Joss J. Thomas

Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial

__Background__ In laboratory animals, exposure to most general anaesthetics leads to neurotoxicity manifested by neuronal cell death and abnormal behaviour and cognition. Some large human cohort studies have shown an association between general anaesthesia at a young age and subsequent neurodevelopmental deficits, but these studies are prone to bias. Others have found no evidence for an association. We aimed to establish whether general anaesthesia in early infancy affects neurodevelopmental outcomes. __Methods__ In this international, assessor-masked, equivalence, randomised, controlled trial conducted at 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand, we recruited infants of less than 60 weeks’ postmenstrual age who were born at more than 26 weeks’ gestation and were undergoing inguinal herniorrhaphy, without previous exposure to general anaesthesia or risk factors for neurological injury. Patients were randomly assigned (1:1) by use of a web-based randomisation service to receive either awake-regional anaesthetic or sevoflurane-based general anaesthetic. Anaesthetists were aware of group allocation, but individuals administering the neurodevelopmental assessments were not. Parents were informed of their infants group allocation upon request, but were told to mask this information from assessors. The primary outcome measure was full-scale intelligence quotient (FSIQ) on the Wechsler Preschool and Primary Scale of Intelligence, third edition (WPPSI-III), at 5 years of age. The primary analysis was done on a per-protocol basis, adjusted for gestational age at birth and country, with multiple imputation used to account for missing data. An intention-totreat analysis was also done. A difference in means of 5 points was predefined as the clinical equivalence margin. This completed trial is registered with ANZCTR, number ACTRN12606000441516, and ClinicalTrials.gov, number NCT00756600. __Findings__ Between Feb 9, 2007, and Jan 31, 2013, 4023 infants were screened and 722 were randomly allocated: 363 (50%) to the awake-regional anaesthesia group and 359 (50%) to the general anaesthesia group. There were 74 protocol violations in the awake-regional anaesthesia group and two in the general anaesthesia group. Primary outcome data for the per-protocol analysis were obtained from 205 children in the awake-regional anaesthesia group and 242 in the general anaesthesia group. The median duration of general anaesthesia was 54 min (IQR 41–70). The mean FSIQ score was 99·08 (SD 18·35) in the awake-regional anaesthesia group and 98·97 (19·66) in the general anaesthesia group, with a difference in means (awake-regional anaesthesia minus general anaesthesia) of 0·23 (95% CI –2·59 to 3·06), providing strong evidence of equivalence. The results of the intention-to-treat analysis were similar to those of the per-protocol analysis. __Interpretation__ Slightly less than 1 h of general anaesthesia in early infancy does not alter neurodevelopmental outcome at age 5 years compared with awake-regional anaesthesia in a predominantly male study population.Summary Background There is pre-clinical evidence that general anaesthetics affect brain development. There is mixed evidence from cohort studies that young children exposed to anaesthesia may have an increased risk of poorer neurodevelopmental outcome. This trial aims to determine if GA in infancy has any impact on neurodevelopmental outcome. The primary outcome for the trial is neurodevelopmental outcome at 5 years of age. The secondary outcome is neurodevelopmental outcome at two years of age and is reported here. Methods We performed an international assessor-masked randomised controlled equivalence trial in infants less than 60 weeks post-menstrual age, born at greater than 26 weeks gestational age having inguinal herniorrhaphy. Infants were excluded if they had existing risk factors for neurologic injury. Infants were randomly assigned to awake-regional (RA) or sevoflurane-based general anaesthesia (GA). Web-based randomisation was performed in blocks of two or four and stratified by site and gestational age at birth. The outcome for analysis was the composite cognitive score of the Bayley Scales of Infant and Toddler Development, Third Edition. The analysis was as-per-protocol adjusted for gestational age at birth. A difference in means of five points (1/3 SD) was predefined as the clinical equivalence margin. The trial was registered at ANZCTR, ACTRN12606000441516 and ClinicalTrials.gov, NCT00756600. Findings Between February 2007, and January 2013, 363 infants were randomised to RA and 359 to GA. Outcome data were available for 238 in the RA and 294 in the GA arms. The median duration of anaesthesia in the GA arm was 54 minutes. For the cognitive composite score there was equivalence in means between arms (RA-GA: +0·169, 95% CI −2·30 to +2·64). Interpretation For this secondary outcome we found no evidence that just under an hour of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at two years of age compared to RA.

Are anesthesia and surgery during infancy associated with altered academic performance during childhood

Background: Although studies in neonatal animals show that anesthetics have neurotoxic effects, relevant human evidence is limited. We examined whether children who had surgery during infancy showed deficits in academic achievement. Methods: We attempted to contact parents of 577 children who, during infancy, had one of three operations typically performed in otherwise healthy children. We compared scores on academic achievement tests with population norms. Results: Composite scores were available for 287 patients. The mean normal curve equivalent score was 43.0 ± 22.4 (mean ± SD), lower than the expected normative value of 50, P < 0.0001 by one-sample Student t test; and 35 (12%) had scores below the 5th percentile, more than expected, P < 0.00001 by binomial test. Of 133 patients who consented to participate so that their scores could be examined in relation to their medical records, the mean score was 45.9 ± 22.9, P = 0.0411; and 15 (11%) scored below the 5th percentile, P = 0.0039. Of 58 patients whose medical records showed no central nervous system problems/potential risk factors during infancy, 8 (14%) scored below the 5th percentile, P = 0.008; however, the mean score, 47.6 ± 23.4, was not significantly lower than expected, P = 0.441. Duration of anesthesia and surgery correlated negatively with scores (r = −0.34, N = 58, P = 0.0101). Conclusions: Although the findings are consistent with possible adverse effects of anesthesia and surgery during infancy on subsequent academic achievement, other explanations are possible and further investigations are needed.

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

Background:Postoperative apnea is a complication in young infants. Awake regional anesthesia (RA) may reduce the risk; however, the evidence is weak. The General Anesthesia compared to Spinal anesthesia study is a randomized, controlled trial designed to assess the influence of general anesthesia (GA) on neurodevelopment. A secondary aim is to compare rates of apnea after anesthesia. Methods:Infants aged 60 weeks or younger, postmenstrual age scheduled for inguinal herniorrhaphy, were randomized to RA or GA. Exclusion criteria included risk factors for adverse neurodevelopmental outcome and infants born less than 26 weeks gestation. The primary outcome of this analysis was any observed apnea up to 12 h postoperatively. Apnea assessment was unblinded. Results:Three hundred sixty-three patients were assigned to RA and 359 to GA. Overall, the incidence of apnea (0 to 12 h) was similar between arms (3% in RA and 4% in GA arms; odds ratio [OR], 0.63; 95% CI, 0.31 to 1.30, P = 0.2133); however, the incidence of early apnea (0 to 30 min) was lower in the RA arm (1 vs. 3%; OR, 0.20; 95% CI, 0.05 to 0.91; P = 0.0367). The incidence of late apnea (30 min to 12 h) was 2% in both RA and GA arms (OR, 1.17; 95% CI, 0.41 to 3.33; P = 0.7688). The strongest predictor of apnea was prematurity (OR, 21.87; 95% CI, 4.38 to 109.24), and 96% of infants with apnea were premature. Conclusions:RA in infants undergoing inguinal herniorrhaphy reduces apnea in the early postoperative period. Cardiorespiratory monitoring should be used for all ex-premature infants.

Predictors of Failure of Awake Regional Anesthesia for Neonatal Hernia Repair: Data from the General Anesthesia Compared to Spinal Anesthesia Study-Comparing Apnea and Neurodevelopmental Outcomes

Background:Awake regional anesthesia (RA) is a viable alternative to general anesthesia (GA) for infants undergoing lower abdominal surgery. Benefits include lower incidence of postoperative apnea and avoidance of anesthetic agents that may increase neuroapoptosis and worsen neurocognitive outcomes. The General Anesthesia compared to Spinal anesthesia study compares neurodevelopmental outcomes after awake RA or GA in otherwise healthy infants. The aim of the study is to describe success and failure rates of RA and report factors associated with failure. Methods:This was a nested cohort study within a prospective, randomized, controlled, observer-blind, equivalence trial. Seven hundred twenty-two infants 60 weeks or less postmenstrual age scheduled for herniorrhaphy under anesthesia were randomly assigned to receive RA (spinal, caudal epidural, or combined spinal caudal anesthetic) or GA with sevoflurane. The data of 339 infants, where spinal or combined spinal caudal anesthetic was attempted, were analyzed. Possible predictors of failure were assessed including patient factors, technique, experience of site and anesthetist, and type of local anesthetic. Results:RA was sufficient for the completion of surgery in 83.2% of patients. Spinal anesthesia was successful in 86.9% of cases and combined spinal caudal anesthetic in 76.1%. Thirty-four patients required conversion to GA, and an additional 23 patients (6.8%) required brief sedation. Bloody tap on the first attempt at lumbar puncture was the only risk factor significantly associated with block failure (odds ratio = 2.46). Conclusions:The failure rate of spinal anesthesia was low. Variability in application of combined spinal caudal anesthetic limited attempts to compare the success of this technique to spinal alone.

Anesthetic neurotoxicity: a difficult dragon to slay.

It has become difficult to open an anesthesiology journal without seeing an article about anesthetic neurotoxicity. This issue of Anesthesia & Analgesia is no exception. Most of the work has been done in animals and suggests that harm can come to the developing brain when it is exposed to a broad array of commonly used anesthetic and sedative agents. The critical question, of course, is, does it happen in children? DiMaggio et al., in this issue of the Journal, approach this by using an administrative database of siblings to determine whether anesthesia and surgery in the first 3 years of life are associated with subsequent developmental or behavioral disorders. Their study shows that children exposed to anesthesia and surgery have a much greater likelihood of being diagnosed with a developmental or behavioral disorder than do unexposed children, but that within a matched twin pair, in which one sibling was exposed to anesthesia and surgery and the other was not, there was no greater risk of an adverse outcome. This clearly adds new information to the literature. But can this answer the question, “are anesthetics neurotoxic in children?” The manifestations of anesthetic neurotoxicity in children, if it exists, are nebulous. Unlike fetal alcohol syndrome, in which one sees a distinctive pattern of altered development, any adverse effect of anesthetic exposure on young children must be small, or it would be easy to demonstrate and would have been suspected long ago. We emphasize that by “small” we do not mean unimportant. The brain is an exquisitely fine-tuned organ, and even minimal damage to the development of neural circuits might have major functional ramifications. But the fact remains that although the animal studies on anesthetic neurotoxicity are compelling, the task of translating this finding to infants is huge because we do not know how and when the putative toxicity will manifest itself in humans. Then there is the formidable problem of distinguishing anesthetic effects from the impact of surgery or from the underlying pathophysiology that led the child to need surgery in the first place. Because anesthesia and surgery are inseparable, this will not be easy. This issue will not be resolved conclusively by any one study. Rather, many experiments based on different approaches will be needed. Officials of the U.S. Food and Drug Administration spoke to this recently when they wrote, “Generating definitive data about the effects of anesthetics on the developing brain will most likely take numerous animal and human studies spanning many years. Planning, conducting, and interpreting these studies will pose enormous challenges to the medical and scientific community. It seems unlikely that any single individual or organization will be able to muster the resources to take on this project.” So, what needs to be done? The “gold standard” would be a prospective, randomized controlled trial (RCT), perhaps of regional versus general anesthesia in infants. At least one such trial is enrolling patients (the GAS Study). However, as noted in an editorial in Anesthesiology, our incomplete knowledge makes designing an RCT very difficult. What age children should be enrolled (i.e., what is the vulnerable period in humans)? What kind of surgery should be included (i.e., do certain diseases/disorders predispose to anesthetic neurotoxicity via some unknown mechanism, or are children with certain disorders predisposed to problems even in the absence of anesthesia)? Does it matter what general anesthetic agents are used (volatile agents versus IV agents; -aminobutyric acid agonists versus N-methyl-d-aspartate antagonists)? Will the use of sedation in conjunction with regional anesthesia confound the study? Does exposure time/surgical duration matter? And perhaps more important, what is a meaningful outcome measure and when do we measure it? Do we seek developmental deficits in preschool; learning deficits in elementary school; social deficits in adolescence; or might it involve the loss of cognitive reserve and early dementia in old age? Does a short-term interim measure adequately predict long-term outcomes? Does an abnormality on a single neurocognitive test given at 3 years of age mean that the child will not get into the college of his or her choice? The information needed to answer these methodological questions can be gathered either from multiple RCTs (which, given the design difficulties, requires a kind of trial-and-error approach) or can be gained more rapidly and inexpensively via epidemiologic studies. Ideally, these would be based on well-designed prospective data-gathering efforts, but this approach shares many of the problems of an RCT (particularly the need for a very long postsurgical follow-up time). An From the *Department of Anesthesia, University of Iowa Carver College of Medicine, Iowa City; †Department of Anesthesia, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; ‡Department of Anesthesia, University of California, San Diego; and §Veterans Affairs Medical Center, San Diego, CA.

Neurodevelopmental outcome at two years of age after general and awake-regional anaesthesia in infancy: a randomised controlled trial

__Background__ In laboratory animals, exposure to most general anaesthetics leads to neurotoxicity manifested by neuronal cell death and abnormal behaviour and cognition. Some large human cohort studies have shown an association between general anaesthesia at a young age and subsequent neurodevelopmental deficits, but these studies are prone to bias. Others have found no evidence for an association. We aimed to establish whether general anaesthesia in early infancy affects neurodevelopmental outcomes. __Methods__ In this international, assessor-masked, equivalence, randomised, controlled trial conducted at 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand, we recruited infants of less than 60 weeks’ postmenstrual age who were born at more than 26 weeks’ gestation and were undergoing inguinal herniorrhaphy, without previous exposure to general anaesthesia or risk factors for neurological injury. Patients were randomly assigned (1:1) by use of a web-based randomisation service to receive either awake-regional anaesthetic or sevoflurane-based general anaesthetic. Anaesthetists were aware of group allocation, but individuals administering the neurodevelopmental assessments were not. Parents were informed of their infants group allocation upon request, but were told to mask this information from assessors. The primary outcome measure was full-scale intelligence quotient (FSIQ) on the Wechsler Preschool and Primary Scale of Intelligence, third edition (WPPSI-III), at 5 years of age. The primary analysis was done on a per-protocol basis, adjusted for gestational age at birth and country, with multiple imputation used to account for missing data. An intention-totreat analysis was also done. A difference in means of 5 points was predefined as the clinical equivalence margin. This completed trial is registered with ANZCTR, number ACTRN12606000441516, and ClinicalTrials.gov, number NCT00756600. __Findings__ Between Feb 9, 2007, and Jan 31, 2013, 4023 infants were screened and 722 were randomly allocated: 363 (50%) to the awake-regional anaesthesia group and 359 (50%) to the general anaesthesia group. There were 74 protocol violations in the awake-regional anaesthesia group and two in the general anaesthesia group. Primary outcome data for the per-protocol analysis were obtained from 205 children in the awake-regional anaesthesia group and 242 in the general anaesthesia group. The median duration of general anaesthesia was 54 min (IQR 41–70). The mean FSIQ score was 99·08 (SD 18·35) in the awake-regional anaesthesia group and 98·97 (19·66) in the general anaesthesia group, with a difference in means (awake-regional anaesthesia minus general anaesthesia) of 0·23 (95% CI –2·59 to 3·06), providing strong evidence of equivalence. The results of the intention-to-treat analysis were similar to those of the per-protocol analysis. __Interpretation__ Slightly less than 1 h of general anaesthesia in early infancy does not alter neurodevelopmental outcome at age 5 years compared with awake-regional anaesthesia in a predominantly male study population.Summary Background There is pre-clinical evidence that general anaesthetics affect brain development. There is mixed evidence from cohort studies that young children exposed to anaesthesia may have an increased risk of poorer neurodevelopmental outcome. This trial aims to determine if GA in infancy has any impact on neurodevelopmental outcome. The primary outcome for the trial is neurodevelopmental outcome at 5 years of age. The secondary outcome is neurodevelopmental outcome at two years of age and is reported here. Methods We performed an international assessor-masked randomised controlled equivalence trial in infants less than 60 weeks post-menstrual age, born at greater than 26 weeks gestational age having inguinal herniorrhaphy. Infants were excluded if they had existing risk factors for neurologic injury. Infants were randomly assigned to awake-regional (RA) or sevoflurane-based general anaesthesia (GA). Web-based randomisation was performed in blocks of two or four and stratified by site and gestational age at birth. The outcome for analysis was the composite cognitive score of the Bayley Scales of Infant and Toddler Development, Third Edition. The analysis was as-per-protocol adjusted for gestational age at birth. A difference in means of five points (1/3 SD) was predefined as the clinical equivalence margin. The trial was registered at ANZCTR, ACTRN12606000441516 and ClinicalTrials.gov, NCT00756600. Findings Between February 2007, and January 2013, 363 infants were randomised to RA and 359 to GA. Outcome data were available for 238 in the RA and 294 in the GA arms. The median duration of anaesthesia in the GA arm was 54 minutes. For the cognitive composite score there was equivalence in means between arms (RA-GA: +0·169, 95% CI −2·30 to +2·64). Interpretation For this secondary outcome we found no evidence that just under an hour of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at two years of age compared to RA.

Growth in an Anesthesiologist- and Nurse Anesthetist-Supervised Sedation Nurse Program Using Propofol and Dexmedetomidine.

In 2007, the Department of Anesthesia at the University of Iowa established an anesthesiologist-supervised nurse-managed sedation program. In 2008, the use of propofol and dexmedetomidine by nurses was approved in Iowa. We reviewed 11,038 elective sedation cases done between January 1, 2007, and June 30, 2014. Caseload increased from 170 to 470 cases/quarter. Propofol use increased from 0% to approximately equal to 70% of cases and dexmedetomidine from 0% to approximately equal to 25% of cases. There were no safety issues. The number of nurses working each day (on average) increased from 2.2 to 4.7, but supervising providers remained at 1/day. There were no changes in general anesthesia or monitored anesthesia care cases performed for comparable procedures. Trained, supervised nurses can safely administer propofol or dexmedetomidine to selected patients for a wide variety of procedures.

Are Anesthesia and Surgery during Infancy Associated with Decreased White Matter Integrity and Volume during Childhood

Background: Anesthetics have neurotoxic effects in neonatal animals. Relevant human evidence is limited. We sought such evidence in a structural neuroimaging study. Methods: Two groups of children underwent structural magnetic resonance imaging: patients who, during infancy, had one of four operations commonly performed in otherwise healthy children and comparable, nonexposed control subjects. Total and regional brain tissue composition and volume, as well as regional indicators of white matter integrity (fractional anisotropy and mean diffusivity), were analyzed. Results: Analyses included 17 patients, without potential confounding central nervous system problems or risk factors, who had general anesthesia and surgery during infancy and 17 control subjects (age ranges, 12.3 to 15.2 yr and 12.6 to 15.1 yr, respectively). Whole brain white matter volume, as a percentage of total intracranial volume, was lower for the exposed than the nonexposed group, 37.3 ± 0.4% and 38.9 ± 0.4% (least squares mean ± SE), respectively, a difference of 1.5 percentage points (95% CI, 0.3 to 2.8; P = 0.016). Corresponding decreases were statistically significant for parietal and occipital lobes, infratentorium, and brainstem separately. White matter integrity was lower for the exposed than the nonexposed group in superior cerebellar peduncle, cerebral peduncle, external capsule, cingulum (cingulate gyrus), and fornix (cres) and/or stria terminalis. The groups did not differ in total intracranial, gray matter, and cerebrospinal fluid volumes. Conclusions: Children who had anesthesia and surgery during infancy showed broadly distributed, decreased white matter integrity and volume. Although the findings may be related to anesthesia and surgery during infancy, other explanations are possible.

The Anesthesia-Directed Sedation Service: Models, Protocols, and Challenges

Children undergo painful or distressing procedures in remote locations where anesthesia providers (anesthesiologists, certified registered nurse anesthetists, anesthesia assistants) are not always readily available. In these situations, sedation models with nonanesthesia care providers are necessary to fill the void that anesthesia services cannot provide. Many procedures do not require general anesthesia (even for the pediatric population), and may be accomplished with varying depths of sedation. Anesthesia, as a specialty, offers a special expertise which can be applied to the development, oversight, and implementation of a sedation service. Anesthesiologists already have knowledge of sedatives, analgesics, and anesthetics and possess the advanced intervention skills necessary to rescue from respiratory and hemodynamic compromise. This specialty has taken an active role in establishing guidelines and standards for the sedation of both adults and children over several decades. In addition, the Institute of Medicine recognizes the field of anesthesia as a model of patient safety: anesthesia associated mortality is currently considered to be as low as 1/200,000 or 300,000 anesthetics administered [1]. Sedation can be considered to be an extension of the specialty: knowledge of the cardiovascular and respiratory physiology, as well as the pharmacology of sedative agents are inherent to this discipline.

Surgical practice and outcome in 711 neonates and infants undergoing hernia repair in a large multicenter RCT: Secondary results from the GAS Study

BACKGROUND The GAS study is an international RCT to evaluate neurodevelopmental outcome comparing general plus regional anesthesia versus regional anesthesia alone in 722 neonates and infants who had inguinal hernia repair up to 60 weeks of postmenstrual age. This paper comprises a secondary descriptive analysis of hernias, aspects of surgery and outcomes. METHODS The incidence of unilateral and bilateral hernias, side preponderance, predictive factors for bilateral hernias and surgical approaches were collated. Follow-up outcome data were examined at 2 years. RESULTS Of 711 eligible patients, there were 679 with hernia data showing that 321 hernias were right-sided, 190 left and 168 bilateral. Male to female ratio was 5:1. Of those with unilateral hernias, 25.8% underwent contralateral exploration and in these cases a patent processus vaginalis was found in 68.9%. Bilateral hernias were more common in younger and female patients. At 2 years there was a recurrence rate of 0.99% and in 2.7% of patients a hernia was evident on the contralateral side (metachrony), and this was unrelated to the anesthesia technique. CONCLUSIONS Bilateral hernias are associated with lower gestational age at birth and female gender. There was a low incidence of complications and the anesthesia technique did not affect surgical outcome. LEVEL OF EVIDENCE Level 1 evidence from prospective treatment study.