SmartTots: Quo Vadis?

Few if any issues received more attention in the field of pediatric perioperative care over the past decade than developmental anesthesia neurotoxicity. While the possibility of a plausible association between anesthesia and postoperative personality changes in children was first hypothesized more than 60 years ago,¹ substantial concern on this subject has been ignited by seminal laboratory work, conducted 50 years later, where exposure of newborn rats to a mixture of anesthetics induced widespread apoptosis and persistent cognitive deficits in these animals.² The initial mistrust and rejection generated by this publication in the anesthesia community have been rapidly transformed into an important public health concern after the robust confirmation of developmental anesthesia neurotoxicity in a variety of experimental models and, most importantly, with the availability of human epidemiological data suggesting an association between early life anesthesia exposure and subsequent neurocognitive disturbances.³

To foster both preclinical and clinical research regarding the impact of general anesthesia on the developing brain, the International Anesthesia Research Society together with the US Food Drug Administration has launched a collaborative effort in March 2010. This initiative, called SmartTots (www.smarttots.org), is aimed to make anesthesia safer for pediatric populations and currently serves as a major driving force behind investigations in the field of developmental anesthesia neurotoxicity. In this issue of the Journal, Orser et al⁴ provide us with an important update on SmartTots-related research activities over the past few years. Based on the critical appraisal of rapidly accumulating data about the effects of anesthesia in the immature central nervous system, the authors identify a series of as yet unanswered questions which, in turn, may dictate future research directions in this domain. They also overtly discuss the persistent controversy that divides the clinical community despite more than a decade of intense investigations on the clinical relevance of anesthesia drug toxicity.

Defining roadmaps is a critical component of a successful research agenda. While all experts and caregivers agree that anesthesia in infants and young children may be associated with increased neuromorbidity, there is a substantial dissonance as to the potential reasons behind this possibility. This lack of consensus on identifying the most important questions and, thereby, to set a straightforward research agenda, can easily be explained by the high number and by the vast complexity of events characterizing the perioperative period. Indeed, there are at least 3 major pathways that can lead to neural injury in this context. First, we should consider the potential impact of surgery-triggered neuroinflammatory pathways on the developing nervous system.⁵ Second, rapid and important changes in systemic homeostasis during anesthesia management can also trigger injury.⁶ Third, there is the biological plausibility, backed with the aforementioned strong laboratory evidence, that anesthetics themselves, as powerful modulators of neural activity, may also interfere with physiological patterns of brain development.³ On top of these 3 distinct albeit strongly intertwined pathways, we should not underestimate the well-established role of negative emotional experience, often associated with the perioperative period, on neurocognitive outcome.⁷ At present, we do not know which of these events may play the most important role in neuromorbidity and neither we know how these factors interact with each other to influence neurocognitive outcome.

After the successful debuts of SmartTots, the European Society of Anaesthesiology has launched the European Safe Tots Anaesthesia Research consortium in September 2012 with the primary aim to address the emerging issue of developmental anesthetic neurotoxicity and later impairment of higher brain functions. In this framework, a group of highly dedicated physician-scientists along with basic science researchers have conducted numerous fruitful discussions on this issue. During these brainstorming meetings, it has become extremely clear that the Consortium should not merely focus on the effects of anesthetic drugs but should identify relevant questions related to pediatric perioperative care and its impact on neurocognitive outcome. This approach goes in line with the roadmap proposed by Orser et al,⁴ recommending that “the overall research approach needs to be iterative and nuanced.”

Accordingly, 1 big elephant in the room is the current discrepancy between the scientific questions addressed by laboratory and clinical trials. While laboratory investigations, in line with the aims described on the SmartTots website, focus on “drug type, dosage, and number of exposures” to determine if particular anesthetic drugs pose hazards to young children, clinical trials do not directly address such issues. Rather, they give us information on how the perioperative period, in its inherent complexity, influences outcome. Therefore, if we assume that “data from preclinical studies are essential to inform both the need and optimal design of clinical trials,” there is an urgent need to perform preclinical studies with translational relevance to the clinical situation. Indeed, most experimental studies in the field of developmental anesthesia neurotoxicity have so far been performed in the absence of surgery. Living organisms are not neat orderly systems that can be simply defined and evaluated using reductive methodologies but rather function as irregular, dynamic, and idiosyncratic entities. Therefore, one cannot accurately predict how anesthetics would affect brain development when applied in the presence of a concomitant surgical stimulus because the interaction of these 2 factors could give rise to an emergent property that may not simply deduced from the 2 distinct components. This fact by no means stipulates that experiments on drug issues alone are meaningless. Indeed, they provide us with important information on the mechanisms through which a given drug can influence brain development. Reductionist and holistic approaches are interdependent and complimentary to make sense of a complex phenomenon.

The other big elephant in the room is the lack of an easily identifiable and clinically relevant phenotype associated with early life anesthesia exposure. As Orser et al⁴ note, “the concerns about possible neurotoxic effects of anesthetic drugs on the developing brain sprang from the results of preclinical studies.” This approach, where laboratory research motivates the search for a clinical problem, differs from the usual flow of translational research where a clinical problem guides laboratory research. The evident first hand consequence of this paradox is the difficulty of efficacious fundraising when compared to other domains of medicine such as cardiology, neurology, or oncology. Another important concern goes to the planning of clinical trials. In the absence of a phenotype (or phenotypes), it is in fact hard to define a clinically relevant primary end point. Moreover, in light of the GAS and PANDA studies as well as based on indications from laboratory data, we should probably focus on (much) longer anesthesia exposures. Easy to say but difficult to do. Most young “healthy” children usually undergo short interventions while those few in need for prolonged anesthesia and surgery during early life usually present with significant comorbidities. It should also be remembered that minor differences in executive function that could impact everyday life may not be detected before 10–15 years of age. Putting the ensemble of these major challenges together, successful planning and execution of clinical trials addressing neuroprotective strategies and/or comparing the toxicity profile of different drug regimens will be, at best, very difficult.

So, where are we going? Asking the right questions takes usually as much skill as giving the right answer. The ever-increasing quantity of basic science observations provides strong biological foundations for a possible interference of general anesthetics with the physiological patterns of brain development. How this may translate into clinical relevance remains unclear. Based on the so far available evidence, it is unlikely that we are facing a major public health issue. Diving into big data in fact suggests a statistically significant minimal impact of the perioperative period on neurocognitive outcome but it should be remembered that the impact is several orders of magnitude less than the effect of other factors, such as date of birth, gender, or parental socioeconomic status.⁸ Should we thus stop investigating developmental anesthesia neurotoxicity? The answer is of course a definite no. The lack of our current ability to specifically spot the impact of anesthetics on the developing human brain does not mean that these drugs do not induce subtler but functionally important changes in cognitive and executive function later in life. Neither can we exclude the increased vulnerability of a specific patient population and the fact that some specific conditions during the perioperative period could increase the impact of general anesthetics on brain development. We should therefore actively advocate for the need to study developmental anesthesia neurotoxicity. However, in the absence of decent scientific arguments, arbitrary setting of an age-specific cutoff to warn the public about the potentially harmful effects of “repeated or lengthy use of general anesthetics” will not help to achieve this, and can even contribute to further divide both the scientific and the clinical communities on this issue. Indeed, while the initial 2012 SmartTots consensus statement on the use of anesthetics and sedatives in children has been unanimously endorsed by most major anesthesia societies, many of these organizations openly expressed important concerns about the recent Food Drug Administration drug safety communication regarding the use of general anesthetic and sedation medicines in children <3 years.⁹ Fortunately, there is still a definite convergence of opinions between different actors and stakeholders on the fact that further research is needed in this domain. There are many important remaining questions in the field of developmental anesthesia neurotoxicity and they are not mutually exclusive. Understanding how neurocognitive outcome is driven by the interaction among drug exposure, surgery, and the changing patterns of homeostasis will need the active involvement of the entire anesthesia community. Ultimately, this joint effort will fulfill the objective fixed by SmartTots that is to make anesthesia safer for infants and children.

DISCLOSURES

Name: Laszlo Vutskits, MD, PhD.

Contribution: This author wrote the manuscript.

This manuscript was handled by: Jean-Francois Pittet, MD.