July 2014

Successful SmartTots Workshop Held in Washington, DC

A highly productive SmartTots Workshop was held in Washington, DC on June 20.  More than 50 researchers and stakeholders convened to identify a study or series of studies that would inform the future scientific direction and fundraising activities of the SmartTots initiative, and to consider whether modifications to the 2012 Consensus Statement on the Use of Anesthetics and Sedatives in Children are warranted in light of the additional research findings over the past 18 months.  Significant progress was made toward both objectives.

The workshop commenced with a charge from the SmartTots Steering Committee Co-Chairs, Dr. Santhanam Suresh of Lurie Children’s Hospital in Chicago and Dr. Bob Rappaport, Director of the Division of Anesthesia, Analgesia, and Addiction Products in the FDA Center for Drug Evaluation and Research, followed by presentations from 11 investigators who reported on their studies and findings to date.  The participants then split into two breakout sessions, with one discussing the needed studies while the other considered the Consensus Statement.  The group reconvened in a plenary session to hear reports from the breakout groups and discuss their work.

A complete report on the workshop outcomes will be included in a future SmartTots e-Newsletter.

Research News & Updates

Effect of General Anesthesia in Infancy on Long-Term Recognition Memory in Humans and Rats

Twenty eight children ages 6-11 who had undergone a procedure requiring general anesthesia before age 1 were compared to 28 age- and gender-matched children who had not undergone anesthesia.  In parallel, thirty-three 7-day-old rats were randomized to receive anesthesia or sham anesthesia.  Our findings suggest that general anesthesia in infancy impairs recollection later in life in humans and rats. In rats, this effect is independent of underlying disease or tissue injury. Read more

General anaesthetics and the developing brain: an overview.

Anaesthetic exposure during a critical period of neuronal development can have significant impact on neurocognitive function later in life. Until proven otherwise, it can be recommended to keep anaesthesia and surgery as short as possible, to use short-acting drugs and/or a combination of general anaesthesia and multimodal pain therapy including systemic analgesics, and local or regional anaesthesia, to reduce the overall drug dosage.  Read more

The Neonatologist’s Role in Pediatric Anesthesia Neurotoxicity

A fundamental assumption of anesthetic practice has always been that the effects of sedatives and anesthetic agents resolve when these drugs are metabolized and excreted from the body. This core assumption has recently been challenged by compelling evidence in animals. In this context, we welcome the publication by Morriss et al in this issue of the journal. However, as is true with every human neurotoxicity study to date, their work raises as many questions as it answers. Read more

Cognitive Outcome after Spinal Anesthesia and Surgery During Infancy

Our study found no link between duration of surgery with infant spinal anesthesia (SA) and scores on academic achievement testing in elementary school. We also found no relationship between infant SA and surgery with very poor academic achievement (VPAA) on elementary school testing, although the confidence intervals (CIs) were wide. Read more

Brain regional vulnerability to anaesthesia-induced neuroapoptosis shifts with age at exposure and extends into adulthood for some regions 

The present study confirms the findings of previous studies showing peak vulnerability to anaesthesia-induced neuronal cell death in the newborn forebrain. It also shows sustained susceptibility into adulthood in areas of continued neurogenesis, substantially expanding the previously observed age of vulnerability. The differential windows of vulnerability among brain regions, which closely follow regional peaks in neurogenesis, may explain the heightened vulnerability of the developing brain because of its increased number of immature neurones. Read more

Repeated Exposure to Anesthetic Ketamine Can Negatively Impact Neurodevelopment in Infants: A Prospective Preliminary Clinical Study.

Our results suggest that 3 or more exposures to anesthetic ketamine have the potential to adversely affect neurodevelopment in infants.  Read more

The role of miR-21 in propofol-induced neurotoxicity in developing human neurons (1093.2)

In this study, we assessed the effects of propofol on human embryonic stem cell (hESC)-derived neurons and the role of microRNAs (miRs) in the toxicity observed. hESCs were differentiated into neurons following a four-step differentiation protocol. Exposure to 20 µg/mL propofol for 6 hours induced significant cell death in the hESC-derived neurons and downregulated several microRNAs, including miR-21. Overexpression of miR-21 significantly attenuated the increase in cell death following propofol administration. Read more

Inhibition of aberrant cyclin-dependent kinase 5 activity attenuates isoflurane neurotoxicity in the developing brain

Our results indicated that aberrant CDK5 activity-dependent MEF2 phosphorylation mediates developmental isoflurane neurotoxicity. Inhibition of CDK5 overactivation contributes to the relief of isoflurane neurotoxicity in the developing brain. Read more

Involvement of RAGE in isoflurane-induced neuronal apoptosis

Isoflurane has been reported to cause neurotoxicity and neurocognitive impairments in neonatal rats. Previous reports suggest elevated levels of S100B after anesthesia and brain trauma. The receptor for advanced glycation end products (RAGE) is the only known cell surface receptor for S100B and expressed in the brain. RAGE activation in neurons has also been shown to lead to apoptosis and neurodegeneration. Our research demonstrates that RAGE may be involved in the neuronal apoptosis induced by isoflurane. Read more

The role of miR-124 in modulating hippocampal neurotoxicity induced by ketamine anesthesia

Our study demonstrated that miR-124 played an important role in regulating ketamine induced hippocampal neurodegeneration. Inhibiting miR-124 may provide a molecular target to improve memory performance in both human and animals suffering from over-anesthetic related neurotoxicity. Read more

Sevoflurane in combination with propofol, not thiopental, induces a more robust neuroapoptosis than sevoflurane alone in the neonatal mouse brain

Sevoflurane alone can induce neuronal apoptosis, and this effect is enhanced by propofol. Thiopental did not exacerbate the neurotoxicity of sevoflurane. There is the possibility that the combination of sevoflurane and propofol is a more harmful anesthetic technique than sevoflurane alone in pediatric patients.  Read More

Ketamine administered to pregnant rats in the second trimester causes long-lasting behavioral disorders in offspring.

Data suggest that maternal anesthesia with ketamine during the fetal brain development period can cause fetal brain damage and subsequent neurobehavioral abnormality, which is likely associated with the imbalanced expression of NMDA receptor subunits. Read more

Propofol anesthesia induces proapoptotic tumor necrosis factor-α and pro-nerve growth factor signaling and prosurvival Akt and XIAP expression in neonatal rat brain

These results show that different brain structures respond to propofol anesthesia with a time- and duration-of-exposure-dependent increase in proapoptotic signaling and with concomitant increases in activities of prosurvival proteins. We hypothesized that the fine balance between these opposing processes sustains homeostasis in the immature rat brain and prevents unnecessary damage after exposure to an injurious stimulus. The existence of this highly regulated process provides a time frame for potential therapeutic intervention directed toward suppressing the deleterious component of propofol anesthesia. Read more