Concerned about the potential risk to young children of exposure to general anesthesia, the FDA has launched an initiative, called SAFEKIDS, to study the effects of these agents on the developing brain.

The agency has partnered with five anesthesiology groups and universities on the project, known formally as Safety of Key Inhaled and Intravenous Drugs in Pediatrics: the International Anesthesia Research Society (IARS), Children’s Hospital Boston of Harvard University, Mayo Clinic, Columbia University and the Arkansas Children’s Hospital Research Institute. Investigators at these sites will lead studies—from epidemiologic analyses to randomized controlled trials in humans—of the effects of anesthetic agents on young children.

Although the FDA will provide some money for the studies, officials hope to enlist the help of private foundations and other wealthy donors to come up with most of what they estimate will be hundreds of millions of dollars needed to pay for the research.

“This is such a critical international public health issue, I can’t imagine we won’t find the funds we need from private sources,” said Bob Rappaport, MD, director of the Division of Anesthesia, Analgesia and Rheumatology Products at the FDA Center for Drug Evaluation and Research, in Rockville, Md., who is overseeing the program for the agency.

Depending on what information emerges from SAFEKIDS, regulators could ask drug companies to modify the labels on certain anesthetics—such as volatile compounds—to warn about the cognitive risk to young patients, Dr. Rappaport said. The findings also could spur pharmaceutical firms to develop “better products,” or agents that counteract the brain effects of anesthetics, should such effects be proven to exist, he said.

Studies in animals have suggested that volatile anesthetics may be harmful to neurons in the brain. No data in humans have directly demonstrated such a link. However, several recent studies have hinted at a connection between exposure to anesthesia in early childhood and cognitive and behavioral problems in later life.

In a retrospective study published in the April issue of Anesthesiology, for example, Mayo Clinic researchers reported an association between repeated, although not single, exposures to anesthesia before age 4 and subsequent development of learning disabilities.

The researchers found that two exposures to anesthetics before age 4 raised by 50% the likelihood of being identified as having learning disabilities—in reading, writing and math—by age 19. Three or more exposures raised the risk for learning problems 2.6-fold. Exposure times under two hours did not appear to be linked to learning difficulties, the researchers said.

That makes sense in light of new evidence in animals, particularly primates, said Randall Flick, MD, chair of pediatric anesthesia at Mayo Clinic in Rochester, Minn., and a co-author of the study. “The increasing animal data suggests that the exposure times have to be longer than we thought before, and that the children have to be younger,” Dr. Flick said. “The more data we gather, the more refined the question becomes.”

Until more data become available, however, anesthesiologists will have to deal with a groundswell of public anxiety about the risks of anesthesia in children—fueled by coverage of the issue in the popular press, said Gregory Crosby, MD, president-elect of the Society of Neurosurgical Anesthesia and Critical Care.

“I think studying outcomes is the right thing to do, but I’m amazed, frankly, at how quickly this thing caught on fire. It’s consuming people,” said Dr. Crosby, associate professor of anesthesia at Brigham and Women’s Hospital and Harvard Medical School, in Boston. “After all, what we have is a smoking gun but no victim. In the setting of surgical illness, clinical outcome studies will be hard-pressed to assign any adverse effect to anesthesia itself. Also, given the incredible plasticity and capacity for recovery of the developing brain, I’m a little concerned that the hype is overblown and that patients, parents and physicians will get scared unnecessarily.”

Hearing Triggered Program

The possible tie between general anesthesia and cognitive damage has been suggested for more than a decade, starting with a seminal 1999 study in Science showing that rat pups exposed to N-methyl-d-aspartic acid (NMDA) antagonists produced neuronal cell death through apoptosis. Those findings prompted the FDA to form an expert working group and to sponsor studies to evaluate the potential neurotoxic effects of NMDA antagonists, such as ketamine, on the developing brain.

In March 2007, the FDA’s Anesthesia and Life-Support Drugs advisory committee held the first official and public inquiry into the relationship, which, if proved, has enormous consequences for patients and clinicians alike.

SAFEKIDS, which grew out of that hearing, initially was supported by $1.5 million from unspent Congressional appropriations, Dr. Rappaport said. Because the government cannot solicit funding, the FDA will leave that step to other members of the group. Fundraising should begin in earnest over the next six to 12 months, he said. In the meantime, the search is on for members of both scientific and governance committees, as well as for a prominent figurehead who can assist in attracting large donations to the effort.

The FDA last August notified anesthesia researchers that it would be organizing four projects related to SAFEKIDS. These included finding an administrative partner for the initiative, which turned out to be IARS; and funding several studies, with grants of up to $308,000, on the long-term neurotoxicity of anesthetics, the pharmacodynamics and pharmacokinetics of these drugs and animal research into the issue.

Michael K. Cahalan, MD, chair of anesthesiology at the University of Utah School of Medicine, in Salt Lake City, and the IARS liaison to SAFEKIDS, said the FDA chose his society as a partner for its international membership and its “apolitical” nature.

IARS will be primarily responsible for raising the money for SAFEKIDS and for distributing the funds “based on the priorities of the [project’s] scientific advisory board,” Dr. Cahalan said. The society is not planning to raise the dues of its 15,000 members to pay for the research, he added.

Tom Cooper, executive director of IARS, said the group has received $99,000 from FDA and has committed $50,000 of its own resources for the first 18 months of the project. The research group does not have a total budget in mind, however. “IARS is making a long-term commitment to the success of the SAFEKIDS initiative,” Mr. Cooper said.

Given the shaky economy, Dr. Cahalan acknowledged, SAFEKIDS may be forced to do more with less. “It’s a tough time to raise money. There are lots of other good causes.”

The FDA has been working with Mayo Clinic investigators on a follow-up to the recently published research. Dr. Flick said the second Minnesota study will be a matched-cohort design in which each child exposed to anesthesia before his or her second birthday will be matched with two others who did not undergo surgery. The study will be completed by mid-summer, he said, with data ready for publication in the fall.

Compounding the issue, Dr. Flick said, will be trying to tease apart the effects of anesthesia from those of surgery itself. “We never do surgery without anesthesia and we rarely do anesthesia without surgery. To be able to differentiate those two things is likely to be very difficult.”

In an attempt to address that problem, the FDA is collaborating with Harvard researchers on the GAS trial, a randomized controlled comparison of the effects on cognitive development of general and regional anesthesia.

Investigators in the multicenter GAS study, which aims to enroll 660 healthy newborns undergoing inguinal hernia repair (some with circumcision), will test participants for neurodevelopment at age 2 and for intelligence at age 5.

Mary Ellen McCann, MD, MPH, assistant professor of anesthesia at Harvard Medical School and at Children’s Hospital Boston, said the prospective nature of GAS makes it stronger than previous efforts to assess the effects of anesthesia on early childhood development. A weakness, however, is the relatively short duration of anesthesia—no more than two hours. “It won’t answer the question of how prolonged anesthesia affects young children,” Dr. McCann said.

Although several other hospitals in the United States have expressed interest in joining the study, so far only Children’s Hospital Boston has begun enrolling patients in this country, as have institutions in Australia, Italy, Canada and the United Kingdom.

Every child in GAS will receive a standardized anesthetic. For general, the protocol is sevoflurane, air and oxygen, with the possible addition of a caudal anesthetic or field block. Patients may be given a neuromuscular blocker but do not receive opioids during the case, although they may receive them or other drugs in the PACU. For regional, the protocol is caudal or spinal anesthetic or both, continuous bupivacaine, or a regional block with bupivacaine. Whatever the choice, the total dose administered should not exceed 2.5 mg/kg.

Researchers already have begun the developmental testing on the first cohort of children enrolled in GAS. “The study will continue unless it is determined partway through the trial that one anesthetic is preferable to another,” Dr. McCann said. “Our hypothesis is that both types lead to equivalent outcomes.”

Dr. McCann said she would be “surprised” to find a difference between anesthetic regimens and developmental outcomes. “It’s a remote possibility, and that is why we are doing the study,” she said. “If both types of anesthesia prove to be the same in terms of development, then we can reassure parents that short general anesthetics are safe for even very young children.”

Dr. Cahalan said even a randomized trial comparing general with regional anesthesia was unlikely to control adequately for all the variables in the surgical experience. “Imagine that it’s not just an effect of anesthesia but a combination of certain amounts of stress and agents” that leads to brain damage, he said. “Just testing regional versus general will not be able to show that.”

What’s more, regional anesthesia typically is not used by itself for the surgical procedures that are most common in neonates and young children, Dr. Cahalan said. “It’s pretty hard to give a child just a regional anesthetic alone for the kinds of surgery infants receive.”

A Decade Later, More Questions Than Answers

Even before the announcement of SAFEKIDS and the release of the latest data on learning disabilities, many anesthesiologists had been advising parents to postpone elective surgeries in very young children. But that precaution is not necessarily the safest step. Although delaying some surgeries might make sense, Dr. Flick said, for others, such as myringotomy to open ear tubes, waiting even a few months could be more harmful to the acquisition of language skills than any possible damage anesthesia might cause. “We have to be careful of the unintended consequences,” he said.

Experts generally agree that the populations considered to be at highest risk for anesthesia-related cognitive problems are developing neonates and elderly patients.

In addition to the latest Mayo Clinic data, recent observational studies presented at the 2008 annual meeting of the American Society of Anesthesiologists found hints of a problem. One study found that children undergoing hernia repair were twice as likely as those who had no surgeries to end up with diagnoses of developmental and behavioral disorders. In another, Dutch children who underwent urologic procedures showed a trend linking anesthesia exposure to cognitive problems.

Animal data indicate that anesthetics may affect brain cells in three ways, said Dr. Crosby, who has studied the issue extensively in the elderly. The drugs may disrupt the proper formation of synapses in developing neurons, which could explain the learning problems observed in young rodents exposed to general anesthesia. Anesthetic agents also have been shown to induce programmed cell death in neurons, another possible driver of stunted learning. The studies to date confirm that NMDA antagonists and GABAergic agents induce neuroapoptosis in developing rodent and primate brains.

Some evidence also has linked exposure to general anesthesia with potentially deleterious changes in the brain protein amyloid-β, thus implicating anesthetics in either the development or acceleration of Alzheimer’s disease. These studies, performed mainly in cell culture, have found that certain general anesthetics promote particularly “sticky” amyloid-β molecules and increase production of the substance.

To Dr. Crosby, the studies make a fairly compelling case. “In my heart, I believe that general anesthetics can harm the brain if you are very young or old; but if this effect exists, it’s going to be quite subtle,” he said. “It’s quite possible that it could have been missed for decades or a century, and that unless you go looking for it, you’re not going to see it. But we shouldn’t be too quick to take the blame—illness and surgery aren’t nontoxic either.”

Suggested Reading

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2. Culley DJ, Yukhananov RY, Baxter MG, Crosby G. Long-term impairment of acquisition of a spatial memory task following isoflurane-nitrous oxide anesthesia in rats. Anesthesiology. 2004;100:309-314.
3. Eckenhoff RG, Johansson JS, Wei H, et al. Inhaled anesthetic enhancement of amyloid-beta oligomerization and cytotoxicity. Anesthesiology. 2004;101:703-709.
4. Ikonomidou C, Bosch F, Miksa M, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science. 1999;283:70-74.
5. Jevtovic-Todorovic V 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.
6. Mellon RD, Simone AF, Rappaport BA. Use of anesthetic agents in neonates and young children. Anesth Analg. 2007;104:509-520.
7. Planel E, Richter KE, Nolan CE, et al. Anesthesia leads to tau hyperphosphorylation through inhibition of phosphatase activity by hypothermia. J Neurosci. 2007;27:3090-3097.
8. Wilder R, Flick R, Sprung J, et al. Early exposure to anesthesia and learning disabilities in a population-based cohort. Anesthesiology. 2009;110. E-pub ahead of print.
9. Xie Z, Dong Y, Maeda U, et al. The common inhalation anesthetic isoflurane induces apoptosis and increases amyloid beta protein levels. Anesthesiology. 2006;104:988-994.
10. Xie Z, Dong Y, Maeda U, et al. The inhalation anesthetic isoflurane induces a vicious cycle of apoptosis and Aβ accumulation. J Neurosci. 2007;27:1247-1254.