Balancing Paediatric Anaesthesia
Balancing Paediatric Anaesthesia
Logistical and ethical reasons make conducting clinical research in paediatric practice difficult, and therefore safe and efficacious advances are dependent on good preclinical research. For example, notable advances have been made in preclinical studies of pain processing that correlate well with patient data. Other areas of paediatric anaesthetic research remain in their infancy including mechanisms of anaesthesia and anaesthetic neuroprotection and neurotoxicity. Animal data have identified the potential 'double-edged' sword of administering anaesthetic agents in the young; although these agents can be neuroprotective in certain circumstances, they can be neurotoxic in others. The potential for this toxicity must be balanced against the importance of providing adequate anaesthesia for which there can be no compromise. We review the current state of preclinical research in paediatric anaesthesia and identify areas which require further exploration in order to provide the foundations for well-conducted clinical trials.
The deleterious effects of insufficient anaesthesia and analgesia in children were highlighted 20 yr ago. Since then clinical and preclinical studies have demonstrated the importance of providing adequate analgesia to the young. However, we are now faced with a potentially even more vexing problem; animal research suggests anaesthetic agents may be neurotoxic to the developing nervous system leaving the clinician with a dilemma of how much anaesthesia or analgesia to provide. Unfortunately, for commonly used agents, such as isoflurane, the neurotoxic burden correlates with the depth of anaesthesia. A further apparent paradox is the ability for anaesthetic agents to protect the brain in pathological situations such as hypoxia-ischaemia yet also be inherently toxic. It is clear that these factors, although intertwined, may be difficult to balance. We have sought to review the current literature analysing the importance of providing adequate analgesia, hypnosis, and anaesthesia in children balanced against the potential to induce neurotoxicity in the brain. A second conundrum existing between the neuroprotective and neurotoxic actions of anaesthetics is also explored.
An important, early caveat to introduce is the difficulty in extrapolating findings from the developing nervous systems of animals to humans. It is clear that direct extrapolation of rodent developmental data (an altrical species) to humans (a precocial species) may be confounded. The understanding of neurodevelopmentally equivalent ages across species is similarly controversial. Much of the work described here has utilized 7-day-old neonatal rat pups, but the exact equivalent age in the human remains a source of discussion with estimates ranging from preterm to 1-2 yr post-term in humans based on neuro-anatomical and neuro-physiological research. This is consistent with resistance to minimum alveolar concentration (MAC) of anaesthetic which peaks in the first year of human life and at 9 days in rats (7-day-old data are not available); thus we believe the rat data could model anaesthetic effects in the first year of human life. Unfortunately, we cannot be more precise than this estimate at present. A conservative approach is therefore recommended. Hasty extrapolation of any findings to humans would be inadvisable, but inappropriate dismissal of the preclinical findings could prove more detrimental. Rodent data should form the foundation for future studies involving anaesthetic regimens in non-human primates or clinical studies (where appropriate) to inform us about the potential vulnerability of the developing human nervous system. Until we understand the consequences of these findings, in these latter models, we should remain cognizant of the potential effects of our pharmacopoeia on development.
Notwithstanding these concerns, preclinical data have explained much about the developing human and will continue to be a test-ground for future clinical exploitation. Rather than be daunted by the difficulties in applying preclinical research, we should be buoyed by the advances made to date and continue to explore possible preclinical solutions to clinical problems.
Abstract and Introduction
Abstract
Logistical and ethical reasons make conducting clinical research in paediatric practice difficult, and therefore safe and efficacious advances are dependent on good preclinical research. For example, notable advances have been made in preclinical studies of pain processing that correlate well with patient data. Other areas of paediatric anaesthetic research remain in their infancy including mechanisms of anaesthesia and anaesthetic neuroprotection and neurotoxicity. Animal data have identified the potential 'double-edged' sword of administering anaesthetic agents in the young; although these agents can be neuroprotective in certain circumstances, they can be neurotoxic in others. The potential for this toxicity must be balanced against the importance of providing adequate anaesthesia for which there can be no compromise. We review the current state of preclinical research in paediatric anaesthesia and identify areas which require further exploration in order to provide the foundations for well-conducted clinical trials.
Introduction
The deleterious effects of insufficient anaesthesia and analgesia in children were highlighted 20 yr ago. Since then clinical and preclinical studies have demonstrated the importance of providing adequate analgesia to the young. However, we are now faced with a potentially even more vexing problem; animal research suggests anaesthetic agents may be neurotoxic to the developing nervous system leaving the clinician with a dilemma of how much anaesthesia or analgesia to provide. Unfortunately, for commonly used agents, such as isoflurane, the neurotoxic burden correlates with the depth of anaesthesia. A further apparent paradox is the ability for anaesthetic agents to protect the brain in pathological situations such as hypoxia-ischaemia yet also be inherently toxic. It is clear that these factors, although intertwined, may be difficult to balance. We have sought to review the current literature analysing the importance of providing adequate analgesia, hypnosis, and anaesthesia in children balanced against the potential to induce neurotoxicity in the brain. A second conundrum existing between the neuroprotective and neurotoxic actions of anaesthetics is also explored.
An important, early caveat to introduce is the difficulty in extrapolating findings from the developing nervous systems of animals to humans. It is clear that direct extrapolation of rodent developmental data (an altrical species) to humans (a precocial species) may be confounded. The understanding of neurodevelopmentally equivalent ages across species is similarly controversial. Much of the work described here has utilized 7-day-old neonatal rat pups, but the exact equivalent age in the human remains a source of discussion with estimates ranging from preterm to 1-2 yr post-term in humans based on neuro-anatomical and neuro-physiological research. This is consistent with resistance to minimum alveolar concentration (MAC) of anaesthetic which peaks in the first year of human life and at 9 days in rats (7-day-old data are not available); thus we believe the rat data could model anaesthetic effects in the first year of human life. Unfortunately, we cannot be more precise than this estimate at present. A conservative approach is therefore recommended. Hasty extrapolation of any findings to humans would be inadvisable, but inappropriate dismissal of the preclinical findings could prove more detrimental. Rodent data should form the foundation for future studies involving anaesthetic regimens in non-human primates or clinical studies (where appropriate) to inform us about the potential vulnerability of the developing human nervous system. Until we understand the consequences of these findings, in these latter models, we should remain cognizant of the potential effects of our pharmacopoeia on development.
Notwithstanding these concerns, preclinical data have explained much about the developing human and will continue to be a test-ground for future clinical exploitation. Rather than be daunted by the difficulties in applying preclinical research, we should be buoyed by the advances made to date and continue to explore possible preclinical solutions to clinical problems.
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