Apnea after Awake Regional and General Anesthesia in Infants: The General Anesthesia Compared to Spinal Anesthesia Study—Comparing Apnea and Neurodevelopmental Outcomes, a Randomized Controlled Trial

POSTOPERATIVE apnea is a complication in young infants; the risk being greater in neonates who were premature.^1–3  Reducing the risk of apnea and identifying infants at risk of apnea may reduce morbidity and guide clinicians on the optimal age for surgery and the length and intensity of postoperative observation. Spinal anesthesia is a technique that may reduce the risk of apnea. Three small trials comparing spinal and general anesthesia (GA) have reported a reduced risk of apnea in high-risk infants receiving spinal anesthesia.^1,4,5  These studies are difficult to interpret because of small numbers, different ways of defining and identifying apnea, and different GA agents used.⁶  A 2003 Cochrane review called for a large, well-designed randomized trial to address this issue.⁷ 

The General Anesthesia compared to Spinal anesthesia (GAS) study, comparing apnea and neurodevelopmental outcomes, is a prospective randomized trial where 722 infants undergoing inguinal herniorrhaphy were randomized to regional anesthesia (RA) or GA. The trial was designed primarily to address the long-term effect of GA on the developing brain with the primary outcome being neurodevelopmental outcome at 5 yr. An important secondary aim of the GAS study is to compare the immediate postoperative benefits of RA with GA, in particular, reduction in apnea. This article compares the incidence of apnea in each group and identifies other factors associated with apnea; specifically, we hypothesized that RA would reduce the risk of apnea. Other short-term outcomes in each group are also described.

In a multinational prospective randomized trial with 2 parallel arms, we enrolled patients in 7 countries and 28 sites (table 1). Institutional review board or human research ethics committee approval was obtained for each site, and written informed consent was obtained from parents or guardians. Eligibility criteria included infants up to 60 weeks postmenstrual age (PMA) scheduled for unilateral or bilateral inguinal herniorrhaphy (with or without circumcision) born at greater than 26 weeks gestation. Exclusion criteria included any contraindication for either anesthetic technique, a history of congenital heart disease requiring surgery or pharmacotherapy, mechanical ventilation immediately before surgery, known chromosomal abnormalities or other known acquired or congenital abnormalities that might affect neurodevelopment, previous exposure to volatile GA or benzodiazepines as a neonate or in the third trimester in utero, any known neurologic injury such as cystic periventricular leukomalacia or grade 3 or 4 intraventricular hemorrhage, any social or geographic factor that may make follow-up difficult, or having a primary language at home where neurodevelopmental tests are not available. Eligible infants were identified from operating room schedules or at preadmission clinics and recruited in the clinic or in the preadmission areas of the operating floor.

The GAS study is registered in Australia and New Zealand at ANZCTR: ACTRN12606000441516 first registered on October 16, 2006, principal investigators: Andrew Davidson, Mary Ellen McCann, and Neil Morton; in the United States at ClinicalTrials.gov: NCT00756600 first registered on September 18, 2008, principal investigators: Andrew Davidson, Mary Ellen McCann, and Neil Morton; and in the United Kingdom at UK Clinical Research Network: 6635 (International Standard Randomised Controlled Trial Number, 12437565; Multi-Centre Research Ethics Committee No, 07/S0709/20), principal investigator: Neil Morton. The protocol for the GAS study has been previously published by The Lancet.⁸ 

A 24-h web-based randomization service was managed by The Data Management & Analysis Centre, Department of Public Health, University of Adelaide, South Australia. Children were randomized with a 1:1 allocation ratio to either RA or GA. Randomization was in random permuted blocks of two or four and stratified by site and gestational age at birth: 26 to 29 weeks and 6 days, 30 to 36 weeks and 6 days, and 37 weeks and more. The anesthesiologist, surgeon, and nurses in the postoperative care units were aware of group allocation; therefore, the study was unblinded for type of anesthetic given.

The RA arm received regional nerve blocks: spinal alone, spinal with caudal, spinal with ilioinguinal, or caudal alone. The local anesthetic used was bupivacaine or levobupivacaine. In addition, some patients received caudal chloroprocaine intraoperatively to prolong the block. The type of regional technique and the local anesthetic used were at the discretion of the anesthesiologist. In the RA arm, all forms of sedation or GA were avoided if possible; however, if any sedation or GA was required, this was regarded as a protocol violation. Oral sucrose drops were permitted in the RA arm and paracetamol in both arms. The GA arm received sevoflurane for induction and maintenance in an air/oxygen mixture along with nerve blockade with caudal or ilioinguinal bupivacaine or levobupivacaine. The form of airway support and use of neuromuscular-blocking agents was at the discretion of the anesthesiologist. No opioids or nitrous oxide was allowed intraoperatively. Blood pressure, heart rate, oxygen saturation, and temperature were recorded every 5 min intraoperatively.

Postoperatively children were observed closely and constantly by the research assistant for at least the first hour or until discharge if discharged before 1 h. The research assistant was a nurse, scientist, or physician. All were trained to detect apnea and familiar with the definition of a significant apnea. Electronic monitoring and the alarm settings on monitors were not standardized. During this period, any apnea was noted. Respiratory support and oxygen saturation were also recorded every 5 min. After the first hour, children were observed as per the usual routine at each hospital. The level of observation and monitoring was not standardized beyond the first hour. Hospital records were reviewed to identify apnea events. The management and significance of any apnea during this period was determined from the hospital record. Hemoglobin was measured either preoperatively or during anesthesia. Intraoperative end-tidal carbon dioxide is not reported as it is not an accurate measure of arterial carbon dioxide in the presence of large leaks around the tracheal tube or face mask.

The prespecified primary outcome for this analysis was observed apnea within 12 h of surgery or until discharge. Apnea was defined as a pause in breathing for more than 15 s or more than 10 s if associated with oxygen saturation less than 80% or bradycardia (20% decrease in heart rate). Early apnea was defined a priori as an apnea occurring within the first 30 min postoperatively in the postanesthesia care unit (PACU), and late apnea was defined as an observed apnea occurring between 30 min and 12 h postoperatively. A post hoc sensitivity analysis was also performed describing late apnea where children were excluded if discharged before 12 h. Level of intervention for postoperative apnea, methylxanthine administration, and other respiratory complications were also noted. A significant intervention was defined a priori as any intervention greater than simple tactile stimulation and included providing oxygen by mask (with or without positive pressure ventilation) or cardiopulmonary resuscitation with external chest compressions.

The sample size for the GAS study was based on the 5-yr neurodevelopmental outcome; the 5 yr follow-up Wechsler Preschool and Primary Scale of Intelligence, Third Edition, full-scale intelligence quotient score, a standardized score with mean 100 and SD 15. Assuming an expected difference of one standardized score point and a 90% chance that a 95% CI will exclude a difference of more than five (the largest difference acceptable to demonstrate equivalence), the trial needed 598 infants in total. Enrolling approximately 720 allowed for 10% loss to follow-up and 10% with a major protocol violation.

Given that this article presents data on a secondary aim of the trial, an a priori power calculation was not conducted for these secondary outcomes. In line with Consolidated Standards of Reporting Trials recommendations, we do not believe that post hoc power calculations are useful, and instead, we present our results along with CIs, which capture the uncertainty in our findings that reflect the sample size. During recruitment, a Data Monitoring Committee met at planned 6 mo intervals. Summary data by allocation were presented to the Data Monitoring Committee, and no formal group comparisons were performed.

The primary analysis for apnea included participants as randomized, excluding participants who withdrew consent or were randomized after surgery. Although the future neurodevelopmental outcomes are to be based on an equivalence design, the apnea data are analyzed as a superiority design. This analysis is reported as intention to treat (ITT). A secondary analysis was performed as per-protocol (APP), which excludes cases where surgery was cancelled, and in the RA arm, any child who received any sevoflurane or sedative medication.

Partial GA/sedation is defined as those in the RA group who received sevoflurane for only some of the surgery or received some other sedative medication during surgery. Full GA is defined as receiving sevoflurane from before knife to skin to the end of surgery.

The unit of analysis is the participant. Apnea outcomes were analyzed if a participant is recorded as having at least one event. Categorical data are summarized using counts and percentages, and continuous data are summarized using means (SD) or medians (interquartile range). For binary outcomes, a comparison between arms is presented as an odds ratio (OR) as estimated from a logistic regression model. For continuous outcomes, a comparison between arms is presented as a difference in means as estimated from a linear regression model. The distribution of continuous outcomes was examined for normality, and log transformations were applied where appropriate. All estimates are presented with 95% CIs and two-sided P values. Any missing data were not explored because the percentage of missing data was less than 5% for all outcomes. Descriptive analyzes were performed on prespecified subgroups. All outcomes were adjusted for (1) stratified gestational age at birth as a fixed effect and (2) site of randomization using the generalized estimating equation approach with robust SEs.^9,10  Sites with less than 20 randomized infants were combined as a single site in the model. An exchangeable correlation structure was assumed between any two children from the same site.

The early and late apnea outcomes were modeled together by including an additional fixed time effect (early or late time) and a fixed interaction between time and study arm. Because the generalized estimating equation approach only allows for one level of clustering, we tested two different exchangeable correlation structures for this model: (1) first, we accounted for the correlation between two apnea outcomes taken from the same child and (2) second, between outcomes from any two children from the same site. Because almost no difference was observed in the results from the two correlation structures, we show results from the second approach, so that the same correlation structure is used for all presented analyses. We judged that the interaction term provided sufficient evidence (P = 0.03 for ITT analysis and P = 0.09 for APP analysis) to present the effect of the study arm separately for early and late apnea, given the study was not powered to make this comparison.

The predictors of apnea were identified by constructing a logistic regression model adjusted for site of randomization using the generalized estimating equation approach as described in Data Analysis and including allocated study arm as a covariate. An interaction between time and covariate was included for the combined analysis of the early and late apnea outcomes.

When presenting these results to peers, we have been specifically asked for the risk reduction between RA and GA for term and ex-premature infants; thus, we also present a post hoc analysis calculating the absolute risk reduction (ARR) in term and ex-premature infants (less than 37 weeks gestational age at birth). The association between early and late apnea was assessed by constructing a logistic regression model adjusted for site of randomization using the generalized estimating equation approach as described earlier and including allocated study arm and stratified gestational age at birth as covariates. All analyses were carried out using Stata 13 (Stata Corp LP., USA).

Seven hundred twenty-two infants were recruited into the trial between February 9, 2007, and January 31, 2013. Three were withdrawn from analysis. For the ITT analysis, 361 were in the RA arm and 358 in the GA arm (fig. 1). Baseline, demographic, anesthetic, and surgical data are summarized in table 2. There were 394 premature infants and 325 term infants. Outcome data are missing for five RA cases and two GA cases because surgery was cancelled and one RA case because no data were collected. In the RA arm, 70 had a protocol violation involving exposure to sevoflurane or sedation. Thus, for the APP analysis, 286 were in the RA arm and 356 in the GA arm (RA, 355 and GA, 356 in the ITT analysis).

Twenty-five participants (3%; 10 in the RA and 15 in the GA arm) were recorded as having at least one apnea. Most apnea occurred in the early postoperative period (fig. 2), especially in the GA group. Most infants with apnea had a single event; however, one infant had 18 events. The proportions of infants with apnea-related outcomes in each group are presented in table 3 and the adjusted ORs for those outcomes in table 4. There was little evidence that allocation to RA or GA altered the odds of apnea in the overall period up to 12 h after surgery (OR, 0.63 with 95% CI, 0.31 to 1.30, P = 0.2133 by ITT). However, for early apnea, there was evidence that the odds of apnea were less in the RA arm (OR, 0.20; 95% CI, 0.05 to 0.91; P = 0.0367 by ITT). The odds for needing a significant intervention for early apnea were also less in the RA arm (OR, 0.09; 95% CI, 0.01 to 0.64; P = 0.0164). These effects were seen for both ITT and APP analyses, the effects being greater in the APP analysis. The level of intervention for apnea was also less in the RA arm (table 5). Of the infants with postoperative apnea, 86% in the GA arm and 50% in the RA arm received an intervention as tactile stimulation, supplemental oxygen, bag mask ventilation, or CPR to treat apnea. Details of the nine (1.3%) children requiring the positive pressure ventilation or cardiopulmonary resuscitation within 5 days of surgery are shown in table 6. Of these nine children, six children who had this event within 30 min of surgery were in the GA arm (1.7% of the GA arm). However, 2 infants in the RA group did not have apnea in PACU, yet experienced multiple apneic episodes starting 6 to 7 h postoperatively on the inpatient ward, which was treated with continuous positive airway pressure or bag and mask ventilation with transfer to intensive care.

A brief exposure to anesthesia or sedation in the RA arm was not observed to increase apnea incidence; however, if a full GA was administered, the risk of apnea approached the risk associated with a planned GA (table 3).

The apnea rate was relatively low, and this is reflected in a low ARR. In all infants, the ARR for early apnea with allocation to RA was 0.03 (95% CI, 0.004 to 0.05). In preterm infants, the ARR for early apnea with allocation to RA was 0.04 (95% CI, 0.004 to 0.08), and in term infants, the ARR for early apnea with allocation to RA was 0.006 (95% CI, −0.006 to 0.02).

Characteristics of infants who had early and late apnea are listed in table 7 along with logistic regression models for determining the factors associated with apnea (table 8). Indeed all apnea occurred in ex-premature infants except one case. This one infant was born at 37 weeks and 1 day, had an unremarkable history, had a general anesthetic at approximately 44 weeks PMA, and two apneas 20 min postoperatively that responded to gentle stimulation. Thus, the incidence of apnea among preterm infants was 6.1% compared with 0.3% in term infants. After adjusting for group allocation, there was evidence for an association between apnea and the following risk factors: prematurity, decreasing gestational age at birth, decreasing weight, decreasing PMA, a history of recent apnea, ever receiving methylxanthine, ever receiving ventilation through a tracheal tube, and ever needing oxygen support. Factors associated with late apnea were similar. Factors associated with early apnea were also similar, albeit with less evidence for an association with a history of recent apnea or ever requiring ventilation with a tracheal tube. The strongest risk factor for apnea was a history of prematurity (OR, 21.87; 95% CI, 4.38 to 109.24). In appropriate subpopulations, there was no evidence for an association between intraoperative use of tracheal tube or neuromuscular-blocking agent and apnea (tables 9 and10).

Early apnea was also a strong predictor of late apnea. In a model with late apnea as the outcome and including gestational age and type of anesthetic, the ORs for early apnea were 24.21 (95% CI, 5.88 to 99.66, P < 0.0001) for the ITT analysis and 46.52 (95% CI, 7.71 to 280.59, P < 0.0001) for APP analysis. For the APP analysis, of the 13 children who had late apnea, only 5 had an early apnea, giving a low sensitivity of 0.38. Although early apnea is a strong predictor of late apnea, it is not a sensitive measure for late apnea.

Other outcome data are shown in table 11. Anesthesia time was shorter in the RA arm (51 vs. 66 min) with little evidence for any difference in surgical times (28 min each). Infants randomized to RA had a substantially greater mean minimum systolic blood pressure (70.7 vs. 54.8 mmHg) and were less likely to need an intervention for hypotension during anesthesia (7 vs. 19%). Infants randomized to RA had a slightly higher minimum intraoperative heart rate (133.9 vs. 127.6 beats per min) and were slightly warmer (36.1° vs. 36.0°C). Infants randomized to RA were less likely to have a significant oxygen desaturation postoperatively (1 vs. 4%) and slightly shorter times to first feed (31 vs. 36 min). Approximately 20% of children were discharged before 12 h; discharge times were similar in each arm (table 12).

In this trial, there was no evidence that RA reduced the overall risk of observed apnea. In subgroup analyses, RA did reduce the risk of early postoperative apnea; however, there was no evidence that RA reduced the risk of late apnea. RA also reduced the degree of postoperative oxygen desaturation and the level of intervention for apnea, implying that apnea after RA was not only less frequent but also of lesser clinical importance. However, overall the incidence of bedside intervention for postoperative apnea was appreciable by current standards of patient safety in pediatric anesthesia.^11–13  Infants in the GA arm also had lower minimum blood pressures intraoperatively. The strongest risk factor for apnea was prematurity.

Strengths of this trial include the size of the study, being multinational, and hence increasing external validity and the use of modern anesthetic agents. The trial does have a number of limitations. First, the GAS study was primarily designed to address the issue of potential neurotoxicity of GA. Exclusion criteria reflect this aim. The trial excluded infants born extremely premature and some infants with significant comorbidity. It is possible that benefits of RA and risk factors for apnea are different in these populations. Second, in this trial, we relied on staff and researchers to identify apnea. Apnea incidence depends on the type of monitoring used.³  In our trial, few sites used impedance pneumography, and none used more sensitive techniques such as thermistry or capnography. It would not have been feasible to obtain and standardize this monitoring across all sites. Similarly, the infants were only constantly monitored for the first hour. After that, monitoring was as per routine or clinical judgment. Therefore, our results likely underestimate the true rate of apnea, especially late apnea. We are also unable to comment on apnea that occurred after discharge; thus, we performed a post hoc analysis for late apnea where we only included children who were not discharged before 12 h. Given the uncertainty surrounding the significance of brief apnea and the likelihood that our trial may have missed brief apnea, it is important to consider not only the recorded apnea but also the incidence of the significant clinical interventions. Our trial was large enough to give some indication of relative frequency of these events; RA reducing the odds for such events. Recording and comparing these events may be more clinically relevant than capturing all brief self-resolving apnea events. The incidence of positive pressure ventilation or CPR occurred in nine infants overall (1.3%) and in six infants (0.8%) in PACU. The events occurred in these six children within 30 min of the end of surgery and all these were in the GA arm, and all were ex-premature infants. This nontrivial event rate underscores the need for close monitoring in this population.^11–13  Another limitation to the trial was lack of blinding. It was impossible to blind nursing staff because an infant recovering from spinal would often have no lower limb motor function; in the GA arm, the airway is often secured by tape that leaves a distinctive mark on the infant’s sensitive skin, and in the RA arm, a puncture site would be visible in the infant’s back. Failure of the RA technique may also confound some of the outcome measures, and thus, it is important that both ITT and APP data and analyses are considered. Importantly some advantage was still seen with the ITT analysis, implying the failure rate does not substantially diminish the advantage of planning to perform an awake regional technique. The factors associated with failure are complex and are described in another publication in Anesthesiology. Finally, the frequency of apnea was low. Although there were enough events to draw some conclusions, the low event rate precluded identifying independent risk factors in multivariable models.

The overall rate of apnea in our trial was 3%. Coté et al. performed a combined analysis of apnea in ex-premature infants from five previous studies. He reported a combined apnea rate of 25%; however, the rate in the contributing studies varied from 5 to 49%.³  Reported rates of apnea vary depending on its definition, the detection method used, and the population studied. Although the definition used by the National Institute of Health, United States, for serious apnea is 20 s duration for apnea of prematurity, most (but not all) studies examining postoperative apnea have used a duration of more than 15 s or more than 10 s if accompanied by either hypoxia or bradycardia.¹⁴  For consistency, we chose the definition used most widely for postoperative apnea. The relatively low rate of apnea in our study may be due to the method used to detect apnea. Those who defined apnea using continuous recording devices (impedance pneumography with or without nasal thermistry) found rates of 31 to 49%.^5,15–19  Those studies that relied on nursing observation and/or responding to alarming from impedance pneumography found rates of 5 to 10%.^2,20  Also in our study, only half the infants in our trial were ex-premature. All bar one infant with apnea was premature, giving a rate of apnea in ex-premature infants as 6%. This is consistent with previous studies that have failed to identify apnea in term infants.^21,22  Coté et al. found that anemia was a strong predictor of apnea. In contrast, we found no evidence for an association between anemia and apnea.

Differentiating early and late apnea is important as the etiology and management may differ. Determining which infants are at risk of late apnea may help identify those that require extended observation. When considering late apnea, we found a similar and low rate in both groups. It is not possible from our results to determine how much this apnea rate is related to the surgery and how much they reflect the “background” rate of apnea in these children.

In our trial, we found that early apnea is a strong predictor of late apnea. However, early apnea is an insensitive measure. Thus, although any infant with early apnea is at an increased risk of subsequent apnea, absence of early apnea is not a guarantee that the infant will not have a late apnea—more than half of the infants with late apnea had no early apnea, confirming previous study results.¹⁸ 

In this trial, the GA arm had a substantially lower average minimum systolic blood pressure. The ideal blood pressure for infants undergoing surgery is unknown. These data will be further described in a subsequent publication. The first implication of our trial is that aiming to perform an awake regional anesthetic has distinct benefits in reducing the odds for apnea that required significant intervention in the PACU. If the surgeon and family agree, if there are no contraindications, and if the anesthetist is familiar with the technique, then awake RA is potentially the preferred technique in this population. However, our study highlights the importance of a back-up plan for GA because the incidence of failure of RA is appreciable (20%).The second implication of our trial relates to which children should be monitored for an extended period postoperatively. To reduce the risk of late apnea, surgery should be delayed as long as safe and feasible, and extended monitoring should be considered for at least those children who are premature and those who have early postoperative apnea. The monitoring should occur in a location where healthcare providers are trained in neonatal apnea intervention and will be able to respond quickly to an alarm. However, although awake RA may still be preferable for reasons mentioned earlier, we found no evidence that it reduces the risk of late apnea in this population.

Our study excluded many infants who were extremely premature or had significant comorbidity. Further studies are required to quantify the benefits of awake RA in these high-risk groups. Although our study recruited more participants than all previous similar studies combined, it may still be too few to identify rare and serious complications such as death from apnea after discharge, or subdural hematoma or central nervous system infection from awake RA. Larger ongoing surveillance studies are needed to quantify these risks.

The authors would like to acknowledge all of these collaborators for their assistance and advice with the GAS study: Mark Fajgman, M.B.B.S., F.A.N.Z.C.A., Department of Anaesthesia, Monash Medical Centre, Melbourne, Australia; Daniela Tronconi, R.N., Department of Anesthesia, Istituto Giannina Gaslini, Genoa, Italy; David C. van der Zee, M.D., Ph.D., Department of Pediatric Surgery, Wilhelmina Children’s Hospital, University Medical Centre, Utrecht, The Netherlands; Jan B. F. Hulscher, M.D., Ph.D., Department of Surgery, University Medical Center Groningen, Groningen University, Groningen, The Netherlands; Rob Spanjersberg, R.N., Department of Anesthesiology, University Medical Center Groningen, Groningen University, Groningen, The Netherlands; Michael J. Rivkin, M.D., Department of Neurology, Children’s Hospital Boston, Boston, Massachusetts; Michelle Sadler-Greever, R.N., Department of Anesthesia and Pain Medicine, University of Washington, Seattle, Washington, and Department of Anesthesia and Pain Medicine, Seattle Children’s Hospital, Seattle, Washington; Debra Faulk, M.D., Department of Anesthesiology, Children’s Hospital Colorado, Denver, Colorado, and Department of Anesthesiology, University of Colorado School of Medicine, Denver, Colorado; Danai Udomtecha, M.D., Sarah Titler, M.D., Susan Stringham, R.N., Pamela Jacobs, R.N., and Alicia Manning, A.D.N., Department of Anesthesia, The University of Iowa Hospital and Clinics, Iowa City, Iowa; Roxana Ploski, B.S., and Alan Farrow-Gillespie, M.D., Department of Anesthesiology, Children’s Medical Center Dallas, Dallas, Texas, Department of Anesthesiology, University of Texas Southwestern Medical Center, Dallas, Texas, and Dallas and Children’s Medical Center at Dallas and Outcome Research Consortium, Dallas, Texas; Timothy Cooper, M.A., Psy.D., Division of Developmental Medicine and the Center for Child Development, Monroe Carell Jr Children’s Hospital at Vanderbilt, Nashville, Tennessee; Elizabeth Card, M.S.N., A.P.R.N., R.N., F.N.P.-B.C., C.P.A.N., C.C.R.P., Perioperative Clinical Research Institute, Vanderbilt University Medical Center, Nashville, Tennessee; Wendy A. Boardman, B.A., Department of Anesthesiology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; Theodora K. Goebel, R.N., B.S.N., C.C.R.C., Department of Anesthesiology and Critical Care Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.

All hospitals and centers were generously supported by anesthesiology departmental funding. In addition to this funding, specific grants received for this study are as follows: Australia and New Zealand: The Australian National Health & Medical Research Council, Canberra, Australian Capital Territory, Australia; Australian and New Zealand College of Anesthetists, Melbourne, Victoria, Australia; Murdoch Childrens Research Institute, Melbourne, Victoria, Australia. This study was supported by the Victorian Government’s Operational Infrastructure Support Program in Melbourne, Victoria, Australia; Department of Anaesthesia and Pain Management, Royal Children’s Hospital, Melbourne, Victoria, Australia; Department of Anaesthesia, Monash Medical Centre, Melbourne, Victoria, Australia; Department of Anaesthesia and Pain Management, Princess Margaret Hospital for Children, Perth, Western Australia, Australia; Department of Paediatric Anaesthesia, Women’s Children’s Hospital, Adelaide, South Australia, Australia and Department of Paediatric Anaesthesia and Operating Rooms, Starship Children’s Hospital, Auckland, New Zealand. United States: National Institutes of Health, Bethesda, Maryland; Food and Drug Administration, Silver Spring, Maryland; Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children’s Hospital, Boston, Massachusetts: Department of Anesthesia and Pain Medicine, Seattle Children’s Hospital, Seattle, Washington; Department of Anesthesiology, Children’s Hospital Colorado, Denver, Colorado; Department of Anesthesia, University of Iowa Hospital, Iowa City, Iowa; Department of Anesthesiology, Children’s Medical Center Dallas, Dallas, Texas; Department of Pediatric Anesthesiology, Anne and Robert H. Lurie Children’s Memorial Hospital, Chicago, Illinois; Department of Anesthesiology, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire; Department of Pediatric Anesthesia, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Anesthesiology and Critical Care, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; and Department of Anesthesia and Pediatrics, The University of Vermont/Fletcher Allen Health Care, Burlington, Vermont. Italy: Italian Ministry of Health, Rome, Italy; Department of Anesthesia, Istituto Giannina Gaslini, Genoa, Italy; Department of Anesthesiology and Paediatric Intensive Care, Ospedale Vittore Buzzi, Milan, Italy; and Department of Anaesthesia, Ospedale Papa Giovanni XXIII, Bergamo, Italy. The Netherlands: Fonds NutsOhra, Amsterdam, The Netherlands; Department of Anesthesiology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands; and Department of Anesthesiology, University Medical Center Groningen, Groningen, The Netherlands. Canada: Canadian Institute of Health Research, Ottawa, Ontario, Canada; Canadian Anesthesiologists’ Society, Toronto, Ontario, Canada; Pfizer Canada, Inc., Kirkland, Quebec, Canada; Department of Anesthesia, Montreal Children’s Hospital, Montreal, Quebec, Canada; and Département d’Anesthésie, CHU Sainte-Justine, Montreal, Quebec, Canada. United Kingdom: Health Technologies Assessment—National Institute for Health Research United Kingdom, Southampton, United Kingdom. Anesthesiology Departmental Funding: Department of Anaesthesia, Royal Hospital for Sick Children, Glasgow, United Kingdom; Department of Anaesthesia, Birmingham Children’s Hospital, Birmingham, United Kingdom; Anaesthetic Department, Sheffield Children’s Hospital, Sheffield, United Kingdom; Department of Paediatric Anaesthesia, Bristol Royal Hospital for Children, Bristol, United Kingdom; Department of Anaesthetics, Royal Belfast Hospital for Sick Children, Belfast, United Kingdom; and Department of Anaesthesia, Pain Relief and Sedation, Alder Hey Childrens’ NHS Foundation Trust, Liverpool, United Kingdom.

The authors declare no competing interests.

Australia: Andrew J. Davidson, M.D., and Geoff Frawley, M.B.B.S. (Anaesthesia and Pain Management Research Group, Murdoch Childrens Research Institute, Melbourne, Australia; Department of Anaesthesia and Pain Management, The Royal Children’s Hospital, Melbourne, Australia; Department of Paediatrics,University of Melbourne, Melbourne, Australia); Pollyanna Hardy, M.Sc. (National Perinatal Epidemiology Unit, Clinical Trials Unit, University of Oxford, Oxford, United Kingdom); Sarah J. Arnup, M.Biostat., and Katherine Lee, Ph.D. (Clinical Epidemiology and Biostatistics Unit, Murdoch Childrens Research Institute, Melbourne, Australia); Rodney W. Hunt, Ph.D. (Department of Neonatal Medicine, The Royal Children’s Hospital, Melbourne, Australia; Neonatal Research Group, Murdoch Childrens Research Institute, Melbourne, Australia; and Department of Paediatrics, University of Melbourne, Melbourne, Australia); Robyn Stargatt, Ph.D. (School of Psychological Science, La Trobe University, Melbourne, Australia; Child Neuropsychology Research Group, Murdoch Childrens Research Institute, Melbourne, Australia); Suzette Sheppard, B.Sc., Gillian Ormond, M.Sc., and Penelope Hartmann, B.Psych. (Hons) (Department of Anaesthesia and Pain Management, Murdoch Childrens Research Institute, Melbourne, Australia); Philip Ragg, M.B.B.S. (Department of Anaesthesia and Pain Management, The Royal Children’s Hospital, Melbourne, Australia); Marie Backstrom, R.N. Cert (Department of Anaesthesia, Monash Medical Centre, Melbourne, Australia); David Costi, B.M.B.S. (Department of Paediatric Anaesthesia, Women’s and Children’s Hospital, Adelaide, Australia); Britta S. von Ungern-Sternberg, M.D., Ph.D. (Department of Anaesthesia and Pain Management, Princess Margaret Hospital for Children, Perth, Australia; and Pharmacology, Pharmacy and Anaesthesiology Unit, School of Medicine and Pharmacology, The University of Western Australia, Perth, Australia).

New Zealand: Niall Wilton, M.R.C.P. and Graham Knottenbelt, M.B.B.C.H. (Department of Paediatric Anaesthesia and Operating Rooms, Starship Children’s Hospital, Auckland, New Zealand).

Italy: Nicola Disma, M.D., Giovanni Montobbio, M.D., Leila Mameli, M.D., Pietro Tuo, M.D., and Gaia Giribaldi, M.D. (Department of Anesthesia, Istituto Giannina Gaslini, Genoa, Italy); Alessio Pini Prato, M.D. (Department of Pediatric Surgery, Istituto Giannina Gaslini, Genoa, Italy); Girolamo Mattioli, M.D. (DINOGMI Department, University of Genoa, Genoa, Italy); Andrea Wolfler, M.D., Francesca Izzo, M.D., and Ida Salvo, M.D. (Department of Anesthesiology and Paediatric Intensive Care, Ospedale Pediatrico Vittore Buzzi, Milan, Italy); Valter Sonzogni, M.D., Bruno Guido Locatelli, M.D., and Magda Khotcholava, M.D. (Department of Anaesthesia, Ospedale Papa Giovanni XXIII, Bergamo, Italy).

The Netherlands: Jurgen C. de Graaff, M.D., Ph.D., Jose T. D. G. van Gool, R.N., Sandra C. Numan, M.Sc., and Cor J. Kalkman, M.D., Ph.D. (Department of Anesthesiology, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, Utrecht, The Netherlands); J. H. M. Hagenaars, B.Sc., Anthony R. Absalom, M.B.Ch.B., F.R.C.A., M.D., Frouckje M. Hoekstra, M.D., and Martin J. Volkers, M.D. (Department of Anesthesiology, University Medical Center Groningen, Groningen University, Groningen, The Netherlands).

Canada: Davinia E. Withington, B.M. (Department of Anesthesia, Montreal Children’s Hospital, Montreal, Canada; and McGill University, Montreal, Canada); Koto Furue, M.D. (Département d’Anesthésie, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Canada); Josee Gaudreault, M.Sc.A. (Department of Anesthesia, Montreal Children’s Hospital, Montreal, Canada).

United States: Mary Ellen McCann, M.D., Charles Berde, M.D., Sulpicio Soriano, M.D., Vanessa Young, R.N., B.A., Navil Sethna, M.D., Pete Kovatsis, M.D., and Joseph P. Cravero, M.D. (Department of Anesthesiology, Perioperative and Pain Medicine, Children’s Hospital Boston, Boston, Massachusetts); David Bellinger, Ph.D. and Jacki Marmor, M.Ed. (Department of Neurology, Children’s Hospital Boston, Boston, Massachusetts); Anne Lynn, M.D., Iskra Ivanova, M.D., Agnes Hunyady, M.D., and Shilpa Verma, M.D. (Department of Anesthesia and Pain Medicine, University of Washington, Seattle, Washington; and Department of Anesthesia and Pain Medicine, Seattle Children’s Hospital, Seattle, Washington); David Polaner, M.D., F.A.A.P. (Department of Anesthesiology, Children’s Hospital Colorado, Denver, Colorado; and Department of Anesthesiology, University of Colorado, Denver, Colorado); Joss Thomas, M.D., Martin Meuller, M.D., and Denisa Haret, M.D. (Department of Anesthesia,The University of Iowa Hospitals and Clinics, Iowa City, Iowa); Peter Szmuk, M.D., Jeffery Steiner, D.O., and Brian Kravitz, M.D. (Department of Anesthesiology, Children’s Medical Center Dallas, Texas; Department of Anesthesiology, University of Texas Southwestern Medical Center, Dallas, Texas; and Children’s Medical Center at Dallas and Outcome Research Consortium, Dallas, Texas); Santhanam Suresh, M.D. (Department of Pediatric Anesthesiology, Ann & Robert H Lurie Children’s Hospital of Chicago, Northwestern University, Chicago, Illinois); Stephen R. Hays, M.D. (Department of Pediatric Anesthesia, Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville,Tennessee); Andreas H. Taenzer, M.D., M.S. (Department of Anesthesiology,Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire); Lynne G. Maxwell, M.D. (Department of Anesthesiology and Critical Care Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania); Robert K. Williams, M.D. (Department of Anesthesia and Pediatrics, College of Medicine, University of Vermont, Vermont Children’s Hospital, Burlington,Vermont).

United Kingdom: Neil S. Morton, M.D., F.R.C.A. (Academic Unit of Anaesthesia, Pain and Critical Care, University of Glasgow, Glasgow, United Kingdom; Department of Anaesthesia, Royal Hospital for Sick Children, Glasgow, United Kingdom); Graham T. Bell M.B.Ch.B. (Department of Anaesthesia, Royal Hospital for Sick Children, Glasgow, United Kingdom); Liam Dorris, D.Clin.Psy., and Claire Adey, M.A.(Hons) (Fraser of Allander Unit, Royal Hospital for Sick Children, Glasgow, United Kingdom); Oliver Bagshaw, M.B.Ch.B., F.R.C.A., F.F.I.C.M. (Department of Anaesthesia, Birmingham Children’s Hospital, Birmingham, United Kingdom); Anthony Chisakuta, B.Sc. (HB), M.B.Ch.B., M.Sc., M.M.E.D.Sc., F.F.A.R.C.S.I. (Department of Anaesthetics, Royal Belfast Hospital for Sick Children, Belfast, United Kingdom); Ayman Eissa, M.D. (Anaesthetic Department, Sheffield Children’s Hospital, Sheffield, United Kingdom); Peter Stoddart, M.B.B.S., B.Sc., M.R.C.P. (UK), F.R.C.A. (Department of Paediatric Anaesthesia, Bristol Royal Hospital for Children, Bristol, United Kingdom); Annette Davis, M.B.Ch.B., F.R.C.A. (Department of Anaesthesia, Pain Relief and Sedation,Alder Hey Childrens’ NHS Foundation Trust, Liverpool, United Kingdom).

Trial Steering Committee: Prof. Paul Myles (Chair); Members: Andrew J. Davidson, M.D., Mary Ellen McCann, M.D., Neil S. Morton, M.D., F.R.C.A., Nicola Disma, M.D., Davinia E. Withington, B.M., Jurgen C. de Graaff, Ph.D., Geoff Frawley, M.B.B.S., Rodney W. Hunt, Ph.D., Dr. David Bellinger, Dr. Charles Berde, Prof. Andy Wolf, Prof. Neil McIntosh, Prof. John Carlin, and Prof. Kate Leslie; Attendees: Gillian Ormond, M.Sc., Pollyanna Hardy, M.Sc., Sarah J. Arnup, M.Biostat., Robyn Stargatt, Ph.D., Ms Suzette Sheppard, and Dr. Katherine Lee.

Data Monitoring Committee: Dr. Jonathan de Lima (Chair), Prof. Greg Hammer, Prof. David Field, Prof. Val Gebski, and Prof. Dick Tibboel.