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PEDIATRIC ANESTHESIA

Recovery After Anesthesia for Short Pediatric Oncology Procedures: Propofol and Remifentanil Compared with Propofol, Nitrous Oxide, and Sevoflurane

Department of Anaesthesia, Great Ormond Street Hospital for Children NHS Trust, London, UK

Address correspondence and reprint requests to Hilary R. Glaisyer, MRCP, FRCA, Department of Anaesthesia, Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, London, WC1N 3JH, United Kingdom. Address e-mail to glaish{at}gosh.nhs.uk or hrg{at}doctor.com.

	Abstract

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Anesthesia techniques in children undergoing short painful oncology procedures should allow rapid recovery without side effects. We compared the recovery characteristics of two anesthetic techniques: propofol with sevoflurane and nitrous oxide and a total IV technique using propofol and remifentanil. Twenty-one children, undergoing two similar painful procedures within 2 wk were studied in a single-blind manner within patient comparison. The order of the techniques was randomized. Propofol and remifentanil involved bolus doses of both propofol 3–5 mg/kg and remifentanil 1–4 µg/kg. Propofol with sevoflurane and nitrous oxide involved propofol 3–5 mg/kg with 2%–8% sevoflurane and 70% nitrous oxide. The primary outcome variable was the time taken to achieve recovery discharge criteria; other recovery characteristics were also noted. The mean age of the children was 6.5 yr (range, 2.5–9.8 yr). Nineteen had lymphoblastic leukemia and two had lymphoma. All children had intrathecal chemotherapy and one had bone marrow aspiration. Most procedures lasted <4 min. The mean time to achieve recovery discharge criteria was appreciably shorter after propofol and remifentanil than propofol with sevoflurane and nitrous oxide by nearly 19 min (P = 0.001). All other time comparisons had similar trends and statistical differences. Seven parents expressed a preference for the propofol and remifentanil technique compared with one preferring propofol with sevoflurane and nitrous oxide. Children are apneic during the procedure and require respiratory support from an anesthesiologist. Discharge readiness from the recovery ward was achieved on average 19 min earlier after propofol with remifentanil compared with the combination of propofol, sevoflurane and nitrous oxide. Parents more often preferred propofol with remifentanil.

	Introduction

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The treatment of many childhood malignancies requires repeated, short painful procedures such as lumbar puncture (LP) and bone marrow aspiration (BMA). Most adults will tolerate these under local anesthesia alone but most children need help to reduce their distress (1). Strategies vary among institutions, probably largely influenced by culture and resources (2,3), and include behavioral or psychological techniques (4), nitrous oxide analgesia (5), various forms of sedation (6–9), and anesthesia (10–17). In our hospital, many of our patients are too young, too ill, or not cooperative enough for any technique other than anesthesia.

Because resources are limited, anesthesia services should be as efficient as possible and should use techniques that allow rapid recovery. Most children have indwelling IV catheters (usually central) and prefer a painless IV induction. Our standard technique has been IV propofol followed by inhaled sevoflurane and nitrous oxide, but in 1999 we introduced a total IV technique using a combination of propofol and remifentanil (18). In this study we have compared the recovery characteristics of the two techniques; propofol and remifentanil (PR) versus propofol, nitrous oxide and sevoflurane (PSN).

	Methods

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The study was approved by the local ethics committee. Parents gave written informed consent and, if they were old enough, children gave their assent also. Twenty-one children, aged 2 to 10 yr, were recruited if they were scheduled to undergo 2 similar painful procedures separated by no more than 2 wk. For the first procedure, children were randomized to receive one of two anesthetic techniques; the other technique was used subsequently and both techniques were therefore studied by within-patient comparisons. The study design was single-blind; children, parents, and recovery staff were unaware which technique had been used, but, during the procedure itself, the two anesthetic techniques could not be disguised. Patients were excluded if they were ASA physical status grade >III, were unable to respond appropriately to verbal commands, or if they had been in pain, been nauseated, or received sedative or analgesic medication within the previous 12 h.

Children were not premedicated and anesthesia was induced IV with propofol via a central venous line. A parent was present until their child was unconscious. Anesthesia was supplemented or maintained either by IV remifentanil with propofol or by inhaled sevoflurane with nitrous oxide. Children were initially supine and then turned to the lateral position as soon as they were asleep and still. The same anesthesiologist (HG) supervised anesthesia for every procedure.

For the PR technique anesthesia was induced with propofol 3 mg/kg followed by remifentanil 1 µg/kg and each drug was administered over 10–15 s. Drug preparation and dilution are detailed in the Appendix. Oxygen alone was administered via an anesthesia breathing system and ventilation was assisted if necessary. The procedure started soon after the injection of remifentanil and usually while breathing was assisted. Further injections of remifentanil 0.5 µg/kg or propofol 0.5–1 mg/kg were given depending on whether the patient moved or showed signs of awakening in response to positioning for the procedure or during the procedure itself.

For the PSN technique anesthesia was induced with a sleep dose of propofol (3–5 mg/kg) that was sufficient to allow acceptance of the face mask. This was followed by an injection of normal saline to simulate the remifentanil to ensure that neither parent nor child knew which technique had been used. After the parent departed anesthesia was continued with 2%–8% sevoflurane and 66% nitrous oxide in oxygen; sevoflurane was adjusted to ensure the patient could be placed in a "curled up" position ready for the procedure. The minimum sevoflurane concentration used was 2% and was increased up to 8% if the patient moved during skin preparation or the procedure itself. Anesthesia administration stopped as soon as the procedure was achieved.

During anesthesia, pulse oximetry, electrocardiogram, noninvasive arterial blood pressure, and gas monitoring were applied as soon as possible depending upon the child’s cooperation. Arterial blood pressure was recorded automatically every 3 min. The anesthesiologist noted the slowest heart rate, lowest arterial blood pressure and oxygen saturation, any untoward event, and the times (to the nearest minute) of the start of anesthesia, the start of the procedure, and the end of the procedure. Movement during the procedure was noted.

During recovery experienced nurses recorded observations. Children were left undisturbed, apart from their name being called every minute until they first opened their eyes. Oxygen saturation was monitored continuously and noninvasive arterial blood pressure was measured every 5 min until awake. Distress behavior was assessed using a simple scoring system, modified from that of Hannallah et al. (19), in which crying, moving and agitation were scored separately (0, 1, or 2, maximum distress score = 6). Any analgesia required or side effects, such as nausea and vomiting, were noted. The times (to the nearest minute) at which children first opened their eyes, interacted spontaneously, drank, ate and were ready for discharge from the recovery ward and the hospital were recorded. The criteria for discharge from the recovery ward included being awake, comfortable, able to cough or breathe deeply, move all limbs voluntarily, and maintain oxygen saturations more than 93% in air. Children were considered ready to return home when they had had food or drink and were fully mobile, pain free, and without nausea. All children remained in hospital for at least 1 h after the procedure. Before discharge home, parents and children were interviewed by an anesthesiologist (HG) who asked: "What was the anesthetic experience like?" and also, after the second procedure, "Which technique do you prefer and why?"

The primary outcome variable was the time taken to achieve recovery discharge criteria after the end of procedure. Twenty-one patients give 90% power to determine a difference in the recovery time between the 2 anesthetic techniques of 1 sd to a statistical significance of 5%. Statistical comparisons were made with paired Student’s t-test and Wilcoxon’s ranked sum and McNemar’s tests where appropriate.

	Results

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The mean age of the patients was 6 yr and 6 mo (median, 4 yr 5 mo; sd, 2 yr 6 mo; range, 2–9 yr 10 mo) and the mean body weight was 21.9 kg (median, 18.6 kg; sd,7 kg; range, 13–36 kg). Nineteen had acute lymphoblastic leukemia and two had non-Hodgkin’s lymphoma. One patient had a LP and BMA under both PR and PSN techniques and all others had LPs. Nine patients had PR first.

The time of anesthesia before the procedure and the duration of the procedure itself were usually <3 min (Table 1). The anesthesia times, however, were longer for the PSN technique; 13 patients were ready for the procedure in <1 min with the PR technique compared with 6 with PSN. The durations of the procedures were similar for both techniques. The mean dose of propofol was 3.7 mg/kg when used with remifentanil (mean dose, 1.2 µg/kg), compared with 4.6 mg/kg with sevoflurane/nitrous oxide. Additional anesthesia was required (one during PR and five during PSN) for positioning the children for the procedures and when minor movement occurred during the procedure itself.

Table 2 shows the times taken to achieve various events during recovery. The mean time taken to achieve recovery discharge criteria was appreciably shorter after PR than PSN by nearly 19 min (confidence interval 8.5–28.7 min, P = 0.001). All other time data have similar patterns and statistical differences. For example, with PR eyes opened on average 15 min earlier (confidence interval 8.6–21.7 min, P < 0.001) and drinking occurred 24 min earlier (confidence interval 8.6–39.8 min, P < 0.01). Times were also compared between first and second procedures irrespective of the anesthetic technique and there were no statistical differences.

The Hannallah scores were similar for both techniques. Nineteen children had a score of 1 or less after PR compared with 17 after PSN. One child after each technique had a score of 6. These differences were not statistically significant (P = 0.303, Wilcoxon’s signed ranks test). No child required analgesia or complained of nausea or vomiting. Parents commented on prolonged recovery or sleepiness after PSN in three children, one of whom was distressed because of sudden awakening after a "long sleep;" another complained of shivering. Seven parents expressed a preference for the PR technique compared with one for PSN; the remainder did not have a preference.

Bradycardia (<60 beats/min) occurred during recovery in four patients (two after PR and two after PSN); treatment was not required and heart rate returned to normal on waking. Oxygen saturations <94% occurred in six patients during or after PSN (lowest 82%) compared with one patient during PR (lowest 92%). Eight children had either systolic or diastolic hypotension (<80/40 mm Hg) during or after PR compared with 13 related to PSN; hypotension was brief and did not require therapy. There was no statistical difference between the techniques in the number of patients with either hemodynamic depression or oxygen desaturation (McNemar’s test, P = 0.32).

	Discussion

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Our data show that total IV anesthesia with bolus administration of propofol and remifentanil allowed rapid return to consciousness and that children were, on average, ready to leave the recovery area by 13 minutes. Also, the characteristics of the technique included speedy induction, minimal movement during the procedure, no need for scavenging and few aftereffects. In short, there were clear advantages for patients and caregivers alike and this was reflected in the preferences of parents.

Propofol alone can be effective but large doses may be required to suppress movement as a result of pain; in 2 studies the mean dose ranged from 5 to 8.8 mg/kg (11,15). Some clinicians use local anesthesia to prevent movement and to reduce the propofol dose but we have found no published data to demonstrate these effects. Further, local anesthesia either topically applied or by infiltration adds to preparation or procedure times.

Two studies in children having short painful procedures support the use of systemic analgesia to reduce the dose of propofol. Keidan et al. (14), in a randomized controlled comparison, showed that remifentanil reduced the dose of propofol, and this is supported by a retrospective study by Jayabose et al.,(13) who found that the dose of propofol was smallest when combined with both midazolam and fentanyl premedication. In both studies recovery times were shorter with analgesia supplementation. Recovery is dependant both on the criteria set and the judgement of individual observers and therefore the recovery times of different studies should be compared with caution.

The ideal analgesic should match the pain of the procedure. For brief procedures, fentanyl or alfentanil may be too long acting, although they may be appropriate if there is discomfort later, such as headache after dural puncture (20). Bauman et al. (10) combined fentanyl with propofol and found that recovery was longer than after methohexitone combined with remifentanil.

Remifentanil, even in large doses, allows rapid recovery as a result of its fast metabolism (21), and therefore it can be used for pain, whatever the severity, provided that it is brief. Remifentanil by infusion has been described for bronchoscopy in children who are not tracheally intubated and who are kept sufficiently sedated with a combination of midazolam (oral premedication, 0.5 mg/kg) and propofol (22). In women, propofol (2 mg/kg) and remifentanil (1.5 mg/kg) supplemented with nitrous oxide is suitable for uterine curettage (23).

Other short-acting hypnotic anesthetics are useful and have been described for oncology procedures. Methohexitone has been used alone and also combined with remifentanil, and the doses of methohexitone were 4.6 mg/kg (17) and 1–2 mg/kg, (10) respectively. Etomidate also acts rapidly but was associated with a 10% incidence of vomiting compared with zero vomiting after propofol; both were combined with either alfentanil or fentanyl (16).

Remifentanil alone as an analgesic can be used in cooperative patients. In adults, a remifentanil alone technique has been reported for colonoscopy (24) and for fiberoptic tracheal intubation but recall of events was common and this would be a disadvantage for repeated procedures in children. Litman (7) attempted to sedate 20 children (aged 2–12 years) for oncology procedures with midazolam 0.5 mg/kg (IV) and then infused remifentanil (bolus 1 µg/kg followed by 0.1 µg · kg^–1 · min^–1 infusion). The technique failed to sedate three children and apnea occurred in one. Apnea has also been reported with a combination of midazolam and fentanyl (25)

Respiratory depression is a common feature of remifentanil administration but, like the drug’s analgesic action, the depression is also short lived. Even when remifentanil is carefully infused, Keidan et al. (14) found that 8 of 41 children had respiratory depression with a bolus of remifentanil (0.15 µg) followed by an infusion (0.1 µg · kg^–1 · min^–1) although eight patients still moved during the procedure. This shows that it is difficult to achieve reliable satisfactory conditions without respiratory depression. We have therefore accepted apnea as part of our technique, and supporting respiration by face mask is our standard practice. Indeed, when there is apnea, patients do not move during the procedure and with standard airway skills hypoxia should not occur more than for any other anesthesia technique. Bradycardia and hypotension are potential undesirable effects of remifentanil but in this study they were observed less often than for the PSN technique; treatment was not necessary for any patient. Chest wall rigidity was not observed.

The two techniques, PR and PSN, could be disguised sufficiently to ensure that children, parents, and recovery nurses remained "blind," but the technique could not be hidden from the anesthesia and procedure team and some bias was therefore possible. Nevertheless, the procedure room was separate from the recovery area and we believe unintentional bias was unlikely. Five nurses were used for recovery observations and variation in their judgement was a potential source of error. Nevertheless, the nurses were experienced and worked as a team and we believe that any variation was small in comparison with the large differences in recovery times. Using within-patient comparisons helps to overcome the potential problems of comparing groups of different patients. However, the behavior of children varies from day to day and, as an example, one child who was disturbed after PR was calm on subsequent occasions with the same technique. A simplified Hannallah score (19) was used to describe behavior in recovery that we believe was due to distress rather than pain. Verbal rating was not considered applicable in our youngest children and arterial blood pressure was considered separately.

In this study remifentanil achieved both immobility and recovery faster than sevoflurane and nitrous oxide, probably because of pharmacokinetic factors. Another important reason is that the immobilizing dose of sevoflurane (or minimum alveolar concentration) may be much larger than its hypnotic dose (or minimum alveolar concentration awake), and this will limit its potential for fast recovery if used without potent analgesia. Sevoflurane combined with remifentanil may be as fast as PR but is unlikely to be preferred by children with venous access. In our experience, when a procedure is prolonged, PR can be used but recovery may not be so rapid.

For children who require multiple painful procedures, PR provides high quality fast anesthesia that should allow maximum efficiency of resources. This technique, however, has the potential for cardiorespiratory depression and therefore care by anesthesiologists, using comprehensive resuscitation and monitoring equipment, is essential. If anesthesia considered so rapid and safe were requested for all children having painful procedures, resources in any hospital would soon be overwhelmed. Anesthesia should therefore remain a part of a care structure where the level of care is appropriate to the procedure. Interventions that do not require anesthesiologists, such as behavior therapy, analgesia, and conscious sedation, are effective for many situations and should be available.

	Appendix

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Preparation and Dilution of Propofol and Remifentanil

Both propofol and remifentanil were prepared in separate syringes and diluted to 20 mL with normal saline to contain 5 mg/kg and 4 µg/kg, respectively. Remifentanil is available as dry powder that has to be dissolved in water. One mg of remifentanil was diluted in 50 mL normal saline to produce a dilution of 20 µg/mL: 4 µg/kg was drawn into a 20 mL syringe and then diluted to 20 mL with normal saline.

	Footnotes

 
Accepted for publication September 27, 2004.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Glaisyer, H. R. Articles by Sury, M. R. J. Search for Related Content PubMed PubMed Citation Articles by Glaisyer, H. R. Articles by Sury, M. R. J. Related Collections Anesthetic Techniques Pediatrics Pharmacology