cortisol followed a similar pattern from after the induction to 24 h in the ICU for each group.
Repeated-measures ANOVA with the Greenhouse-Geisser F-test indicated highly significant differences for each stress hormone within the three groups. By using a two-tailed Bonferroni P < 0.0125 as the criterion, epinephrine and norepinephrine levels were significantly larger at the end of surgery for all groups, and epinephrine remained significantly larger in the fentanyl-midazolam group after 24 h after operation in the ICU. ACTH decreased from the postinduction level and declined significantly during CPB. Conversely, cortisol levels declined slightly after sternotomy for all groups and then increased during CPB. After the operation, all three groups showed peak levels that were significantly larger than baseline and then declined over 24 h in the ICU.
Glucose and lactate data are shown in Figure 3. There were no significant group differences at any time point. The group-by-time interaction F-test from repeated-measures ANOVA was not statistically significant for any variable, indicating that the groups shared a similar pattern of change over time. However, there was a highly significant time effect for glucose and lactate. Each group demonstrated a significant increase in glucose and lactate during CPB that persisted until the end of surgery and then returned to normal baseline values
The measured plasma fentanyl concentrations for Groups 1, 2, and 3 are presented in Table 2. Within groups, there was a significant time effect for Group 2 (P < 0.001) and Group 3 (P = 0.05). Compared with after the induction (T1), Groups 2 and 3 both showed significantly larger fentanyl concentrations at the end of surgery (P < 0.001). The bolus group demonstrated comparable fentanyl levels at all 4 time points, and at T2, the level was significantly larger than Groups 2 and 3 (P < 0.006).
A significant dose-response relationship was found between fentanyl level versus glucose (n = 14; regression coefficient, −0.60;P = 0.04) and fentanyl versus cortisol (n = 14; regression coefficient, -2.06;P = 0.03) in Group 2 only (i.e., larger levels of fentanyl during the continuous infusion were associated with smaller glucose and cortisol levels). No significant dose-response relationship was demonstrated in Groups 1 and 3 between fentanyl level and glucose (P = 0.56, P = 0.43, respectively) or cortisol (P = 0.22, P = 0.63, respectively). None of the groups demonstrated a significant dose-response between fentanyl and lactate, epinephrine, norepinephrine, and ACTH levels (P > 0.15 in each case).
All patients had an uncomplicated induction without hypotension; no patient required inotrope support before CPB. Although the mean arterial pressure decreased during bypass for each group, there were no significant differences between baseline and at the end of surgery. Heart rate was constant for all three groups across the time course, and although the fentanyl-midazolam group had slightly higher values, there were no significant differences among the groups in any of the hemodynamic variables measured.
Vasoactive infusion support, duration of mechanical ventilation, and length of ICU and hospital stay are shown in Table 3. One patient in the fentanyl-midazolam infusion group failed extubation on two occasions secondary to severe mitral regurgitation from a residual mitral valve cleft. A second patient in the fentanyl-midazolam group had sudden cardiac arrest on the third postoperative day and required extracorporal membrane oxygenation for 4 days. This patient had an uncomplicated immediate postoperative course and had been discharged to the general cardiology ward on postoperative Day 2. The arrest occurred during feeding, and aspiration was thought to be a significant contributing factor. After 8 days, he was extubated without any problems, and his remaining hospital stay was uneventful. Because these events appeared unrelated to the use of intraoperative midazolam, these two patients were excluded from the subsequent analysis. Although not reaching significance, the duration of vasoactive support tended to be longer in the fentanyl-midazolam group. There were no differences among the groups in total duration of mechanical ventilation and ICU stay and hospital stay; however, a significantly larger number of patients in the fentanyl-midazolam group exceeded the CPGs in these areas (P <0.02, P <0.05, P <0.02 respectively), Table 3.
There were no intra- or postoperative deaths. In addition, none of the patients suffered from persistent metabolic acidosis, disseminated intravascular coagulation, or seizures. One patient in the fentanyl-bolus group, one in the fentanyl-infusion group, and three in the fentanyl-midazolam group required pacing because of temporary heart block. One patient in the fentanyl bolus group developed transient junctional ectopic tachycardia during the first postoperative night and was treated with mild hypothermia to control ventricular rate. Cardioversion was not necessary for any patient.
All patients in this study demonstrated an endocrine and metabolic response to surgical stress, but without apparent adverse events. There was no difference between fentanyl administered as a continuous infusion compared with a bolus technique, and the addition of midazolam to large-dose opioid anesthesia did not result in less stress hormone release than large-dose opioid anesthesia alone.
Neonates and infants undergoing DHCPB surgery are able to generate a significant stress response (1). Wood et al. (10) reported a 17-fold increase in epinephrine and 10-fold increase in norepinephrine levels in infants after one hour of circulatory arrest at 18°C. Nevertheless, the reported magnitude of the stress response after cardiac surgery is variable and influenced by patient age, type of anesthesia, level of hypothermia, and the duration of CPB and circulatory arrest (4,11–13). Sufentanil anesthesia produces less stress hormone release and improved outcome after neonatal cardiac surgery compared with halothane and morphine anesthesia (2). A conclusion from this study supported the notion that reducing the stress response with large-dose opioid anesthesia, and extending this into the immediate postoperative period, was important to reduce the morbidity and mortality associated with congenital cardiac surgery in neonates.
The interpretation of stress hormone release during cardiac surgery is problematic and there is considerable variability according to patient age, surgery, and anesthesia technique. The changes we detected in cortisol levels were similar to the increases in epinephrine and norepinephrine during surgery. This change is different from that described in an earlier study by Anand et al. (2), in which the cortisol level was observed to decrease throughout surgery in neonates anesthetized with large-dose sufentanil. An increase in cortisol during CPB has been reported in adults and children under different anesthesia techniques, and with no apparent effect from either prime composition or whether pump flow was pulsatile or nonpulsatile (14,15). The increase in cortisol levels we measured during surgery is perhaps further evidence for the lack of substantial stress response attenuation in our patients, despite the large-dose synthetic opioid anesthesia.
ACTH showed a similar pattern of change in all three groups, significantly decreasing during CPB and remaining small in all three groups at 24 hours in the ICU. This finding conflicts with what little data exist for pediatric cardiac surgery. Pollock et al. (15) measured an increase in ACTH levels in children during pulsatile and nonpulsatile CPB; however, the children in their study were older than one year, and the anesthetic technique was quite different. The large dose of methylprednisolone added to the bypass circuit prime, standard practice at our institution for many years, could have also contributed to the decrease in ACTH levels.
The plasma fentanyl concentration in Group 1 tended to be larger after the induction and was significantly larger at T2 compared with the other 2 groups; however, by the end of surgery, all three groups had comparable fentanyl levels. The increase at T2 could be related to the rebolus of fentanyl at the time of sternal incision and reflect a larger plasma concentration before redistribution. As there were no significant differences in the stress hormone levels among the groups, and based on intraoperative fentanyl levels drawn at the same time as stress hormone levels, we were unable to demonstrate an effect of either dosing schedule or method of fentanyl administration on stress hormone release.
Midazolam is commonly used in conjunction with opioids during cardiac surgery to deepen the level of anesthesia and ensure hypnosis (16). We were unable to demonstrate any additional suppression of the stress response in the midazolam group, nor advantage in hemodynamic stability or total duration of mechanical ventilation and ICU stay and hospital stay. Midazolam was used in all patients to provide sedation in the ICU, but was not controlled according to study protocol. While significantly more patients in the fentanyl-midazolam group were outside the institutional CPGs for duration of mechanical ventilation and ICU and hospital stay, it is not possible to conclude that the intraoperative use of midazolam contributed to delayed recovery. Further controlled studies are necessary to evaluate the postoperative use of midazolam in this patient population.
The relative increase from baseline of both catecholamine and cortisol levels in our study, without adverse outcome, are in contrast to findings previously reported from our institution nearly a decade ago. Anand et al. (2) demonstrated a relatively small 0.5- to 1-fold increase in epinephrine levels and approximately a 0.5-fold increase in norepinephrine levels by the end of surgery in neonates anesthetized with large-dose sufentanil. Although the change in norepinephrine levels is comparable, the magnitude of the change in epinephrine levels by the end of surgery in our patients was considerably larger (8-fold increase in Group 1, 12-fold increase in Group 2, and a 15-fold increase in Group 3), and occurred despite a much shorter duration of circulatory arrest. The absolute magnitude of the stress hormone response in infants is unknown and it is, therefore, not possible to say to what extent the stress response was attenuated in our infants. We did not enroll a control group anesthetized with small-dose fentanyl and an inhaled anesthetic. This is not usual practice in our institution, and it was felt that following randomization to the study this technique would not be suitable for all possible patients that could be enrolled in the study.
Direct comparisons between the two studies clearly are not possible. In the earlier study, patients in were younger (mean age, 5.3 days), the diagnoses, surgical procedures, and bypass techniques were different (e.g., 15 of 45 patients underwent a Stage I repair for hypoplastic left heart syndrome), and a larger circuit prime volume and different laboratory assays were used to measure the neuroendocrine response (2). The magnitude of the change in neuroendocrine response may also be different between the two studies, particularly as the original study included neonates managed in the ICU before surgery. Further, sufentanil was used in the early study whereas fentanyl is currently more commonly used in our institution for congenital cardiac surgery. At equipotent doses (5–10:1 ratio), sufentanil and fentanyl have a similar pharmacodynamic profile and stress hormone release during cardiac surgery (3,17,18). In contrast, one study involving adult volunteers suggested that sufentanil may have an increased affinity for the μ1 receptor compared with fentanyl (19), although there are no data to support this in pediatric patients. The total bolus dose of sufentanil used in the early study (total 30 μg/kg) is relatively larger than the total bolus dose of fentanyl used in this study (100 μg/kg), which may account for the smaller increase in epinephrine levels in the early study (2).
Nevertheless, the increase in stress hormone levels in our patients was considerably larger than reported by Anand et al. (2) for either their sufentanil group or those anesthetized with a more “stressful” halothane/morphine technique. Despite the relatively smaller dose of synthetic opioid used in our study and the measured stress response, there was no mortality or early morbidity detected. Significant changes in surgical and CPB techniques and perioperative management have occurred in the past decade, and the use of large-dose opioid anesthesia techniques directed at obtunding the endocrine stress response in infants undergoing DHCPB may therefore have less influence on determining early postoperative outcome.
In conclusion, we measured a significant endocrine stress response in infants undergoing deep hypothermic congenital cardiac surgery despite using large-dose fentanyl anesthesia, but without significant adverse postoperative outcome. No specific advantage to adding midazolam or administering fentanyl as a continuous infusion or bolus was demonstrated. Over the past decade, the mortality and morbidity for neonates and infants undergoing congenital cardiac surgery have continued to decline, related to improvements in medical and surgical management, as well as bypass techniques. Our study indicates that a large-dose fentanyl technique, with the intention of providing “stress free” anesthesia in infants with well compensated congenital cardiac disease, does not appear to be an important determinant of early outcome after congenital cardiac surgery.
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© 2001 International Anesthesia Research Society
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