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Departments of
*Anesthesiology and Critical Care Medicine and
Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
Departments of Anesthesiology and Pediatrics, Children’s National Medical Center, George Washington University Medical Center, Washington, DC;
§Department of Anesthesia and Pediatrics, Children’s Hospital and Regional Medical Center, University of Washington School of Medicine, Seattle, Washington;
||Department of Anesthesiology, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania;
¶Department of Anesthesiology, Primary Children’s Medical Center, Salt Lake City, Utah;
#Anesthesia Clinical Development and
**Department of Clinical Statistics, Glaxo Wellcome, Inc., Research Triangle Park, North Carolina
Address correspondence to Peter J. Davis, MD, Department of Anesthesia, Children’s Hospital of Pittsburgh, 3705 Fifth Ave., Pittsburgh, PA 15213-2583.
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Abstract |
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Implications: This is a study designed to examine the efficacy and safety of a short-acting opioid, remifentanil, when used in pediatric patients. The frequent incidence of postoperative pain observed in the postoperative recovery room suggests that better intraoperative prophylactic analgesic regimens for postoperative pain control are necessary to optimize remifentanil’s use as an anesthetic for children.
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Introduction |
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There are few studies of remifentanil in pediatric patients (4). In an open label multicenter study comparing remifentanil- to alfentanil-, propofol-, and isoflurane-anesthetized pediatric patients, the recovery variables of remifentanil were similar to the other anesthetics, despite patients’ receiving a "relative overdose" of remifentanil (4).1
This study was designed to evaluate, in a double-blinded manner, the anesthetic maintenance and recovery properties of remifentanil and compare this to a clinically comparable fentanyl-based anesthetic technique in pediatric ambulatory surgical patients undergoing tonsillectomy, with or without adenoidectomy, and with or without myringotomy and tube insertion.
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Methods |
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All children were premedicated with midazolam. For children less than 20 kg, midazolam was administered either intranasally (0.2–0.3 mg/kg) or orally (0.5–0.75 mg/kg). For children larger than 20 kg, midazolam was administered orally (0.5–0.75 mg/kg), with a maximum dose of 15 mg.
All patients underwent induction of anesthesia with either halothane or sevoflurane, with nitrous oxide and oxygen. After an IV catheter was inserted, atracurium 0.3 to 0.5 mg/kg was administered to facilitate tracheal intubation and prevent chest wall rigidity. Supplemental atracurium was administered as indicated by monitoring the patient’s train-of-four ratio. Throughout the operative procedure, ETCO2 was monitored and maintained at 35–45 mm Hg. Before surgical manipulation, ondansetron (100 µg/kg, maximal dose of 4 mg) and dexamethasone (0.25–0.5 mg/kg, maximal dose 8 mg) were administered IV to prevent postoperative nausea and vomiting, and 50 µg/kg of morphine was administered to reduce postoperative pain and discomfort.
After the trachea was intubated, patients received either a placebo bolus dose and a continuous infusion (0.25 µg · kg-1 · min-1) of remifentanil, or the patients received a bolus dose of fentanyl (2 µg/kg) and a placebo continuous infusion. The nitrous oxide and oxygen were administered with the potent inhaled anesthetic used for induction at 0.3% minimum alveolar anesthetic concentration (MAC) (sevoflurane 0.8% or halothane 0.3%). Thus, four treatment groups were possible. Syringes of both remifentanil and fentanyl were prepared by the hospital pharmacist. The concentrations of both opioids were 20 µg/mL. Consequently, equal volumes of drug would be administered to the patient for both continuous infusions and bolus injections. The opioid doses were based on clinical practice.
In all groups, signs of inadequate anesthesia (increases in arterial blood pressure or heart rate more than 20% from baseline or responses such as movement, tearing, or sweating) were treated with an additional bolus dose (1 µg/kg) and an increase in the infusion rate by 50%. Baseline cardiovascular measurements were defined as the investigator’s choice of vital signs before the administration of the preanesthetic medication, midazolam, but before the induction of anesthesia or the vital signs after the induction of anesthesia, but before intubation. The decision as to which set of vital signs was representative of a baseline value was determined by the investigator before the infusion of the study drugs. After a maximum of four supplemental doses were administered, further increases in anesthesia requirements were met by increasing the inhaled potent anesthetic concentration. Patients who received increased inhaled anesthetics were considered treatment failures.
In patients who had a 20% or more decrease in blood pressure (compared with baseline), lactated Ringer’s solution (10 mL/kg) was infused. If hypotension persisted, the remifentanil or placebo continuous infusion was decreased by 50%, and if still uncontrolled, the concomitant inhaled anesthetic (sevoflurane or halothane) was decreased or discontinued.
Atropine (0.01 mg/kg) was administered for bradycardia. Bradycardia was defined as heart rates less than 80 bpm for at least 1 min for children less than 8 yr and heart rates less than 60 bpm for at least 1 min in children 8 yr and over.
Ten minutes before the anticipated end of surgery, the study drug infusion rate was decreased to 0.05 µg · kg-1 · min-1. At the end of surgery, any residual neuromuscular block was antagonized with edrophonium or neostigmine and atropine. Once the train-of-four ratio had returned to baseline and a sustained tetanus was present, nitrous oxide, sevoflurane, halothane, and the continuous study drug infusion were discontinued. For 10 min after the discontinuation of anesthesia, no physical stimulation (e.g., no suctioning of the oropharynx, no jaw thrust, or triple airway maneuver) was performed. If after 10 min the patient had not responded, then stimulation was allowed. With the patient spontaneously breathing 100% oxygen and adequate airway reflexes present, the patient’s trachea was extubated. If after 10 min the patient had an inadequate ventilation, naloxone was administered.
In the recovery room, a study nurse, also blinded to the administered anesthetics, recorded the time the patient met postanesthesia care unit (PACU) discharge criteria and the time the patient met hospital discharge criteria. The study nurse also recorded any adverse postoperative events. The PACU discharge time (time from cessation of the anesthetic until the patient was eligible for discharge from the PACU) was predicated on meeting a postanesthesia assessment recovery score of 6, (with a maximal score of 6, for two consecutive periods) (5). PACU scores were assessed every 5 min from entry into the recovery room until discharge. The criteria for hospital discharge were discharge from the PACU, as well as having pain, nausea, and vomiting controlled and the ability to drink fluids once in the ambulatory unit. In addition, the hospital discharge time without the criteria for taking oral fluids was also recorded.
The side effects of each treatment group were also assessed. The quality of anesthesia recovery was assessed as to whether the patient was agitated or comfortable by using an objective pain-discomfort score (OPDS) (5). The OPDS, on a scale of 0 to 10, was assessed on arrival to the PACU and 5, 10, 15, 20, 30, 40, 50, and 60 min after arrival by the study nurse who was blinded to the study. If patients were in pain (OPDS 
6), morphine 50 µg/kg was administered. Subsequent postoperative pain was treated at the discretion of the investigators.
The 24-h incidence of vomiting was assessed. Vomiting was defined as expulsion of any stomach contents through the mouth. Retching (i.e., dry heaves) was an attempt to vomit that was not productive of any stomach contents. An emetic episode was defined as a single vomit or retch or any number of continuous vomits and/or retches. Parents were given a diary to take home and asked to record the occurrence of vomiting, the administration of medications, and any side effects. Parents were contacted by telephone 24 h later to collect information from the diary as well as to determine patient and parent satisfaction. Because nausea is difficult to quantify in children, it is not reported in this paper.
Cardiovascular events—bradycardia, dysrythmias, and hypotension—were recorded. The incidence of postoperative hypoxemia and the incidence of serious adverse events (SAE) were also noted. In the study, SAE was defined as an event that required inpatient hospitalization or an event that prolonged the current hospitalization.
Summary statistical computations were performed by using SAS version 6.08 (SAS Institute, Inc., Cary, NC). Two-sided statistical tests were performed to detect a difference among treatment groups. Statistical significance was interpreted as a significance level of P 
0.05. Cox proportional hazards modeling, adjusting for site effects, was used to detect among treatment differences in nonnormally distributed continuous variables, e.g., time to extubation or time to discharge. P values were obtained from likelihood ratio tests.
Logistic regression analysis, adjusting for site effects, was used to detect among-treatment differences in dichotomous response variables, e.g., proportion of subjects with treated responses. P values were obtained from likelihood ratio tests. Fisher’s exact test was performed when logistic regression exhibited convergence problems, e.g., every subject had the same dichotomous response within at least one treatment group. The extended Mantel-Haenzel test was applied when more than two levels of ordinal response were of interest.
Analysis of variance, adjusting for sites and baseline, was used to detect among-treatment differences in normally distributed continuous variables, e.g., hemodynamic changes after surgical stimuli.
If the overall model indicated a significant treatment effect, then the following treatment comparisons were performed: 1) remifentanil/halothane (remi/hal) versus fentanyl/halothane (fent/hal), 2) remifentanil/sevoflurane (remi/sevo) versus fentanyl/sevoflurane (fent/sevo), and 3) remi/hal versus remi/sevo. If there was no evidence of a significant interaction between the opioid and inhaled anesthetics, the additional treatment comparison of remifentanil versus fentanyl (controlled for gases) was performed.
The study’s sample size was based on the primary end point of time to extubation. Two hundred patients, 50 evaluable subjects per treatment group, would provide at least 80% power to detect a difference of 2 min in the time to extubation at a 0.05 significance level.
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Results |
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Specific responses to surgical stimulation, insertion of the mouth gag and the excision of the tonsils were also noted. Twenty-two percent of the remifentanil patients and 20% of the fentanyl patients had either tachycardia or hypertension or autonomic (tearing or sweating) response with placement of the mouth gag (P = 0.968). In addition, there was no difference in the incidence of hypertension or tachycardia or autonomic responses between remifentanil-anesthetized patients (35%) and fentanyl-anesthetized patients (47%) during the excision of the tonsil (P = 0.188).
Figures 4 and 5 show the changes in systolic blood pressure and heart rate, respectively, at selected times of the procedure. Although there were statistically significant differences among the groups with regard to systolic blood pressure and heart rate, these hemodynamic differences were not clinically significant.
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Discussion |
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The differences in the distribution of the extubation times were statistically significant. However, the clinical significance of these differences is less clear. At each minute after discontinuation of the anesthetic, more remifentanil-anesthetized patients were tracheally extubated than the patients receiving fentanyl, but by 11 minutes, differences between groups were minimal. However, the design of the study may have precluded finding larger differences in extubation times. Because no physical stimulation (suctioning, jaw thrust, etc.) was allowed for the first 10 minutes after discontinuation of the anesthetic, it is conceivable that with physical stimulation (i.e., suctioning or jaw thrust) some patients might have been extubated earlier. Conversely, patients who required stimulation tended to narrow the differences in extubation times from those who did not. Noteworthy is a significantly greater percentage of patients anesthetized with fentanyl required physical stimulation or naloxone administration at 10 minutes after discontinuation of the anesthetic than the remifentanil-anesthetized patients, and that within the first 10 minutes after the discontinuation of the anesthetic, more patients in the remifentanil groups tended to be extubated than patients in the fentanyl groups. Because interventions were introduced, some patients were censored in the analysis of the extubation and PACU and hospital discharge times. Consequently, survival curves were constructed to analyze these data. Survival analysis does not compare the treatment group median recovery times, but rather survival analysis compares the entire distribution of times between groups. Thus, even though the median recovery times of the groups may be similar, the distribution of times can be statistically significantly different.
Even though remifentanil-anesthetized patients were extubated earlier, this early extubation did not necessarily translate into shorter eligible times for PACU or hospital discharge. Of interest was that the difference in the extubation times and PACU discharge times appear to be more affected in the halothane-anesthetized patients compared with the sevoflurane group. Although these inhaled anesthetic concentrations were administered in comparable MAC equivalents (0.3 MAC), the higher solubility of halothane may have enhanced the differences in the early phases of recovery between fentanyl and remifentanil as opposed to the more insoluble sevoflurane. Although opioids can reduce the MAC of potent inhaled anesthetics (6–8), and work by Lang et al. (9) has demonstrated the MAC-sparing effect of remifentanil for isoflurane, it is unclear whether remifentanil or fentanyl reduces the MAC equally for each of the inhaled anesthetics. Consequently, if the opioid-sparing effect of remifentanil or fentanyl differs between halothane and sevoflurane, the difference in extubation time and PACU discharge time may have resulted from our inadvertent administration of unequal MAC equivalents of the potent inhaled anesthetics as opposed to differences in the solubilities of the potent anesthetics.
Although the early recovery variables appear to be influenced by the choice of opioid and inhaled anesthetic, the late recovery variable, hospital discharge time, was unaffected by the choice of anesthetic. Part of the explanation for this may be related to other events or factors that influence recovery from anesthesia.
Patient pain (i.e., the patient discomfort scores) on arrival and in the PACU could have influenced PACU and hospital discharge times. In this blinded study, patients anesthetized with remifentanil had significantly higher objective pain discomfort scores than patients receiving fentanyl. This finding of higher objective pain scores in remifentanil-anesthetized patients is similar to the results noted in the open-labeled remifentanil pediatric study, in which the remifentanil-anesthetized children’s pain discomfort scores were higher than those for the children who had received either propofol or alfentanil (4). Because PACU and hospital discharge are predicated on adequate pain control, remifentanil’s lack of adequate postoperative analgesia or our inadequate intraoperative prophylactic pain regimen, may have been a significant factor delaying recovery and discharge. Although patients in our study had 50 µg/kg of morphine administered intraoperatively, postoperative pain relief was still inadequate in the remifentanil-anesthetized patients. The lower pain discomfort scores in the fentanyl-anesthetized patients probably reflect fentanyl’s residual analgesic effect. The higher pain discomfort scores in the remifentanil-anesthetized patients observed in both this study and the open-labeled pediatric study reaffirm the limitations of remifentanil with regard to its ability to provide postoperative pain control.
Another aspect of recovery from anesthesia is the time to home discharge. The definition of when patients are "ready for discharge" is a factor influencing time to home discharge. In this study, adequate pain and vomiting control were needed as well as having patients able to take and retain oral fluids. Although Schreiner et al. (10) have shown that the taking and retaining of oral fluids unnecessarily delays ambulatory surgical discharge, in some centers fluid retention for tonsillectomy patients was a hospital discharge criteria. However, even when taking and retaining of oral fluids was eliminated as a hospital criterion for hospital discharge, the choice of anesthetics did not influence patient discharge time. The findings of early extubation times not translating into faster hospital discharge times have also been noted for the newer, less soluble inhaled anesthetics desflurane and sevoflurane and the IV anesthetic propofol (11–14).
With the exception of pain in the PACU, we noted that the other postoperative side effects of remifentanil were similar to fentanyl. The lack of difference in the incidence of emesis among the groups may have been a function of the high incidence of emesis associated with tonsillectomy as well as the prophylactic use of both ondansetron and dexamethasone (15–17). Although there was no difference in the 24 incidences of emesis among the groups, half of the emesis occurred during the patient’s hospital stay. Thus, emesis and efforts to control emesis are another set of factors irrespective of the anesthetic that may delay hospital discharge.
The incidence of postoperative hypoxemia was similar for remifentanil and fentanyl. This finding is in contrast to that observed in the open-labeled study in which alfentanil-anesthetized patients had a significantly higher incidence than the patients anesthetized with remifentanil (4). Whether these differences in postoperative hypoxemia are a function of the individual drug kinetics, the methods of administration (bolus versus continuous infusion) or the patient’s underlying surgical condition, is unclear.
A possible criticism of our study is that the doses of remifentanil and fentanyl may not be comparable. Although no dose-dependent studies in children have been performed, the doses chosen were based on clinical practices. The fact that the number of intraoperative supplemental doses and the incidence of inadequate anesthesia responses were comparable between the two groups supports their equivalency.
In summary, when remifentanil and fentanyl are administered in a blinded fashion using preset criteria for their administration and titration, we noted that continuous infusions of remifentanil were as effective as bolus fentanyl. Although patients could be tracheally extubated earlier with remifentanil, this did not translate to earlier eligible times for PACU or hospital discharge. The high incidence of postoperative pain observed in the postoperative recovery room suggests that better intraoperative prophylactic analgesic regimens for postoperative pain control are necessary to optimize remifentanil’s use as an anesthetic for children.
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Acknowledgments |
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The authors sincerely thank Kathleen Fertal, RN, Children’s Hospital of Pittsburgh, Pittsburgh, PA; Rosetta Chiavacci, BS, RN, Children’s Hospital of Philadelphia, Philadelphia, PA; Mary Kay Nespeca, RN, Children’s Hospital and Regional Medical Center, Seattle, WA; Kelly A. Hummer, RN, BSN, Children’s National Medical Center, Washington DC; Allison Ross, MD, and Rhonda B. Dear, RN, Duke University Medical Center, Durham, NC; Shawna Baker, RN, Dixie Hunter, RN, Karen Osborne, RN, Pat Pugh, RN, and JoAnne Tanner, MSN, RN, Primary Children’s Medical Center, Salt Lake City, UT, for their contributions to this project, and Susan Danfelt for her secretarial support. The authors thank the CRNAs and recovery room nurses of Rush SurgiCenter for their help with the study.
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Footnotes |
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