Pediatric Anesthesia NeuroDevelopment Assessment Research Articles

Anesthesia for the young child undergoing ambulatory procedures

Sedation and anesthesia are often necessary for children at any age, and are frequently provided in ambulatory settings. Concerns have mounted, based on both laboratory studies including various mammalian species and retrospective human clinical studies, that the very drugs that induce sedation and anesthesia may trigger an injury in the developing brain, resulting in long-lasting neurobehavioral consequences. New retrospective studies further augment these concerns. Specifically, recent studies support that a single anesthesia exposure before age 3 may increase the risk for long-term disabilities in language acquisition and abstract reasoning, and that exposure to two or more anesthetics before age 2 nearly doubles the risk for an attention-deficit hyperactivity disorder diagnosis by age 19. However, methodological limitations preclude final conclusions or change in practice based on these reports, as retrospective studies cannot prove causation. Ongoing prospective clinical studies such as 'General Anesthesia and Apoptosis Study', 'Pediatric Anesthesia NeuroDevelopment Assessment', and 'Mayo Safety in Kids' trials will offer more answers in the future. Meanwhile, laboratory experiments continue to describe differential morphologic injury to individual structures in the neuropil, and have identified mitochondrial dysfunction and neuroinflammation as potential links in the injury process. Additionally, concepts for protection against anesthesia-induced neurotoxicity continue to be tested in the laboratory. Results from ongoing prospective clinical trials and translational research will help clarify whether anesthesia-associated neurotoxicity affects the developing human brain, including whether it causes long-term disability, and may further identify the injury mechanisms and potential strategies for protection. Currently, the available evidence does not support a change in practice.

Anesthetic neurotoxicity in the newborn and infant

Every year, millions of children undergo anesthesia. Emerging evidence from experimental in-vitro and in-vivo models supports a role for neuropathologic injury and neurobehavioral deficits at older age after early exposure to various anesthetic regimens. Clinical studies have sought to identify a phenotype of developmental anesthesia neurotoxicity in humans, but the current evidence is limited to data from retrospective studies with their associated confounders. Experimental models have been used to further define the injury and to help identify potential mechanisms of this neurotoxicity. A recent clinical trial from an Australian birth cohort suggests a single anesthesia exposure as a neonate or infant may increase the risk for language and abstract reasoning deficits later in life, though residual data confounders may remain. Several ongoing clinical trials like Mayo Safety in Kids, Pediatric Anesthesia NeuroDevelopment Assessment, and General Anesthesia and Apoptosis Study will likely offer more clear answers in the future. In the interim, experimental models have described roles for neuroinflammation, mitochondrial damage from reactive oxygen species, and the presence of several neuronal morphology changes from anesthesia exposure. Additionally, several potential neuroprotective agents and strategies have been tested in the laboratory. Whether anesthesia-associated neurotoxicity affects the developing human brain and whether this leads to clinically measurable deficits remains unclear.

Feasibility and Pilot Study of the Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) Project

Animal studies have documented that exposure of the developing brain to commonly used anesthetic agents induces neurotoxicity and late abnormal neurobehavioral functions as adults. Results from clinical studies have all been analyzed using existing data sets, and these studies produced inconsistent results. To provide more definitive evidence to address the clinical relevance of anesthetic neurotoxicity in children, an interdisciplinary team of investigators designed and developed the Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) project. We present pilot study results in 28 sibling pairs recruited and tested at the Columbia University Medical Center (CUMC) and Children's Hospital of Boston (CHB) for the PANDA project. The PANDA project uses an ambidirectional cohort design. We performed prospective neuropsychological assessment in 28 exposed-unexposed sibling pairs from 6 to 11 years of age. The exposed siblings were ASA 1 or 2 and had received a single episode of anesthesia for inguinal hernia repair before the age of 36 months and the unexposed siblings had no anesthesia before the age of 36 months. All the sibling pairs were English speaking and were 36 weeks of gestational age or older. Each sibling pair underwent a direct testing using the Wechsler Abbreviated Scale of Intelligence (WASI) and the NEuroPSYchological Assessment, second edition (NEPSY II), and the parents completed questionnaires related to behavior using CBCL and Conners rating. Data are presented as means±SD. We conducted descriptive analyses of the demographic data. We compared both the exposed and the unexposed sibling groups on WASI and NEPSY II, and total and T scores from CBCL and Conners rating were analyzed as continuous data using the paired t test between the two groups. A P<0.05 was considered significant. After the Institutional Review Board approval for the study at both CUMC and CHB, the full PANDA study protocol was implemented to perform a pilot feasibility study. Our success rate was 96.7% in obtaining detailed medical and anesthesia records in our historical cohort. The scores for verbal IQ (exposed=106.1±16.3, unexposed=109.2±17.9), performance IQ (exposed=109.1±16.0, unexposed=113.9±15.9), and full IQ (exposed=108.2±14.0, unexposed=112.8±16.8) were comparable between the siblings. There were no differences between the two groups in T scores for any of the NEPSY II subdomains, CBCL, or Conners rating. An abstraction protocol with web-based electronic data capture forms also was developed in conjunction with the International Center for Health Outcomes and Innovation Research (InCHOIR). The pilot study provided useful information for feasibility to recruit the sample size and to obtain relevant clinical data. For the final study protocol, both the neuropsychological battery and the age range for testing were revised. Our results confirmed the feasibility of our study approach and yielded pilot data from neuropsychological testing.

Preclinical Research Into the Effects of Anesthetics on the Developing Brain

Every year millions of children are treated with anesthetics and sedatives to alleviate pain and distress during invasive procedures. Accumulating evidence suggests the possibility for deleterious effects on the developing brain. This has led to significant concerns among pediatric anesthesiologists and to the formation of the Pediatric Anesthesia NeuroDevelopmental Assessment (PANDA) group and its biannual symposium. Not surprisingly, the majority of the data in this field have thus far been derived through laboratory research. Accordingly, this review summarizes the current state of animal research in this field, introduces some of the findings presented at the PANDA symposium, and addresses some of the difficulties in translating these findings to pediatric anesthesia practice, as discussed during the symposium. The symposium participants' consensus was that significant preclinical and clinical research efforts are still needed to investigate this important concern for child health.

Elective Procedures and Anesthesia in Children

The Pediatric Anesthesia NeuroDevelopment Assessment research group at Columbia University Medical Center Department of Anesthesiology has conducted biannual national Symposia since 2008 to evaluate study data and invigorate continued thinking about unresolved issues of pediatric anesthesia neurotoxicities. The third Symposium extended the dialogue between pediatric anesthesiologists and surgeons in panel presentations and discussions by four surgical specialists. This paper reports the prevailing opinions expressed by a pediatric general surgeon, urologist, plastic surgeon and ophthalmologist and explores factors related to delayed operative intervention, need for multiple procedures, and parental concerns.