There has been accumulating evidence of the potential risks of anaesthetic agents, such as risks of enhanced apoptosis in animal models and long-term functional effects in  those various animal models also. All anaesthetic agents appear to be affected, which I guess should not be too much of a surprise. A molecule which is capable of making you comatose for a short time presumably has an effect on the brain!

Whether these impacts cause lasting damage in humans has been very difficult to ascertain. How would you do a prospective RCT with and without anaesthesia? Long term evaluations of the subjects in such a study would be very difficult and expensive. And yet such a study has been done, the GAS trial randomized young infants to sevoflurane inhalation in one arm, and awake regional anaesthesia (which was either a spinal or a caudal) with bupivacaine in the other. They included over 700 infants of less than 60 weeks post-menstrual age who were having hernia repairs. Many of the children (about 55%) were of course premature babies, which is why the entry criterion of 60 weeks PMA was chosen, which works out to a corrected age of up to 4 months. They included babies down to 26 weeks gestation at birth. 70 of the babies in the awake regional anesthesia group had to instead have a general anesthetic; the paper does not state why this was the case, but either technical failure or need for sedation are not uncommon in kids of this age. The authors analyzed by treatment actually received (per protocol analysis) and also secondarily by intention to treat, which I think when looking for toxicity is the appropriate type of analysis.

This report (Davidson AJ, et al. Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial. The Lancet. 2016;387(10015):239-50.) is actually a report fo the secondary outcomes of the trial, the primary outcome will be 5 year IQ testing.

This follow-up published so far, to 2 years of age, shows no difference between the groups in the GAS trial. Interestingly the composite scores on the Bayley 3 scales of infant development all average a bit below 100, whereas in general in the population they are above 100 because of the way the scales were normalized. The actual scores reported, in both groups, are quite similar to the scores from very preterm children reported by the Victoria group in Australia, who were all less than 30 weeks gestation. The lack of difference between groups in the GAS trial might mean that sevoflurane given for an average of about 50 minutes is safe, or that regional anesthesia, with bupivacaine, is equally as toxic! There is actually some evidence of bupivacaine neurotoxicity, but there should be very little reaching the central nervous system, so I don’t think that is likely to be the explanation of the lowish scores in both groups. Perhaps all of the risks that increase the rate of having an inguinal hernia also are associated with slightly lower Bayley 3 scores at 2 years, or just the stress of having a surgery. About 14% of the babies in the study had to have at least one other anaesthetic, and over 30% had to be hospitalised for something else. These extra risks for developmental effects were in both groups, which might reduce any impact of the anaesthetic approach, and might also account for the slightly low scores.

The only way to be absolutely sure would be to do an RCT of surgery with different anaesthetic approaches, and include a 3rd no surgery group. However, in general, surgery in early infancy is not optional. Apart from circumcision, aesthetic surgery is uncommon! Which brings me back to the new FDA warning. The results of observational studies of anaesthesia exposure and developmental outcomes are inconsistent, some showing adverse effects, and others. especially with short or single exposures, showing little or no impact. It isn’t clear to me what triggered the FDA to release its new warning, their last advisory committee meeting was in 2014, and I don’t know if there is anything much new since then, apart from the GAS trial which doesn’t show adverse effects.

The new warning starts like this:

The U.S. Food and Drug Administration (FDA) is warning that repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in children younger than 3 years or in pregnant women during their third trimester may affect the development of children’s brains.

I really don’t understand what the motivation of the FDA is to issue this warning, are they hoping that children will not have unnecessary prolonged or repeated surgery because of this warning, which they otherwise would have done? Why 3 years precisely? The observational studies have had varying entry criteria, and if the agents are toxic at 2 and a half years, they probably are at 3 and a half also. There also doesn’t actually appear to be any data about effects on the fetal brain, at least not in humans, and anaesthesia in pregnant women is never performed without a really good indication.

It is quite rare that a major surgery requiring prolonged anaesthesia can be delayed in a young infant, and when it can be delayed safely, that is already done. Maybe the FDA are trying to get more funding for their SmartTots initiative, which is an important initiative, but the burden this new warning places on anesthetists (American spelling for a mostly American impact) may be substantial. An editorial in the FPNEJM makes some of these same points, and also notes

At Texas Children’s Hospital, approximately 13,000 (anesthetics) involve patients under 3 years of age, and about 1300 of these patients undergo anesthesia for more than 3 hours; two thirds of these cases of prolonged anesthesia are for procedures related to congenital heart disease. Essentially all these prolonged procedures are for serious or life-threatening congenital conditions for which there are no alternative treatments and for which treatment cannot be delayed until the patient reaches 3 years of age. Approximately 1400 patients at Texas Children’s Hospital who are less than 3 years of age undergo two or more procedures requiring general anesthesia in any year, and 2000 undergo sedation or anesthesia for magnetic resonance imaging examinations. After deliberation among its leaders in anesthesiology, surgery, and hospital risk management, the hospital has changed its practice in response to the FDA warning. The FDA warning itself will now be discussed before surgery with parents of all children younger than 3 years of age who would be receiving an anesthetic. And the hospital has adopted the warning’s recommendation that a discussion occur among parents, surgeons and other physicians, and anesthesiologists about the duration of anesthesia, any plan for multiple general anesthetics for multiple procedures, and the possibility that the procedure could be delayed until after 3 years of age; parent-education materials will also cover these topics.

I have no problem with informing parents of possible risks, but when there is (as there usually is) no medically appropriate alternative to the surgery the many thousands of worrying discussions with the parents may not achieve much except increased anxiety.

Adding a discussion of possible, and unproven, long-term adverse effects of unknown severity and unknown importance for quality of life, to the discussions which are already taking place of risks of surgery, risks of intubation, other risks of anesthesia seems questionable.  There are many other potential, unproven, possible risks also.

Some procedures, especially in the preterm infant, are also often performed using high dose opiates, which in some animal models also cause apoptosis. These agents aren’t mentioned in the FDA warning, but we shouldn’t suppose that they are safe for the long term either.

Maybe the message should be, “don’t do surgery in young infants unless you need to” which I think we can all agree to.