“They show convincing evidence that general anesthetics per se, even at irrelevantly high concentrations, are insufficient to blunt cortical experience to noxious stimuli in the immature brain.”
ADVERSE experiences during the perinatal period are associated with altered pain sensitivity and long-term behavioral sequels, including significant emotional problems during childhood and major psychotic episodes, anxiety, depression, and suicides in adolescence or adulthood.1 Exposure to painful stimuli is one major cause of these harmful incidents, especially in preterm neonates undergoing a large number of invasive procedures during their early postnatal period.2 Because these premature infants possess extremely immature physiologic and neurobehavioral systems, painful experiences induce long-term impairments and increased noxious stimuli-induced neuronal activity in the central sensory processing and might also affect the development of brain areas involved in higher order cognitive and emotional functions.1–3
Little is known about whether and to what extent general anesthetics blunt the impact of painful stimuli on developing neuronal networks. Indeed, because exposure to these drugs leads to dose-dependent suppression of neuronal activity patterns in the central nervous system, an intriguing hypothesis would be that general anesthetics alleviate the effects of noxious inputs on immature circuitry and, thereby, attenuate long-term consequences of painful experiences. In this issue of Anesthesiology, Chang et al.4 provide compelling evidence against this possibility. The authors performed intracortical recordings of both spontaneous and noxious-evoked cortical activity from the somatosensory cortex of young rats in the presence of increasing concentrations of isoflurane at distinct stages of the brain growth spurt. In 7-day-old (P7) animals, they first show that isoflurane induces silencing of the spontaneous cortical activity in concentrations as low as 1.5%. In contrast, noxious-evoked potentials are still detectable at isoflurane concentrations up to 5% in this same age group, and, importantly, the resistance of pain-triggered cortical signals to isoflurane was further enhanced after surgical incision before noxious stimuli. In marked contrast with observations made in P7 pups, painful stimuli-related increase in neuronal activity in the cerebral cortex shows greater sensitivity to increasing concentrations of isoflurane in older (P14 to P30) animals. Indeed, by P30, electrical-evoked nociceptive potentials are completely suppressed by 5% of isoflurane both in the presence and in the absence of skin incision, thereby suggesting that the differential effects of isoflurane on spontaneous and noxious-evoked potentials are developmental stage dependent and specifically restricted to early postnatal life in these animals.
These important new data have fundamental, translational, and clinical interest. They provide us with important new insights into the developmental stage–dependent differential processing of spontaneous and pain-evoked activity in the immature cerebral cortex. Although the detailed mechanisms underlying qualitative and quantitative differences in cortical responses to noxious stimuli between early and later stages of the brain growth spurt remain to be elucidated, accumulating experimental data suggest that it might be linked to the transition from nonspecific neuronal bursts to more localized activity patterns in cortical networks after sensory experience.5 These major changes in signaling modalities are correlated with the maturation of GABAergic interneurons, which, in turn, will contribute to specifically compartmentalize noxious-activated neuronal networks via contact inhibition. Indeed, the functional transition of GABAergic neurotransmission from excitatory toward inhibitory modalities, mediated primarily via the up-regulation of the cation chloride cotransporter KCC2, coincides with the changes in the processing of painful experiences during early life. A steep increase in KCC2 expression takes place during the second postnatal week in the rodent cerebral cortex, and a similar process commences during the third trimester of gestation in humans.6 If there is indeed a causal link between the developmental increase of KCC2 expression, and thereby the functional maturation of GABAergic neurotransmission, and the changes in the cortical processing of painful stimuli remains to be determined. In this context, it is interesting to note that pathologic pain processing in adults is accompanied by abnormally low KCC2 levels in the spinal cord.6
The study by Chang et al. also provides us with important considerations regarding the field of experimental research on developmental anesthesia neurotoxicity. In fact, the majority of laboratory studies devoted to study the relationship between exposure to anesthetics and neuronal development have been conducted in the absence of surgery. Therefore, it is currently unknown whether anesthetics-induced changes in developing neuronal networks can be modified, in one way or another, by concomitant surgical stimuli-triggered painful experience.7 This study convincingly demonstrates peripheral noxious stimulus–evoked increases of neuronal activity in the cerebral cortex at early stages of the brain growth spurt even in the presence of isoflurane anesthesia. From a pathophysiologic standpoint, this means that adding painful stimuli, represented by surgery, to the anesthesia protocols will further modify neuronal activity patterns, and thereby homeostasis, in the cerebral cortex of these young animals. The consequences of this added complexity remain to be determined, because evaluation of morphofunctional parameters and neurocognitive outcome was out of scope of the current work. Although peripheral-evoked noxious stimuli could further worsen the impact of general anesthetics on the developing brain, one could, in contrast, also speculate that anesthesia might in fact protects against these aggressions. To bring these thoughts further, one intriguing possibility would be that the negative morphologic and behavioral impact of anesthetics-induced changes in neuronal activity patterns in early postnatal life could be counterbalanced by neuronal activity patterns induced by concomitant noxious stimuli. These as yet unanswered questions are of utmost importance and should be urgently put on the research agenda on the field.
Last but not least, data provided by Chang et al. have also potential clinical implications. As a matter of fact, although it is now generally accepted that appropriate pain management should be the mainstay of anesthesia practice, many neonates and young infants may not receive adequate analgesia during, or at some stages of, the perioperative period. Administration of sufficient amounts of opioids before endotracheal intubation after volatile-based mask induction in this fragile patient population is probably often missed, and some practitioners still consider the need for administration of opioids based on the absence or presence of movements in children under volatile-based anesthesia. The idea behind this practice probably stems from the fact that exposure to anesthetics can reduce somatosensory information processing in the spinal cord, which, indirectly, would lead to decreased or absent noxious-evoked activity in higher order structures of the central nervous system. This study provides compelling evidence that “the level of cortical-evoked activity cannot be inferred from the presence or absence of a visible reflex response.” The fact that noxious-evoked cortical activity in younger animals showed increased resistance to isoflurane suggest that younger patient populations might be more sensitive to painful stimuli during anesthesia and surgery. In this context, one should also actively consider the more extensive use of regional anesthesia because recent experimental observations suggest that peripheral nerve blockades reduce the impact of incoming nociceptive inputs on higher order brain structures in the early postnatal period.8 Although it is very difficult to extrapolate developmental stages between rodents and humans, correlative neuroanatomical observations suggest that, in terms of cortical development, P7 rat pups represent the early third trimester of pregnancy and P14 might correspond to term birth and the first few postnatal years, whereas P30 depicts adolescence in the human scale.9 Therefore, data presented herein suggest that the most vulnerable populations to surgical stimuli-evoked changes in cortical neuronal network homeostasis under general anesthesia are premature infants and that the capacity of general anesthetics to blunt noxious-evoked processing in the cerebral cortex increases by age. The clinical relevance of these observations in terms of analgesics needs remain to be determined. Indeed, no opioids or other analgesics were coadministered with isoflurane in this study. Hence, the question whether and to what extent these drugs could alter painful stimuli-induced developmental stage–dependent cortical information processing in the wide range of pediatric patient populations remains open. Whatever the answers are to these questions of high complexity, the experiments presented by Chang et al. represent landmark observations regarding the impact of painful stimuli on the immature cerebral cortex under general anesthesia. They show convincing evidence that general anesthetics per se, even at irrelevantly high concentrations, are insufficient to blunt cortical experience to noxious stimuli in the immature brain. Therefore, this study should be considered as an important step in our quest to understand the impact of surgical aggression on the young brain.
The author is not supported by, nor maintains any financial interest in, any commercial activity that may be associated with the topic of this article.