Secondary Logo

Journal Logo

Epidemiologic Analysis of Elective Operative Procedures in Infants Less Than 6 Months of Age in the United States

Einhorn, Lisa M. MD*; Young, Brian J. MD; Routh, Jonathan C. MD, MPH; Allori, Alexander C. MD, MPH; Tracy, Elisabeth T. MD§; Greene, Nathaniel H. MD, MHS

doi: 10.1213/ANE.0000000000002185
Healthcare Economics, Policy and Organization: Original Clinical Research Report
Free
SDC

BACKGROUND: This study uses publicly available data to analyze the total number of elective, potentially deferrable operative procedures involving infants <6 months of age in the United States. We investigated the factors associated with the performance of these procedures in this population.

METHODS: The State Ambulatory Surgery Database was used to identify patients in California, North Carolina, New York, and Utah during the years of 2007–2010 who were younger than 6 months of age at the time that they underwent outpatient (ambulatory) surgery. Operations that could reasonably be postponed until 6 months of age were classified as potentially deferrable procedures. Hernia repairs were analyzed separately from other deferrable procedures. Primary outcomes included the total number of elective procedures and the number and rates of potentially deferrable procedures per state per year in this population.

RESULTS: Over the study period, a total of 27,540 procedures were identified as meeting inclusion criteria; of those, 7832 (28%) were classified as potentially deferrable, 4315 of which were hernia repairs. The average rates of potentially deferrable nonhernia procedures in California, North Carolina, New York, and Utah were 8.3, 43.8, 30.0, and 11.7 per 10,000 person-years, respectively. In multivariable analysis, private insurance (odds ratio [OR] = 1.36), self-pay status (OR = 1.50), and treatment in a different state (OR = 0.48–3.16) were independent predictors of a potentially deferrable procedure being performed on an infant younger than 6 months.

CONCLUSIONS: Potentially deferrable procedures are still performed in infants <6 months of age. There appears to be significant variation in timing of these procedures among states. Insurance status and geography may be independent predictors of a procedure being potentially deferrable.

Published ahead of print June 16, 2017.

From the *Division of Pediatric Anesthesia, Department of Anesthesiology; Division of Urology; Division of Plastic, Maxillofacial and Oral Surgery; §Division of Pediatric Surgery, Department of Surgery; and Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina.

Accepted for publication April 6, 2017.

Published ahead of print June 16, 2017.

Funding: None.

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

Reprints will not be available from the authors.

Address correspondence to Nathaniel H. Greene, MD, MHS, Department of Anesthesiology, Duke University School of Medicine, 2301 Erwin Rd, 5671 HAFS, Durham, NC 27710. Address e-mail to nathaniel.greene@dm.duke.edu.

In the United States, it is estimated that 6 million children undergo general anesthesia annually.1 Each year, approximately 450,000 children younger than 18 years of age are admitted for surgery, a quarter of which are children younger than 3 years of age.2 The performance of elective operations on infants and young children who require general anesthesia remains controversial due to heightened concerns regarding neurotoxicity and abnormal neurodevelopment from anesthetics.3–5 Evidence from animal studies has served as the basis for these concerns.6,7 Therefore, in 2007, the US Food and Drug Administration (FDA) released a recommendation that all elective procedures in infants be delayed until at least 6 months of age.8 In 2009, the Strategies for Mitigating Anesthesia-Related Neurotoxicity in Tots (SmartTots) collaborative was established to coordinate and fund research dedicated to ensuring the safety of infants and children undergoing general anesthetics or sedation.9 SmartTots, along with the American Academy of Pediatrics and the FDA, released a consensus statement in 2012 that recommended the avoidance of elective procedures performed under general anesthetics until 3 years of age.10,11 Most recently, the FDA issued a warning in 2016 regarding the administration of prolonged anesthetics of >3 hours in duration to children younger than 3 years of age for elective procedures.

Despite these concerns, to date there is no report in the medical literature that evaluates change of practice based on these recommendations. Therefore, the purpose of this investigation was to determine (1) the rate of elective outpatient (ambulatory) procedures performed in infants younger than 6 months of age, (2) the rate of a subset of procedures that we consider to be “potentially deferrable” until the child is older, and (3) patient characteristics and demographics that may be associated with a procedure being potentially deferrable within this subset. We hypothesized that a significant number of potentially deferrable procedures continued to be performed in this vulnerable population following FDA and SmartTots recommendations.

Back to Top | Article Outline

METHODS

Database

The Healthcare Cost and Utilization Project (HCUP) State Ambulatory Surgery Database (SASD) aggregates data collected from ambulatory (including <23-hour admissions) surgical encounters at hospitals in 34 participating states and reformats these data into a single database. The SASD includes a core set of clinical and nonclinical variables on all patients within a given state for a given year; unlike several other databases, the SASD collects data irrespective of payer or type of insurance. State reporting to the database is mandatory and includes all surgical arenas, as well as procedures performed in hospitals and ambulatory surgery centers. By querying the SASD, we identified a cohort of patients younger than 6 months of age (and a reference group of infants between 6 and 12 months of age) in the states of California, North Carolina, New York, and Utah during the years of 2007 to 2010. While there are subsets of the SASD available for each participating state, these 4 states were chosen because they had 4 years of consecutive data, had age variables that indicated age in days at time of procedure, and were comprehensive in scope. Together, they represent a substantial portion of the US population. While data for later years are available in some of the states, some states have also stopped participating in HCUP as of 2012, making extension of analysis of these specific states beyond 2011 infeasible. Population estimates of the states represented were obtained from the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (WONDER) database, which uses US Census data as its primary source.

This study was determined to be exempt from review by the Duke University Institutional Review Board, because these data are publicly available without identifiable information.

Back to Top | Article Outline

Study Cohorts

The study sample included all patients who underwent an ambulatory procedure associated with any Current Procedural Terminology (CPT) or International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) procedure codes during the years 2007 to 2010. A total number of 25,344,812 encounters were identified. We then excluded encounters because the age value in years was not equal to zero (24,944,858), because age was missing (279,664), equal to zero days (647), CPT or ICD-9-CM procedural codes were missing or invalid (253), they only had an anesthesia CPT code (205), or CPT codes corresponded to procedures that did not reliably require anesthesia (diagnostic imaging, insertion of bladder catheter, nasogastric tube placement, etc—21,153). After obtaining an exhaustive list of all procedures performed in this cohort, we manually identified CPT or ICD-9-CM procedural codes in patients younger than 6 months that corresponded with herniorrhaphy of reducible inguinal hernias, hypospadias repair with or without circumcision revision, and procedures on congenital digit or skin anomalies, and categorized these as potentially deferrable procedures (see Supplemental Digital Content 1, Appendix 1, http://links.lww.com/AA/B794). Incarcerated or strangulated inguinal hernias were excluded from this study. Initial neonatal circumcisions were not included because the vast majority are performed without general anesthesia. It should also be noted that we defined a “potentially deferrable” procedure as one that can be safely deferred until after 6 months of age without harm to the patient. An “elective” procedure refers to a preplanned procedure that has an expectation that it could be temporarily postponed safely for up to a few weeks if necessary.

Back to Top | Article Outline

Comparison of Infants >6 Months of Age to Those <6 Months of Age

In addition to examining the occurrence of procedures in infants <6 months of age, we also applied the same search criteria to infants >6 months of age with the specific purpose of seeing how rates of procedures change over time when compared to infants <6 months of age. Proportions over time were calculated by state and year to estimate the proportion of particular procedures being performed in infants <6 months of age to infants >6 months of age.

Back to Top | Article Outline

Missing Data Analysis

On further examination of the 279,664 procedures for which patient age is missing, we found the majority of these procedures (278,984) to be from California. Within this cohort, 268,765 procedures had no age data at all, while 10,219 procedures indicated the age of the patient was <12 months of age, but had no further identifying information. To provide a complete estimate for the state of California, we analyzed the 10,219 procedures by applying the observed proportions of procedures in California between infants >6 months of age and infants <6 months of age to this cohort after stratifying by year and procedure type. Because the 268,765 procedures had no information regarding age, we decided to exclude this cohort from analysis (approximately 1.5% of California sample size).

Back to Top | Article Outline

Epidemiologic Analysis

The total number of elective procedures, as well as the number and rates of potentially deferrable procedures, requiring general anesthesia per state per year in this population served as the primary outcomes. Accessing US Census population data via the WONDER database as the denominator population, we estimated the rates of potentially deferrable procedures for each state in each year (as the HCUP SASD includes all ambulatory procedures in a given state for a given year). Because the WONDER database reports the population up to 12 months of age (and not 6 months of age), we calculated rates with a denominator equal to each state’s population divided in half to roughly estimate the numbers of infants <6 months. For infants >6 months of age, we assumed the same denominator population.

Back to Top | Article Outline

Statistical Analysis

We were interested in assessing if deferability of a procedure was affected by other factors including state (geographical location), insurance status (government, private, uninsured), year of encounter, sex, and age (race and ethnicity were reported in different ways among states analyzed and thus not included in the analysis). To evaluate this, we divided our cohort into 3 separate groups based on whether the patient underwent a potentially deferrable procedure, an elective hernia repair, or a nondeferrable procedure. Two scenarios were considered because elective hernia repairs may or may not have been deferrable: (1) Assuming elective hernia repairs are truly not deferrable, we included these cases as nondeferrable procedures against the aforementioned deferrable procedures, or (2) assuming elective hernia repairs are deferrable, we excluded the other deferrable procedures in a subanalysis and only used other nondeferrable procedures as denominator data. We used 2-sample t tests assuming an α of .05 to assess differences between 2 groups of patients in each scenario. Because 2-sample t tests for all potential independent variables achieved statistical significance, we then developed a multivariable logistic regression model to examine differences between reported rates using a procedure being deferrable as a dependent variable and all the following as independent variables: insurance status, geographical location, year of procedure, age, and sex. All records that contained missing covariate data (211 missing insurance status and 10,219 missing detailed age data) were excluded from the multivariable logistic regression analysis.

We also performed a priori and post hoc power calculations for our 2 outcomes of interest: rates of procedures between states and proportions of procedures that are potentially deferrable. Given the lack of published data on this topic, we performed an a priori power calculation using the proportion outcome with a hypothesis that we would expect a proportion of deferrable procedures to be 20%. We then decided a clinically meaningful difference would be a relative risk increase of 50% (or absolute proportion increase of 10%). Assuming an α of .05, one would need 294 procedures in each group to achieve 80% power when doing a 2-group comparison. After examining our population data, we did a post hoc power calculation using observed population rates as proportions in a similar calculation. Assuming an α of .05, one would need 17,938 children in each group to achieve a power of 80% when starting with a rate like the one observed in California. This assumes a clinically significant difference in rate by a factor of 2. It is important to note that the first calculation refers to procedures, while the second calculation refers to total population. All analyses were performed using Stata SE 14 (StataCorp, LP, College Station, TX).

Back to Top | Article Outline

RESULTS

There were over 25 million total records in the combined SASD databases from California, North Carolina, New York, and Utah over the years 2007 to 2010 that fit our criteria. Of these, 27,540 patients met inclusion criteria based on age.

Back to Top | Article Outline

Patient Characteristics

Table 1.

Table 1.

Table 1 highlights cohort characteristics based on whether the procedure was potentially deferrable, an elective hernia repair, or not deferrable. Over 4 years, there were a total of 3192 potentially deferrable hypospadias, polydactyly, and skin lesion procedures (14%) and 3876 elective hernia repairs (18%). Based on univariate analysis in comparing nondeferrable procedures, patients who underwent potentially deferrable procedures were more likely to be older, male, and have private insurance. These numbers specifically reflect the observed cases in the data set and do not represent additional patients represented by our additional missing data analysis.

Back to Top | Article Outline

Primary Outcomes

Of the 7068 potentially deferrable procedures, 3875 (54.8%) were inguinal hernia repairs (and analyzed separately), 1069 (15.1%) were hypospadias repairs, 295 (4.2%) were polydactyly repairs, and 1829 (25.9%) were skin lesion removals performed over the 4-year period.

Table 2 highlights the total number of elective procedures with missing data analysis adjustments (see Supplemental Digital Content 2, Appendix 2, http://links.lww.com/AA/B795), the number and rates of potentially deferrable hypospadias, polydactyly, and skin lesion procedures performed in patients <6 months of age by state and individual year. The proportion of hypospadias, polydactyly, and skin lesion procedures to all procedures during this time period in California, North Carolina, New York, and Utah was 8.1%, 12.7%, 22.9%, and 5.5%, respectively. These proportions are shown by state per year in Figure 1. The average rates (procedures/10,000 person-years) of potentially deferrable procedures in California, North Carolina, New York, and Utah from 2007 to 2010 were 8.3, 43.8, 30.0, and 11.7, respectively. Notably, New York, North Carolina, and California had qualitative decreases in their potentially deferrable procedure rate, 43.4–30.3, 48.4–40.7, and 10.3–6.8, respectively, from 2007 to 2008 (Figure 2). Table 3 shows the same statistics for elective hernia repairs with missing data adjustments (excluding hypospadias, polydactyly, and skin lesion procedures). In contrast, the rates of elective hernia repairs qualitatively increased in every state from 2007 to 2008, and then subsequently dropped back down to levels below 2007 by 2010, with Utah being the exception where rates in 2010 were similar to 2007 levels. The total count of procedures by type of deferrable procedure across patient age in months is shown in Figure 3.

Table 2.

Table 2.

Table 3.

Table 3.

Figure 1.

Figure 1.

Figure 2.

Figure 2.

Figure 3.

Figure 3.

Table 4 shows a specific analysis of procedure rates in 0- to 5-month olds and 6- to 11-month olds over time for each state to try to understand if procedure timing was changed over the study period. For hypospadias, polydactyly, and skin lesion procedures, there was an absolute proportional decrease in these procedures being performed in 0- to 5-month-olds from 2007 to 2008 in California (10%), North Carolina (5%), and New York (6%), while there was a relative increase in Utah (3%). This absolute decrease is maintained through 2010 in California (9%), North Carolina (6%), and New York (9%), while the rate stayed similar in Utah (−1%). For hernia repairs, there was little movement in this proportion in California (−4%), North Carolina (−3%), and Utah (+4%) from 2007 to 2010, while there was a more substantial decrease observed in New York (−13%).

Table 4.

Table 4.

Table 5.

Table 5.

The result of the multivariable regression models are shown in Table 5. The hypospadias, polydactyly, and skin lesion procedures model indicates that a procedure in an infant <6 months of age in New York is approximately 3 times as likely to be potentially deferrable as compared to California (odds ratio [OR] = 3.16, 95% confidence interval [CI], 2.82–3.54), while a similar procedure in Utah is approximately half as likely to be potentially deferrable. Private insurance was a risk factor for undergoing a potentially deferrable procedure (OR = 1.36, 95% CI, 1.25–1.47), and having no insurance (self-pay status) was also significant (OR = 1.50, 95% CI, 1.13–1.98) when compared to government-based insurance. The year of hospitalization was also an independent predictor of having a potentially deferrable procedure. A procedure was less likely to be potentially deferrable in 2008 (OR = 0.67, 95% CI, 0.60–0.75), 2009 (OR = 0.70, 95% CI, 0.63–0.78), and 2010 (OR = 0.67, 95% CI, 0.59–0.75) than in 2007.

Back to Top | Article Outline

DISCUSSION

There was significant variation among states in both the total number and the rates of potentially deferrable procedures in infants <6 months of age. Adjusting for other factors including geographical location, insurance status, and year thought to affect the probability of a procedure being deferrable did not attenuate this variation. Our findings reveal that a substantial number of infants continue to be exposed to anesthesia during a critical neurodevelopmental period, despite national recommendations to delay elective cases.

There are currently 3 ongoing, large-scale clinical studies to formally evaluate the potential for neurocognitive harm in infants and children undergoing general anesthesia. The general anaesthesia and awake-regional anaesthesia in infancy (GAS) study is a prospective, international, multisite, randomized controlled trial, which is investigating whether awake regional versus sevoflurane-based general anesthesia given to infants between 26 and 60 weeks postconceptual age for inguinal hernia repair results in equivalent neurocognitive outcomes at 2 and 5 years of age. The initial results of this study found no evidence that <1 hour of sevoflurane anesthesia in infancy increase the risk of adverse neurodevelopmental outcomes at 2 years of age.10 The Pediatric Anesthesia and Neurodevelopment Assessment (PANDA) project is another large multicenter study based in the United States, which compares neurodevelopment and cognitive functions in children who have been exposed to anesthesia within the first 3 years of life and those who have not.12 The primary outcome is the assessment of global cognitive function in children aged 8 and 15 years. Initial data suggest that healthy children with a single anesthetic exposure before 36 months of age have no differences in IQ scores later in childhood compared to their siblings without an anesthetic exposure.13 Finally, the Mayo Anesthesia Safety in Kids (MASK) study is using propensity matching to evaluate possible anesthesia-related neurocognitive developmental abnormalities in a cohort of 1000 children who had varying exposure to anesthesia before 3 years of age born in Olmsted County, Minnesota.14 In this study, children will be given the FDA’s National Center for Toxicological Research operant test battery to determine if cognitive deficits exist in those with greater exposure to anesthesia. The results of this study have not yet been published.

Although the completion of these well-designed studies is essential to furthering our understanding of the clinical ramifications of anesthesia on the developing brain, conclusive results resulting in evidence-informed updated recommendations are potentially years away. The purpose of our study was to determine if there are a substantial number of potentially deferrable procedures still being performed in infants <6 months of age, despite neurodevelopmental concerns and published recommendations. While our data suggest that the risk of having a potentially deferrable procedure has declined from 2007 to 2010, our findings indicate that there may still be significant variation in timing of these procedures among states. Our results support that location and insurance status may be independent predictors of potentially deferrable procedures being performed. Both of these variables indicate that regional physician practice preferences, insurance reimbursement, and other factors associated with geographical location may result in this variability. We speculate that we observed a substantial drop from 2007 to 2008 due to the FDA warning; however, these deferrable procedures persisted into 2009 and 2010 with no significant adjusted difference by year between 2008 and 2010. This drop also corresponded with a relative increase in procedures in 6- to 11-month-olds, suggesting that these procedures are being delayed until after 6 months of age. Since the 2007 announcement, the FDA has extended their warning beyond 6 months of age, suggesting that repeated or lengthy use of drugs required for general anesthesia in children younger than 3 years may adversely affect the development of children’s brains. Future epidemiologic studies could examine numbers and rates of deferrable procedures in children up to age 3 years after 2017 data have been collected.

Analyzing elective hernia repairs separately yielded an interesting contrast to the other group of potentially deferrable procedures. The preferred timing appeared quite different as compared to the other procedures as well. Additionally, unlike the other procedures, there seemed to be no significant relation between hernia repairs and the timing of the 2007 FDA announcement, which supports the idea that surgeons may not view these procedures as deferrable. While we expected uninsured patients to have potentially deferrable procedures less often in this time period, we actually saw the opposite result. For elective hernia repairs, self-pay status was associated with a lower probability of an elective hernia repair, and we currently do not have a good explanation for this finding. It would indeed be interesting to look at more states during more years to help delineate some the reasons why this may be true.

Back to Top | Article Outline

Limitations

The limitations of our study should be considered when interpreting these results. The sample of states analyzed represents approximately one-quarter of the US population of children <6 months of age, thus potentially limiting generalizability. We cannot verify that all patients in our cohort received a general anesthetic, because it is possible that some infants included in our study underwent neuraxial anesthesia only. There is currently no available literature that examines what proportion of anesthetics in infants is general versus neuraxial only; however, it is likely a small minority, given the current practice patterns for the procedures selected. Additionally, we calculated the rate of potentially deferrable procedures by using population data collected from the Centers for Disease Control and Prevention WONDER database, which publishes statistics on all infants using US Census data (0–12 months old). To calculate rates in children 0 to 6 months old, we divided this number in half to estimate this population. This is not an exact estimate; however, the ratio of >6- to 12-month olds to 0- to ≤6-month-olds should not be relatively different by our independent variables of interest, making any misclassification present nondifferential. Like many retrospective database studies, there may be errors regarding coding procedures; however, there were no significant changes in the code base over the 4 years of the study. It should also be noted that the structure of the data only allows us to use “procedure” as the unit of analysis rather than “patient.” This matters more when discussing an appropriate denominator, which is why we decided to measure this variation in 2 ways: using procedures performed in a state in the relevant population and using an accurate count of the relevant population.

The decision to analyze elective hernia repairs separately was made based on the belief that some inguinal hernias in this population present a higher risk if left unrepaired than the risk of an anesthetic exposure. Currently, there are no randomized controlled trials examining optimal management of neonatal hernia repairs, and the literature is inconsistent regarding the risks and benefits associated with early versus delayed repair.15,16 There is also considerable practice variability between hospitals in the timing of inguinal hernia repair in neonates,17 and attempts have been made to correlate the age at diagnosis, the duration between diagnosis and hernia repair, and infants’ gestational age with risk of inguinal hernia incarceration without reliable conclusions.18 A multicenter randomized study of early versus delayed repair of inguinal hernias in preterm infants (Hernia in Premature Infants Trial) is currently ongoing. Because it seems most surgeons are still choosing to repair hernias in this population, we wanted to see how the rate of this procedure behaved over time as compared to the more widely accepted attitudes of delaying hypospadias and polydactyly repairs. The difference in behavior observed both in unadjusted and in adjusted forms helps support this decision.

While we found the degree of variation between states surprising (approximately 5-fold between California and North Carolina), this may be slightly overestimated because of the missing data problems in the California data set. We made our best efforts to adjust for these missing data, but our adjustments are only valid if the probability of age being missing had no significant relationship to the CPT codes listed or other variables we were examining in our study. We believe this to be a reasonable assumption, and we were also not surprised that there would be significant variation present by state. There are also likely procedures not accounted for in the missing data cohort without any age information, but if this cohort is similar in age range to the rest of the sample, we calculate both our rates and proportions to have a relative change by <10%. Factors from insurance coverage differences to surgeon preferences may be reasons for these observed differences. It is our hope to investigate and understand these reasons better in future work.

Finally, we are limited by our choice of 4 example procedural groups and the years we have chosen to study. Our findings are specific to these procedures and the CPT/ICD-9-CM procedural codes used to identify them. It is possible that there are other potentially deferrable procedures that are not included in our analysis. It is also possible that practice has altered from 2010 to the present time with changes in the literature. Despite the above limitations, our results have not previously been reported and show that elective surgeries in infants 0–6 months of age still occur with high frequency.

Back to Top | Article Outline

CONCLUSIONS

Our study finds that potentially deferrable procedures continued to be performed with varying rates among states in the years following the FDA warnings and consensus statements. Our results suggest that additional work should be performed in this population to explain the differences in surgical management that exist between states. Future studies may want to focus on elective and potentially deferrable procedures performed in children up to 3 years of age because current recommendations warn that this population may be at high risk for neurodevelopmental changes. Continued education about the potential neurodevelopmental delays associated with infant exposure to anesthesia may reduce the incidence of these potentially deferrable procedures.

Back to Top | Article Outline

DISCLOSURES

Name: Lisa M. Einhorn, MD.

Contribution: This author helped conceive and design the study, interpret and analyze the data, as well as write and edit the manuscript.

Name: Brian J. Young, MD.

Contribution: This author helped design the study, interpret and analyze the data, and edit the manuscript.

Name: Jonathan C. Routh, MD, MPH.

Contribution: This author helped design the study, interpret and analyze the data, and edit the manuscript.

Name: Alexander C. Allori, MD, MPH.

Contribution: This author helped design the study, interpret and analyze the data, and edit the manuscript.

Name: Elisabeth T. Tracy, MD.

Contribution: This author helped design the study, interpret and analyze the data, and edit the manuscript.

Name: Nathaniel H. Greene, MD, MHS.

Contribution: This author helped conceive and design the study, acquire, interpret, and analyze the data, as well as write and edit the manuscript.

This manuscript was handled by: Nancy Borkowski, DBA, CPA, FACHE, FHFMA.

Back to Top | Article Outline

REFERENCES

1. DeFrances CJ, Cullen KA, Kozak LJ. National Hospital Discharge Survey: 2005 annual summary with detailed diagnosis and procedure data. Vital Health Stat 13. 2007;165:1–209.
2. Tzong KY, Han S, Roh A, Ing C. Epidemiology of pediatric surgical admissions in US children: data from the HCUP kids inpatient database. J Neurosurg Anesthesiol. 2012;24:391–395.
3. Sun L. Early childhood general anaesthesia exposure and neurocognitive development. Br J Anaesth. 2010;105suppl 1i61–i68.
4. Loepke AW, Soriano SG. An assessment of the effects of general anesthetics on developing brain structure and neurocognitive function. Anesth Analg. 2008;106:1681–1707.
5. Sinner B, Becke K, Engelhard K. General anaesthetics and the developing brain: an overview. Anaesthesia. 2014;69:1009–1022.
6. Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci. 2003;23:876–882.
7. Brambrink AM, Evers AS, Avidan MS, et al. Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain. Anesthesiology. 2010;112:834–841.
8. Mellon RD, Simone AF, Rappaport BA. Use of anesthetic agents in neonates and young children. Anesth Analg. 2007;104:509–520.
9. Ramsay JG, Roizen M. SmartTots: a public-private partnership between the United States Food and Drug Administration (FDA) and the International Anesthesia Research Society (IARS). Paediatr Anaesth. 2012;22:969–972.
10. Davidson AJ, Disma N, de Graaff JC, et al.; GAS Consortium. Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial. Lancet. 2016;387:239–250.
11. Rappaport BA, Suresh S, Hertz S, Evers AS, Orser BA. Anesthetic neurotoxicity—clinical implications of animal models. N Engl J Med. 2015;372:796–797.
12. Sun LS, Li G, DiMaggio CJ, et al. Feasibility and pilot study of the Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) project. J Neurosurg Anesthesiol. 2012;24:382–388.
13. Sun LS, Li G, Miller TL, et al. Association between a single general anesthesia exposure before age 36 months and neurocognitive outcomes in later childhood. JAMA. 2016;315:2312–2320.
14. Gleich SJ, Flick R, Hu D, et al. Neurodevelopment of children exposed to anesthesia: design of the Mayo Anesthesia Safety in Kids (MASK) study. Contemp Clin Trials. 2015;41:45–54.
15. Lee SL, Gleason JM, Sydorak RM. A critical review of premature infants with inguinal hernias: optimal timing of repair, incarceration risk, and postoperative apnea. J Pediatr Surg. 2011;46:217–220.
16. Vaos G, Gardikis S, Kambouri K, Sigalas I, Kourakis G, Petoussis G. Optimal timing for repair of an inguinal hernia in premature infants. Pediatr Surg Int. 2010;26:379–385.
17. Sulkowski JP, Cooper JN, Duggan EM, et al. Does timing of neonatal inguinal hernia repair affect outcomes? J Pediatr Surg. 2015;50:171–176.
18. Wang KS; Committee on Fetus and Newborn, American Academy of Pediatrics; Section on Surgery, American Academy of Pediatrics. Assessment and management of inguinal hernia in infants. Pediatrics. 2012;130:768–773.

Supplemental Digital Content

Back to Top | Article Outline
Copyright © 2017 International Anesthesia Research Society