Anesth Analg 2006;102:1668-1673
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000219587.02263.A0
PEDIATRIC ANESTHESIA
Intraoperative Administration of Tramadol for Postoperative Nurse-Controlled Analgesia Resulted in Earlier Awakening and Less Sedation than Morphine in Children After Cardiac Surgery
Ya-Chun Chu, MD, PhD,
Su-Man Lin, MD,
Ying-Chou Hsieh, MD,
Kwok-Hon Chan, MD, and
Mei-Yung Tsou, MD, PhD
Department of Anesthesiology Taipei Veterans General Hospital and National Yang-Ming University, School of Medicine, Taipei, Taiwan
Address correspondence and reprint requests to Mei-Yung Tsou, MD, PhD, Department of Anesthesiology, Taipei-Veterans General Hospital, 112, Taiwan. Address e-mail to: mytsou{at}vghtpe.gov.tw.
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Abstract
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In adults, intraoperative administration of tramadol could result in earlier recovery and less sedation than morphine. In this controlled, randomized, double-blind study, we investigated whether an intraoperative initial dose of tramadol could cause more rapid awakening from general anesthesia, less sedation, and earlier tracheal extubation than morphine in children during the immediate postoperative period. Forty children aged 1–6 yr, scheduled for atrial or ventricular septal defect repair and tracheal extubation in the pediatric intensive care unit, were randomly allocated to receive morphine, initial dose 0.2 mg/kg, or tramadol 2 mg/kg given at the end of sternal closure, followed by nurse-controlled analgesia (bolus 0.02 mg/kg of morphine and 0.2 mg/kg of tramadol) with background infusions (0.015 mg · kg–1 · h–1 for morphine and 0.15 mg · kg–1 · h–1 for tramadol). Postoperatively, children receiving tramadol had earlier awakening from general anesthesia (P = 0.02) and were less sedated at 1 and 2 h postoperatively (P = 0.03 and P = 0.01, respectively). Tracheal extubation was earlier in the tramadol group (P = 0.01). Lengths of pediatric intensive care unit stay did not differ between groups. Times to first trigger of nurse-controlled analgesia bolus and objective pain scores during the 48 h observation period were comparable between groups. The incidence of desaturation and emesis were similar between groups. The patients ate well and did not differ on Day 1 or Day 2.
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Introduction
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Provision of adequate sedation and analgesia to critically ill children is an important aspect of care in the pediatric intensive care unit (PICU). Sedation and analgesia can reduce pain and anxiety that, if untreated, can lead to psychological and physical stress. Analgesic and sedative drugs also affect weaning from the ventilator. In addition to analgesic effects, opioids are often chosen as first- or second-line drugs for sedation of patients in the PICU. However, opiates may also depress respiratory drive and cause airway obstruction as a result of over-sedation. When different kinds of opioids were given concurrently, the sedative and respiratory depressant effects are exacerbated (1). As systemic opioids are routinely used in pediatric cardiac anesthesia, postoperative analgesia with morphine may have unpredictable sedative effects, especially in the immediate postoperative period. The analgesic action of tramadol is based on a multimodal mechanism of action that involves activation at the µ-opioid receptor as well as inhibition of norepinephrine and serotonin reuptake in the central nervous system (2). Tramadol may have advantages over conventional opioids in terms of side effects. Potential advantages of administering tramadol for postoperative pain relief include long duration of action (3), rapid recovery (4), and limited respiratory depressant effects (5). Several studies have demonstrated that tramadol provides a comparable analgesic effect to morphine for postoperative pain relief in adults when administered as an intraoperative bolus followed by a continuous infusion or by patient-controlled analgesia (PCA) (6,7).
Intraoperatively administration of opioids can sometimes result in unexpected prolonged recovery and delayed awakening. As opioids are routinely used in cardiac anesthesia, it is our standard management protocol to transport pediatric patients to the PICU directly from the operating room (OR) after cardiac surgery. The patients' tracheas are extubated in the PICU after initial ventilatory support and routine chest radiograph follow-up. However, morphine, the standard regimen for postoperative pain control, when administered intraoperatively, can have significant sedative effects, prolong recovery from anesthesia (8) and delay tracheal extubation. In this study, we assumed that tramadol, initially administered intraoperatively, followed by nurse-controlled analgesia (NCA) with background infusions, would result in patients awakening earlier after anesthesia, being less sedated, and more rapidly tracheally extubated as compared with patients who received an equipotent dose and infusion of morphine.
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Methods
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After institutional approval and written, parental informed consent, the patients were randomized to either the morphine or tramadol group. The concentrations of the study drugs were adjusted to make both regimens indistinguishable. Exclusion criteria were patients with ASA physical status >III, patients younger than 1 yr of age, patients with developmental disabilities and patients with asthma. Nurses in the PICU were instructed to assess the pain intensity using the Children's Hospital of Eastern Ontario Pain Scale (CHEOPS; range 4–13; score of 6 or lower = not distressed) (9) during their regular nursing observations. NCA boluses were administered for scores more than 9/13. A research fellow came at fixed time points and scored the CHEOPS for the efficacy of NCA. Nurses and the research fellow were all blinded to the grouping of the patients.
In all patients, a standardized anesthetic technique was used. Anesthesia was induced with thiopental 5 mg/kg, fentanyl 5 µg/kg, and tracheal intubation was facilitated with atracurium 0.5 mg/kg. Radial arterial and central venous pressure catheters were inserted for hemodynamic monitoring and blood gas determinations. Anesthesia was maintained with 1.5%–2.5% isoflurane (inspired concentration) in 50% oxygen in air with intermittent positive-pressure ventilation. Bolus doses of atracurium and fentanyl were administered as clinically indicated.
With closure of the sternum, patients randomized to the morphine group received an initial dose of morphine 0.2 mg/kg, whereas patients in the tramadol group received an initial dose of tramadol 2 mg/kg. At completion of surgery the children remained tracheally intubated and were transferred directly to the PICU for temporary ventilatory support and intensive care. On arrival at the PICU, patients in the morphine group received NCA with bolus doses of morphine 0.02 mg/kg with a lockout interval of 10 min and background infusion rate of 0.015 mg · kg–1 · min–1. The 4-h limit was 0.3 mg/kg (10). Patients in the tramadol group received bolus doses of tramadol 0.2 mg/kg with the same lockout interval and a background infusion rate of 0.15 mg · kg–1 · min–1. A 4-h limit was set at 3 mg/kg. Emesis was treated with metoclopramide 0.1 mg/kg. Meperidine 1 mg/kg was prescribed as the rescue analgesic. All patients had urinary catheters for the 48-h observation period. Naloxone was ordered on an as-needed basis for all patients receiving NCA as part of our standardized management protocol.
After arrival at the PICU, every patient was monitored and assessed by one nurse continuously. Awakening was demonstrated by spontaneous eye opening, grimacing, and purposeful movements. The PICU intensivist determined the timing of tracheal extubation. The criteria for extubation included awake and responsive mental status, measured tidal volumes >5 mL/kg, respiratory rate appropriate for age, stable hemodynamics, adequate oxygenation and ventilation (pH
7.3, Paco2 
55, base excess >–4, Pao2 90 on Fio2 0.5) and minimal bleeding (<4 mL · kg–1 · h–1). During the study period, the responsible nurses would administer NCA boluses for CHEOPS scores >9/13 or any inconsolable arousal behavior. To minimize the variability of evaluation, 5 nurses were included in the postoperative care of the patients. The independent, blinded research fellow made assessments at 1, 2, 4, 8, 24, 48 h after surgery. Time to awakening, to first NCA bolus, tracheal extubation, and length of PICU stay were recorded from the medical chart. CHEOPS score, sedation score, number of demanding boluses, daily amount of consumption of drugs, respiratory rate, heart rate, noninvasive arterial blood pressure, oxygen saturation, side effects, and feeding condition were assessed on regular follow-up. The level of sedation was assessed by using a 5-point score (11) (1 = fully awake, 2 = slightly drowsy, 3 = asleep but easily arousable verbally, 4 = asleep, easily arousable by tactile stimulation but not verbally, 5 = asleep, not arousable). Emergence behaviors, such as irritability, inconsolable crying, or severe restlessness, were recorded. Respiratory depression was defined as respiratory rate <14 with episodes of Spo2 <95%. Emesis was defined as at least one episode of retching or vomiting movement. Feeding condition was recorded for each patient, including the time and amount. Good feeding was defined as no refusal to feeding and no vomiting during or after the feeding.
To determine the number of patients to be included, we recorded the sedation score of patients receiving intraoperative morphine at 1 h after the surgery in a preliminary study (n = 10, mean sedation score 2.125 ± 0.8). Assuming an 
risk of 0.05, a ß risk of 0.10, and the mean difference of 40%, we calculated that 20 patients should be included in each group. Student's t-test was used to determine the significance of normally distributed parametric values and Wilcoxon's ranked sum test for nonnormally distributed data. Ordinal data were analyzed using the Mann-Whitney U-test. Categorical variables were tested using 
2 test or, when appropriate, Fisher's exact test. The significance level was set at 0.05.
Results
Forty children were studied and all completed the study protocol in the PICU and ward. There were no withdrawal or protocol violations. Demographic data are given in Table 1. The two groups did not differ in age, weight, sex, intraoperative total amount of fentanyl, or duration of cardiopulmonary bypass and surgery. Daily consumption (Table 2) of morphine was 0.51 ± 0.11 mg/kg on Day 1 and 0.4 ± 0.01 mg/kg on Day 2 (P < 0.001). Daily consumption of tramadol was 5.54 ± 0.87 mg/kg and 4.98 ± 0.9 mg/kg on Day 1 and Day 2, respectively (P = 0.053). Daily number of NCA boluses was 7.7 ± 4.7 and 2.7 ± 2.1 on Day 1 and Day 2 (P < 0.001), respectively, for the morphine group; 9.9 ± 3.6 and 6.0 ± 3.3 on Day 1 and Day 2 (P < 0.001), respectively, for the tramadol group. Between the groups, the daily number of NCA boluses was similar on Day 1 (P = 0.11) but was significantly fewer in the morphine group on Day 2 (P < 0.001).
Medians of sedation scores (Table 3) were 2 and 1 for morphine and tramadol, respectively, at 1 h (P = 0.03) and 2 h (P = 0.01) postoperatively. Afterwards, no differences were found. The CHEOPS scores (Table 4) of both groups were comparable during the 48 h observation period, except at 1 h after surgery. Medians of CHEOPS were 8.5 and 8 for the morphine and tramadol groups, respectively, 1 h postoperatively (P = 0.03). In the PICU, time to the first trigger of NCA bolus did not differ between groups (Table 5). Mean time to awakening was 35.2 ± 20.3 min (range, 12–58 min) for the morphine group, and 20.8 ± 17.5 min (range, 7–50 min) for the tramadol group (P = 0.02) (Table 4). Mean time to tracheal extubation was 47.5 ± 15.8 min (range, 24–65 min) for the morphine group, and 30.5 ± 21.3 min (range, 16–69 min) for the tramadol group (P = 0.01) (Table 4). There were no differences of the lengths of PICU stay between groups (Table 4).
Respiratory rate and pulse oximetry showed comparable data between the two groups (data not shown). Mean values of heart rate and arterial blood pressure did not differ at any observation point during the whole course of study (data not shown). The incidences of respiratory depression and postoperative emesis are presented in Table 6. No patient experienced respiratory depression in our study. Five patients in the morphine group and six in the tramadol group experienced at least one episode of vomiting (P = 1.0) on Day 1. Two patients in the morphine and 3 in the tramadol group required antiemetic therapy (P = 0.66). The numbers of patients who had good feeding were also comparable on Day 1 (9 in morphine group versus 12 in tramadol group; P = 0.53). Almost all patients fed well on Day 2.
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Discussion
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Our results demonstrated that children receiving tramadol, the initial dose administered intraoperatively, then NCA with background infusions had more rapid awakening from general anesthesia, less sedation in the immediate postoperative period, and earlier tracheal extubation than children receiving an equianalgesic dose of morphine. Tramadol provided adequate analgesic effect, as did morphine, and was tolerated well in this group of patients. Our primary endpoint was to compare the sedative effects of tramadol and morphine and their effects on the time to tracheal extubation. Kloth and Baum (12) have reported that IV morphine, given after cardiopulmonary bypass, is safe for very early tracheal extubation, i.e., planned extubation either in the OR or immediately on arrival in the PICU. However, their mean dose was 0.062 mg/kg with a range of 0.025–0.125 mg/kg. This is much less than the initial dose of morphine used in this study. Our results showed mean times to awakening (mean, 35.2 versus 20.8 min, morphine versus tramadol) and to tracheal extubation (47.2 versus 30.5 min, morphine versus tramadol) were significantly shorter in the tramadol group. We also showed that patients in the tramadol group had lower sedation scores at 1 and 2 h after surgery than patients in the morphine group. Taken together, those who awakened earlier and appeared less sedated were tracheally extubated earlier. Although our patients underwent simple and uneventful cardiac surgeries and were anticipated to be tracheally extubated early after the operation, very early tracheal extubation has not been a common practice after pediatric cardiac surgeries in this hospital. Thus our data cannot support the advantage of tramadol for tracheal extubation in the OR and avoiding mechanical ventilation. However, our study still provided useful data for reference of the choice of analgesics when very early tracheal extubation was considered. There was an average delay of about 10 min between awakening and tracheal extubation, when the pediatric intensivist made general assessments for the adequacy of tracheal extubation.
There was a paradox between the sedation and CHEOPS scores at postoperative 1 h. The median value of CHEOPS was 8.5 in the morphine group and 8 in the tramadol group. Nevertheless, patients receiving morphine were more sedated and their first activation of NCA bolus was later (not statistically significant) than those receiving tramadol. How could the patients with higher sedation score concomitantly have higher CHEOPS scores? One explanation may be that because children in the morphine group were tracheally extubated later than children in the tramadol group and their arms were restrained for fear of accidental self-extubation, the CHEOPS in unextubated, restrained children will be higher than in children who are not restrained. This may represent the inappropriateness of CHEOPS for pain assessment in the tracheally intubated children.
In children older than 6 years of age, PCA has become commonplace in the management of moderate to severe pain. But for physically or cognitively impaired children younger than 6 years of age, parent-/nurse- controlled analgesia is an alternative. In the PICU, NCA was more feasible than parent-controlled analgesia. However, overdosing or underdosing remained potential problems. Nevertheless, our data showed that no patients appeared oversedated (sedation score 4) in either group after 2 hours postoperatively. Patients in the morphine group showed significant sedation compared with those in the tramadol group in the initial postoperative 2 hours. This may be have been a result of interaction of the sedative effects of morphine with the residual effects of the anesthetics used during the operation. After 2 hours, the advantage of tramadol was no longer demonstrable. Another concern of NCA was underdosing and insufficient analgesia, especially when the nurses had to take charge of too many patients at a time. Our nurses were in charge of 2 patients each in the PICU, where underdosing was less likely to happen. Despite the difficulties in interpreting data (painful versus non-painful, frustrated versus non-frustrated, etc.), all of our patients appeared to achieve adequate analgesia without using the NCA device, as CHEOPS scored by the researcher at various fixed time points showed comparable results between groups. No patient required rescue analgesia. The emergence behaviors during recovery were similar in both groups of patients, except for one patient in the tramadol group who had inconsolable crying and disorientation at postoperative 1 h. Lengths of PICU stay did not differ between groups. There is a minimum PICU stay in our hospital. Therefore, our data cannot fully support that reductions in tracheal intubation time will shorten the lengths of PICU stay.
It has been reported that inadequate analgesia occurs in 65.5% of pediatric patients during the first 24 h of therapy and that this occurs most often in patients with morphine infusion rates of <0.02 mg · kg–1 · h–1 (13). However, continuous opioid infusion and nurse/physician-controlled analgesia were both the important related factors of respiratory depression (14). Thus, we set the morphine infusion rate at 0.015 mg · kg–1 · h–1. The NCA boluses alleviated the problem when there was insufficient analgesia. The equianalgesic dose of tramadol was reported to be close to that of meperidine (15); the analgesic potency is approximately 10% of morphine after parenteral administration. Our results showed that daily consumption of tramadol was about 10 times that of morphine on Day 1 when administered via NCA bolus and a background infusion. Mean morphine consumption decreased 22% on Day 2; this result is comparable to the results from Webb et al. (16). However, mean consumption of tramadol decreased only 10% on Day 2. This was also similar to the demanding numbers of NCA boluses. The numbers of demanding boluses were comparable between two groups on Day 1; however, there were significantly fewer demands from the morphine group on Day 2. One possible reason may be the analgesic effects originating from active metabolites of these opioids. For example, morphine-6-glucuronide (M6G), one of the active metabolites of morphine, was reported to be more potent than morphine (17) and could possibly have exerted an additive effect that led to less morphine consumption on Day 2. Although tramadol also has an active metabolite, (+)-O-desmethyl-tramadol (M1), with a long duration of action, there are no data comparing the relative potency of M6G and M1. These metabolites may account for an important part of the clinical effects of extended infusion that must be considered in clinical practice.
In our study, no patients in either group experienced respiratory depression, perhaps because patients were routinely given supplemental oxygen in the immediate postoperative period. Another reason may be that our study size was calculated to explore the differences in level of sedation in the immediate postoperative period. Comparing our sample size may not have been adequate for observing a difference with an incidence between 0.2% and 0.7% (14). In addition, these measures may not reflect the minute respiratory depressant effects of the drugs we used in the study. Postoperative nausea and vomiting have been reported in 30%-50% of children receiving PCA (18). We observed a somewhat less frequent incidence of postoperative emesis in our patients receiving NCA. Although some studies reported an increased incidence of postoperative nausea and vomiting in adults receiving tramadol (7), we found no significant difference between the two groups. We also noted no feeding differences between groups.
In summary, we have demonstrated tramadol, with an initial loading dose given intraoperatively and then NCA boluses with background infusions, caused earlier awakening from general anesthesia, less sedation, and earlier tracheal extubation in the immediate postoperative period. It has equivalent analgesic efficacy and a comparable incidence of postoperative emesis as morphine in children <6 years of age after cardiac surgery.
This work was supported by the Research fund of Taipei Veterans General Hospital (VGH 89-349). The authors wish to thank Prof. K. C. Wong for a critical review of the manuscript.
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Footnotes
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Accepted for publication February 17, 2006.
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Abstract
Introduction
