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Intrathecal Versus IV Fentanyl in Pediatric Cardiac Anesthesia

Pirat, Arash, MD; Akpek, Elif, MD; Arslan, Gülnaz, MD

doi: 10.1097/00000539-200211000-00017
PEDIATRIC ANESTHESIA: Research Report
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Systemic large-dose opioids are widely used in pediatric cardiac anesthesia, but there are no randomized, prospective studies regarding the use of intrathecal (IT) opioids for these procedures. In this randomized, prospective study, we compared cardiovascular and neurohumoral responses during IT or IV fentanyl anesthesia for pediatric cardiac surgery. Thirty children aged 6 mo to 6 yr were anesthetized with an IV fentanyl bolus of 10 μg/kg. This was followed by a fentanyl infusion of 10 μg · kg−1 · h−1 (Group IV;n = 10), 2 μg/kg of IT fentanyl (Group IT;n = 10), or combined IV and IT protocols (Group IV + IT;n = 10). Heart rate, mean arterial blood pressure, additional fentanyl doses, time to first analgesic requirement, COMFORT and Children’s Hospital of Eastern Ontario Pain Scale scores, and extubation time were recorded. Blood cortisol, insulin, glucose, and lactate levels were measured presurgery, poststernotomy, during the rewarming phase of cardiopulmonary bypass (CPB), and 6 and 24 h after surgery. The patients’ urinary cortisol excretion rates were also measured during the first postoperative day. The findings in all three groups were statistically similar, except for higher blood glucose levels during CPB in Group IT compared with Group IV (P < 0.004). Group IV + IT was the only group in which the increases in heart rate and mean arterial blood pressure from presurgery to poststernotomy were not significant. The 24-h urinary cortisol excretion rates (μg · kg−1 · d−1) were 61.51 ± 39, 92.54 ± 67.55, and 40.15 ± 29.69 for Groups IV, IT, and IV + IT, respectively (P > 0.05). A single IT injection of fentanyl 2 μg/kg offers no advantage over systemic fentanyl (10 μg/kg bolus and 10 μg · kg−1 · h−1) with regard to hemodynamic stability or suppression of stress response. The combination of these two regimens may provide better hemodynamic stability during the pre-CPB period and may be associated with a decreased 24-h urinary cortisol excretion rate.

Department of Anesthesiology, Başkent University Faculty of Medicine, Ankara, Turkey

July 10, 2002.

Address correspondence to Arash Pirat, MD, Başkent Üniversitesi Hastanesi, Anesteziyoloji Anabilim Dalı, 10. Sok. No. 45, Bahçelievler, 06490 Ankara, Turkey. Address e-mail to arashpirat@hotmail.com. No reprints available.

The use of highly potent opioids for pediatric cardiac anesthesia has gained widespread popularity during the last 20 yr. In addition to the important advantage of hemodynamic stability, the large-dose opioid-based anesthetic techniques also blunt the stress response (1,2). Two clinical studies on neonates undergoing cardiac anesthesia have shown that the stress response can impair postoperative recovery and survival in these patients (2,3). However, although opioids provide circulatory stability and suppress the stress response, large doses can cause oversedation, respiratory depression, and prolonged mechanical ventilation after surgery.

Intrathecal (IT) opioid administration can provide more intense analgesia than the IV route and has the advantages of simplicity and reliability (4). In two retrospective descriptive studies, Peterson et al. (5) and Hammer et al. (6) reported that regional anesthesia with local anesthetics, opioids, or both is safe and effective in the management of pediatric patients undergoing cardiac surgery. However, despite these potential benefits, this route of opioid administration has not been the subject of a prospective, randomized, controlled study in pediatric cardiac anesthesia.

We hypothesized that IT fentanyl would be as effective as IV fentanyl with regard to intraoperative analgesia and reducing the stress response during pediatric cardiac anesthesia. Further, we speculated that combining IV and IT fentanyl might provide better intraoperative analgesia and reduce the stress response further than each route alone. Our aims in this study were as follows: 1) to investigate the adequacy of a single IT injection of fentanyl for intraoperative analgesia; 2) to compare the effects of IT and IV fentanyl on stress response; and 3) to assess for a synergistic effect of IT and IV fentanyl administration in pediatric cardiac anesthesia.

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Methods

Our hospital’s Ethics Committee approved the randomized, prospective, controlled study design, and we obtained written consent from the parents of 30 selected pediatric patients. The enrolled patients ranged in age from 6 mo to 6 yr, and all were scheduled for surgical repair of congenital heart defects. Pre-, intra-, and postoperative exclusion criteria were used. The preoperative criteria were previous cardiac surgery, hemodynamic instability, need for mechanical ventilation, and requirement for the administration of vasoactive drugs, opioids, or corticosteroids. The intraoperative criteria were application of deep hypothermic circulatory arrest and requirement for vasoactive drugs other than temporary use of dopamine and dobutamine (to a maximum dose of 10 μg · kg−1 · min−1). The postoperative exclusion conditions were prolonged (>24-h) mechanical ventilation, hemodynamic instability, and need for large-dose opioids or sedatives.

All patients were premedicated with oral midazolam 0.5 mg/kg and hydroxyzine 1 mg/kg. After initial routine hemodynamic monitoring was applied, a peripheral venous catheter was inserted, and anesthesia was induced with a combination of ketamine 1–2 mg/kg and fentanyl 10 μg/kg. Pancuronium 0.15 mg/kg was given IV to facilitate endotracheal intubation, and this was repeated as required during the surgery to maintain paralysis. A constant infusion of midazolam 0.3 mg · kg−1 · h−1 was started after intubation, and this was continued throughout the procedure. Central venous, arterial, and urinary catheters were inserted. Hemodynamic variables (mean arterial blood pressure and heart rate) were recorded at 5-min intervals during surgery and then twice hourly for 24 h postsurgery.

The patients were randomly assigned to one of three groups. Those in the IV fentanyl group (Group IV;n = 10) received a constant infusion of fentanyl (10 μg · kg−1h−1) throughout the operation; the infusion was started with anesthesia induction and stopped before the patients were transferred to the pediatric intensive care unit (PICU). The IV fentanyl dose that was used in this study is a part of our routine anesthesia protocol for pediatric cardiac anesthesia. The aim is to give patients a total of 50 μg/kg of IV fentanyl throughout the operation (10 μg/kg at the induction and 10 μg · kg−1h−1 during the rest of the operation, which lasts an average of 4 h). The children in the IT fentanyl group (Group IT;n = 10) were placed in lateral decubitus position immediately after intubation and catheterization and received an IT injection of 2 μg/kg of fentanyl in 0.15 mL/kg of normal saline through a 2-in., 25-gauge Quincke spinal needle inserted at L3-4 or L4-5. The dose of IT fentanyl was based on previous experience with this route of fentanyl administration at our institution. No similar previous studies have used IT fentanyl to provide intraoperative analgesia and blunt the stress response in pediatric cardiac anesthesia. Successful dural puncture was confirmed by observation of a free flow of cerebrospinal fluid, and the injection was performed with the bevel of the needle oriented in the cephalic direction. Patients assigned to the combined IT and IV fentanyl group (Group IT + IV;n = 10) received both a continuous intraoperative infusion of fentanyl and IT fentanyl, with use of the methods described for the other two groups.

Anesthesia was conducted in standard fashion, and additional IV boluses of fentanyl (2 μg/kg) were given if blood pressure and heart rate increased (>15% above baseline) and it was believed that the increases were due to insufficient depth of anesthesia. All additional fentanyl doses were recorded. Dextrose infusions were not used before or during surgery. Systemic anticoagulation was achieved with heparin 3 mg/kg. The cardiopulmonary bypass (CPB) perfusate was composed of lactated Ringer’s solution, fresh frozen plasma, and whole blood to achieve a calculated hematocrit of 28%–30%. Methylprednisolone 10 mg/kg, furosemide 1 mg/kg, heparin, potassium, and sodium bicarbonate were added to the prime solution as part of standard protocol. Once the target core temperature (24°C–26°C) was achieved, 10 mg/kg of sodium thiopental was added to the CPB circuit because of its cerebroprotective benefits. This same dose was repeated every 40 min thereafter throughout the hypothermic period. A membrane oxygenator was used for CPB, and systemic hypothermia, cold hyperkalemic cardioplegia solution, and topical cooling with ice were used to maximize myocardial preservation.

After surgery, patients were transferred to the PICU, where they were cared for by a nursing team that was unaware of the anesthetic protocol that had been used. The team evaluated each child for level of analgesia and sedation by using the COMFORT scale (7) (before extubation) and the Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS) (8) (after extubation) and administered fentanyl boluses 1–2 μg/kg as required. Analgesia/sedation scores, heart rate, and blood pressure values were recorded every 30 min during the first postoperative day. In addition, the total dose of fentanyl used, arterial blood gas results, and time to extubation were noted.

Arterial blood samples were obtained from all patients after the induction, 5 min after sternotomy, during the rewarming phase of CPB at 35°C, and at 6 and 24 h after surgery. The intraoperative and postoperative (first 24 h) urine outputs were also collected and logged. Serum and urine cortisol levels were measured by fluorescence polarization immunoassay, and serum insulin measurements were done by microparticle enzyme immunoassay. Plasma lactate and blood glucose levels were determined with the enzymatic colorimetric method.

To calculate the sample size needed to test the stated hypothesis, four variables (blood glucose, serum cortisol, serum insulin, and plasma lactate) were selected, and differences among the groups were calculated on the basis of findings from previous studies and on clinical relevance. We used these differences to calculate the sample size required to give the trial a power of 80% (for α < 0.05). We were not able to calculate the sample size for urinary cortisol excretion before we conducted the investigation, because no previous studies have measured urinary cortisol excretion in pediatric cardiac surgery. Statistical analyses were performed with SPSS 9.0 for Windows (SPSS Inc., Chicago, IL). The Friedman and Wilcoxon tests were used to analyze dependent variables, and the Kruskal-Wallis test and Mann-Whitney U-test were used to compare independent variables. All data are presented as mean ± sd. The level of significance was set at P < 0.05.

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Results

The three groups were similar with respect to patient age, weight, body-surface area, and the durations of CPB, aortic cross-clamping, and surgery (Table 1). The patients’ cardiac pathologies are listed in Table 1.

Table 1

Table 1

All three groups showed similar intra- and postoperative hemodynamic changes (Fig. 1). The poststernotomy mean blood pressure and heart rate values were higher than presurgery values in all groups. However, these differences were not significant in Group IT + IV (blood pressure, 67 ± 10 mm Hg versus 72 ± 6 mm Hg, P = 0.49; and heart rate, 112 ± 18 bpm versus 128 ± 17 bpm, P = 0.063), and only the change in heart rate was significant in Group IV (blood pressure, 72 ± 12 mm Hg versus 75 ± 14 mm Hg, P = 0.33; and heart rate, 112 ± 14 bpm versus 139 ± 11 bpm;P = 0.007). The changes in both variables were significant in Group IT (blood pressure, 64 ± 12 mm Hg versus 70 ± 9 mm Hg, P = 0.028; and heart rate, 117 ± 11 bpm versus 130 ± 16 bpm, P = 0.009). There were no significant hemodynamic changes after IT fentanyl administration, and the three groups required similar amounts of additional fentanyl during the operation (Group IV, 2.5 ± 4.0 μg/kg; Group IT, 2.2 ± 3.6 μg/kg; and Group IT + IV, 2.4 ± 3.5 μg/kg;P > 0.05). The total amount of IV fentanyl that was administered during surgery was significantly less for Group IT compared with the other groups (Group IV, 44.8 ± 9.6 μg/kg; Group IT, 12.6 ± 3.6 μg/kg; and Group IT + IV, 49.7 ± 6.1 μg/kg;P < 0.0001 for Group IT versus the other groups).

Figure 1

Figure 1

Regarding postoperative analgesia, there were no significant differences among the groups with respect to postoperative IV fentanyl supplementation (Group IV, 3.7 ± 2.6 μg/kg; Group IT, 5.5 ± 5.3 μg/kg; and Group IT + IV, 3.3 ± 1.5 μg/kg;P > 0.05). The groups were also similar regarding time to first analgesic requirement in the PICU (Group IV, 6.7 ± 6.2 h; Group IT, 7.1 ± 5.8 h; and Group IT + IV, 7.8 ± 7.9 h;P > 0.05) and their COMFORT (Group IV, 14.9 ± 2.4; Group IT, 15.5 ± 3.7; and Group IT + IV, 12.6 ± 2.0;P > 0.05) and CHEOPS (Group IV, 9.1 ± 1.6; Group IT, 8.7 ± 1.8; and Group IT + IV, 8.2 ± 2.0;P > 0.05) scores.

Postoperative arterial blood gas analysis revealed similar gas exchange and acid-base status in all groups (Table 2). Time to extubation was significantly shorter for Group IT + IV than for either of the other groups (P < 0.05;Table 2). None of the children developed nausea, vomiting, or pruritus. In addition, there were no neurologic abnormalities that suggested spinal cord compression, nerve compression, or neurotoxicity.

Table 2

Table 2

Concerning metabolic and hormonal findings, the baseline values for the three groups were similar. During the rewarming stage of CPB, the blood mean glucose value for Group IT was significantly higher than the level in Group IV (256 ± 69 mg/dL and 184 ± 40 mg/dL, respectively;P = 0.004). There were no significant differences among the three groups’ glucose values at any other stage. All groups showed higher blood glucose values during rewarming than in the presurgery and poststernotomy stages, and patients in Group IT had significantly lower glucose values at 6 h postsurgery compared with their rewarming values (P = 0.005;Table 3).

Table 3

Table 3

The groups’ findings for serum cortisol, insulin, and lactate levels (Table 3) were similar at all stages. There was a significant difference (P < 0.05) in serum cortisol levels when rewarming levels were compared with the levels at earlier stages, but the group findings were similar at each test stage. The same was true for insulin levels in Group IT and Group IV. The group findings for urinary cortisol during the operation and in the first 24 h demonstrated that Group IT + IV had the smallest rate of urinary cortisol excretion; however, when this was compared with the rates in the other groups, the difference was not significant (Group IV, 61.51 ± 39 μg · kg−1 · d−1; Group IT, 92.54 ± 67.55 μg · kg−1 · d−1; Group IT + IV, 40.15 ± 29.69 μg · kg−1 · d−1;P > 0.05).

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Discussion

Large-dose opioid anesthesia offers the important advantage of hemodynamic stability (2,3,9,10), which is a major concern in children undergoing cardiac surgery. Large doses of opioids can also blunt the stress response associated with cardiac surgery (2,9), and this, in turn, may improve postoperative recovery (2). On the basis of these data, systemic opioids have become an important component of anesthetic regimens for pediatric cardiac surgery. However, there are problems with giving large doses of these drugs. They can cause respiratory depression and oversedation after surgery, necessitating prolonged mechanical ventilation. The IT route of opioid administration has been known for longer than 20 years (11); however, this route has not been studied as part of the anesthetic protocol for pediatric cardiac surgery in a prospective, controlled, randomized fashion.

In this study, we used three different fentanyl-based anesthetic protocols to investigate the value of IT fentanyl administration in pediatric cardiac anesthesia. Group IV received a constant infusion of fentanyl (10 μg · kg−1 · h−1) to maintain an adequate blood concentration of the drug throughout the operation, thus representing the control group. The protocol used in Group IT allowed us to investigate the effectiveness of IT fentanyl administration (2 μg/kg) for intraoperative analgesia and to assess how this method affects the stress response in children undergoing cardiac surgery. The regimen used in Group IT + IV was designed to reflect the additive or synergistic interaction of these two different routes of fentanyl administration.

The protocol for IT fentanyl administration was based on our experience and was intended to promote the cephalic spread of the drug. The reported duration of action after IT administration of a single dose of fentanyl is three to six hours (12). On this basis, we speculated that a single IT injection could provide adequate duration of analgesia for pediatric cardiac surgery, which lasts an average of four hours. Previous studies in infants have demonstrated that fentanyl doses of 10 μg/kg or less, given as the sole anesthetic, do not block neurohumoral responses (9,13). Research has also shown that combining a large-dose opioid with a benzodiazepine suppresses the stress response to a greater degree than when the opioid is used alone (10). In light of this information, we used a constant midazolam infusion (0.3 mg · kg−1 · h−1) as part of the anesthetic regimen to ensure adequate anesthetic depth in all our patients.

All three groups studied were similar regarding hemodynamic changes during the various stages of surgery, despite the fact that three separate fentanyl regimens were used. The supplementary amounts of fentanyl required in each group were also comparable. These findings suggest that the different fentanyl protocols produce similar anesthesia depth. However, the hemodynamic alterations that we recorded from presurgery to poststernotomy were less pronounced in Group IT + IV compared with the other groups. Although no significant differences were detected among the groups, this finding within the combination group may suggest some additive or synergistic interaction between IT and IV fentanyl at the doses used in this study. It is also noteworthy that doses of IT fentanyl that are relatively large according to our current practice did not cause any hemodynamic changes.

IV fentanyl has a rapid-onset action and causes minimal hemodynamic changes, even when large doses are given (9,13). Duncan et al. (9) demonstrated that balanced anesthesia with fentanyl 25–50 μg/kg and isoflurane 0.5% is sufficient to obtund hemodynamic and stress responses during the prebypass period of surgery. Unfortunately, the pharmacokinetic properties of fentanyl are unpredictable during CPB. This drug has a strong tendency to bind to the surfaces of the CPB circuit (14,15). Also, hemodilution and drug sequestration further decrease the plasma concentration of fentanyl. However, relative hypotension and hypothermia decrease the clearance rate of fentanyl and may increase its plasma concentration during CPB (15,16).

IT fentanyl administration is simple and reliable. Opioids administered via this route provide more potent and longer-lasting analgesia than equivalent IV doses (4,12,17–19). Furthermore, IT opioid administration eliminates the need for continuous IV infusion of these drugs and reduces the total amount of opioid required. IT-administered fentanyl makes direct contact with the surface of the spinal cord, where it has a profound analgesic effect (12,18). In contrast to the intravascular space, the IT space can be regarded as a closed compartment. Considering these aspects of this route, IT fentanyl administration may avoid the above-mentioned pharmacokinetic problems that occur with IV administration during extracorporeal circulation and hypothermia.

Several investigators have reported the use of neuraxial morphine in pediatric cardiac anesthesia (5,6,20). Neuraxial morphine has the potential benefit of providing postoperative analgesia, which might facilitate early postoperative extubation. However, when the primary goal is to provide intraoperative analgesia, as in our study, large doses of IT morphine are required. As noted, this can lead to prolonged postoperative respiratory depression and the need for mechanical ventilation.

Midazolam is often used in conjunction with opioids during cardiac surgery to deepen the level of anesthesia and ensure hypnosis (21). Gruber et al. (21) compared the effects of bolus fentanyl, fentanyl by continuous infusion, and fentanyl-midazolam infusion on stress response in children undergoing cardiac surgery. These investigators stated that there was no additional suppression of the stress response in the midazolam group and no advantage in hemodynamic stability. We followed a standard protocol for thiopental and midazolam use during the operation in all patients. Therefore, any additional effects of these drugs on stress response or hemodynamic variables would have been similar in all cases, allowing for accurate comparison of the different fentanyl protocols used.

In this investigation, we used serum and urinary cortisol, serum insulin, whole-blood glucose, and plasma lactate levels as hormonal and metabolic indicators of the stress response. When the results were compared with baseline measurements, all three groups showed significantly higher blood cortisol and glucose levels during the rewarming phase of CPB. These findings concur with the results of other studies (2,3,9) and are believed to relate to the systemic inflammatory response, hypotension, and hypothermia associated with CPB, independent of the opioid dose used. The pump prime solution may also contribute to the increased glucose level that we observed during CPB. Our results indicate that these changes are also independent of the route of opioid administration.

We noted a more pronounced increase in blood glucose in Group IT than in Group IV during the rewarming phase of CPB. When exogenous glucose sources are under control, as they were in our study, blood glucose measurements reflect overall metabolic status. Different levels of analgesia and different sites of action related to the fentanyl administration route are two possible explanations for this difference between Group IV and Group IT. However, as mentioned previously, it seems that some metabolic and endocrine responses are not susceptible to opioid receptor agonism and are mainly related to factors other than anesthetic level. The serum cortisol and insulin changes we observed in our patients were similar to those that have been reported previously (2,9). The cortisol level in 24-hour urine output is probably a better indicator of the hormonal component of the stress response. Although this value was much lower in Group IT + IV than in either Group IV or Group IT, there was wide variation in the levels within each group, and the differences among the groups were not statistically significant.

Our aim was to investigate the effects of IT and IV fentanyl on the surgery- and CPB-induced stress response. To eliminate other factors known to induce stress, we included only patients who had not been stressed before surgery and who were expected to have minimal hemodynamic problems in the intra- and postoperative periods. Postoperative pain and sedation levels were evaluated to detect any extended or preemptive analgesic effect related to the different fentanyl administration routes. However, there were no significant differences among the groups’ COMFORT and CHEOPS scores or the times to first postoperative analgesic administration.

We cannot explain the significantly shorter extubation times that were recorded for Group IT + IV, but it is important to note that our PICU uses standard extubation criteria. The postoperative arterial blood gas findings and extubation times in our study indicated that, at the doses used, IT fentanyl was not associated with an increased risk of respiratory depression. We did not assess our patients for muscle rigidity, because they were already paralyzed during IT opioid injection.

As mentioned, the patients had no problems with pruritus, nausea, vomiting, urinary retention, or respiratory depression, all of which are well recognized adverse effects of spinal opioid usage. In part, this could be a reflection of the selected patients, all of whom were intubated and had urinary catheters placed after surgery. In addition, the high lipid solubility and relatively short duration of action of fentanyl are other factors that may help explain why we observed none of the common adverse effects of spinal opioid administration after the operation.

The major concern regarding the use of regional techniques in patients who receive systemic anticoagulation and CPB is the risk of peridural hematoma formation. The incidence of peridural hematoma formation has been estimated at 1:220,000 after IT injection and 1:150,000 after epidural interventions (22). However, the true incidence of this serious complication after pediatric cardiac surgery is unknown. Peterson et al. (5) and Hammer et al. (6) reported no cases of peridural hematoma in 270 children who underwent cardiac surgery, and they concluded that regional anesthesia was safe in these patients. Similarly, we observed no clinical evidence of epidural hematoma in our patients. It is likely that the single IT injection technique, which we used in this study, is associated with a less frequent incidence of epidural hematoma because smaller needles are used, and the risk of hematoma formation during placement or removal of the epidural catheter is therefore avoided.

This study has several limitations. We did not mea- sure fentanyl levels, so the possibility of a systemic effect from IT fentanyl could not be eliminated. However, the total amount of fentanyl used in Group IT was much smaller than the amounts used in the other groups (Group IV, 44.8 ± 9.6 μg/kg; Group IT, 12.6 ± 3.6 μg/kg; and Group IT + IV, 49.7 ± 6.1 μg/kg), despite similar hemodynamic, hormonal, and metabolic variables. This finding indicates an alternative site or mechanism of action, as opposed to a systemic effect with IT fentanyl. Another limitation is that power analysis was not performed to determine the required sample size for urinary cortisol excretion. A post hoc power analysis showed that the sample size was too small to detect a significant difference in this variable (a power of 30% for α < 0.05), despite the obviously lower levels in the combination group.

In conclusion, we found that, at the doses used in this study, IT and IV administration of fentanyl produce similar anesthetic depth during pediatric cardiac anesthesia. The only notable difference in results was observed during the rewarming phase of CPB, when the IT protocol was associated with higher blood glucose levels. With respect to pre-CPB hemodynamic values and urinary cortisol excretion, combined IT and IV fentanyl administration appeared to offer advantages over IV fentanyl alone. The absence of any adverse hemodynamic effects or prolonged respiratory depression after IT fentanyl administration is encouraging and suggests that further studies involving larger doses of IT fentanyl or other opioids may be of value. Despite the promise that IT administration may offer, the potential benefits of such an invasive procedure must always be weighed against the potential risks.

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