Brain changes due to hypoxia during light anaesthesia can be prevented by deepening anaesthesia; a study in rats

PLOS ONE, Nov 2019

In anaesthetic practice the risk of cerebral ischemic/hypoxic damage is thought to be attenuated by deep anaesthesia. The rationale is that deeper anaesthesia reduces cerebral oxygen demand more than light anaesthesia, thereby increasing the tolerance to ischemia or hypoxia. However, evidence to support this is scarce. We thus investigated the influence of light versus deep anaesthesia on the responses of rat brains to a period of hypoxia. In the first experiment we exposed adult male Wistar rats to deep or light propofol anaesthesia and then performed [18F]- Fludeoxyglucose (FDG) Positron Emission Tomography (PET) scans to verify the extent of cerebral metabolic suppression. In subsequent experiments, rats were subjected to light/deep propofol anaesthesia and then exposed to a period of hypoxia or ongoing normoxia (n = 9–11 per group). A further 5 rats, not exposed to anaesthesia or hypoxia, served as controls. Four days later a Novel Object Recognition (NOR) test was performed to assess mood and cognition. After another 4 days, the animals were sacrificed for later immunohistochemical analyses of neurogenesis/neuroplasticity (Doublecortin; DCX), Brain Derived Neurotrophic Factor (BDNF) expression and neuroinflammation (Ionized calcium-binding adaptor protein-1; Iba-1) in hippocampal and piriform cortex slices. The hippocampi of rats subjected to hypoxia during light anaesthesia showed lower DCX positivity, and therefore lower neurogenesis, but higher BDNF levels and microglia hyper-ramification. Exploration was reduced, but no significant effect on NOR was observed. In the piriform cortex, higher DCX positivity was observed, associated with neuroplasticity. All these effects were attenuated by deep anaesthesia. Deepening anaesthesia attenuated the brain changes associated with hypoxia. Hypoxia during light anaesthesia had a prolonged effect on the brain, but no impairment in cognitive function was observed. Although reduced hippocampal neurogenesis may be considered unfavourable, higher BDNF expression, associated with microglia hyper-ramification may suggest activation of repair mechanisms. Increased neuroplasticity observed in the piriform cortex supports this, and might reflect a prolonged state of alertness rather than damage.

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Brain changes due to hypoxia during light anaesthesia can be prevented by deepening anaesthesia; a study in rats

February Brain changes due to hypoxia during light anaesthesia can be prevented by deepening anaesthesia; a study in rats Setayesh R. Tasbihgou 0 1 Mina Netkova 0 1 Alain F. Kalmar 0 1 Janine Doorduin 1 Michel M. R. F. Struys 0 1 Regien G. Schoemaker 1 Anthony R. Absalom 0 1 ☯ These authors contributed equally to this work. 1 Co-first authors. 1 1 0 Department of Anaesthesiology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands, 2 Department of Nuclear Medicine and Molecular Imaging, University of Groningen, Groningen, the Netherlands, 3 Department of Anaesthesia, Ghent University , Gent , Belgium , 4 Department of Molecular Neurobiology, GELIFES, University of Groningen , Groningen , the Netherlands 1 Editor: Giuseppe Biagini, University of Modena and Reggio Emilia , ITALY In anaesthetic practice the risk of cerebral ischemic/hypoxic damage is thought to be attenuated by deep anaesthesia. The rationale is that deeper anaesthesia reduces cerebral oxygen demand more than light anaesthesia, thereby increasing the tolerance to ischemia or hypoxia. However, evidence to support this is scarce. We thus investigated the influence of light versus deep anaesthesia on the responses of rat brains to a period of hypoxia. In the first experiment we exposed adult male Wistar rats to deep or light propofol anaesthesia and then performed [18F]- Fludeoxyglucose (FDG) Positron Emission Tomography (PET) scans to verify the extent of cerebral metabolic suppression. In subsequent experiments, rats were subjected to light/ deep propofol anaesthesia and then exposed to a period of hypoxia or ongoing normoxia (n = 9±11 per group). A further 5 rats, not exposed to anaesthesia or hypoxia, served as controls. Four days later a Novel Object Recognition (NOR) test was performed to assess mood and cognition. After another 4 days, the animals were sacrificed for later immunohistochemical analyses of neurogenesis/neuroplasticity (Doublecortin; DCX), Brain Derived Neurotrophic Factor (BDNF) expression and neuroinflammation (Ionized calcium-binding adaptor protein-1; Iba-1) in hippocampal and piriform cortex slices. The hippocampi of rats subjected to hypoxia during light anaesthesia showed lower DCX positivity, and therefore lower neurogenesis, but higher BDNF levels and microglia hyper-ramification. Exploration was reduced, but no significant effect on NOR was observed. In the piriform cortex, higher DCX positivity was observed, associated with neuroplasticity. All these effects were attenuated by deep anaesthesia. Deepening anaesthesia attenuated the brain changes associated with hypoxia. Hypoxia during light anaesthesia had a prolonged effect on the brain, but no impairment in cognitive function was observed. Although reduced hippocampal neurogenesis may be considered unfavourable, higher BDNF expression, associated with microglia hyper-ramification may suggest activation of repair mechanisms. Increased neuroplasticity observed in the piriform cortex supports this, and might reflect a prolonged state of alertness rather than damage. - Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: The study qualified for the Young Investigator Grant from the Dutch association of anaesthesiology (Nederlandse verenining voor anesthesiologie http://www.anesthesiologie.nl/ wetenschap/yong-investigator-grant) to AFK. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Introduction The aim of anaesthesia is to render the patient unconscious, and thus insensible to the pain and suffering of surgery, and thereafter ensure a safe and complication free recovery. Different anaesthetists apply different strategies in an attempt to optimize safety and to optimize the quality of recovery from anaesthesia and surgery. Some aim for lighter anaesthesia, by administering lower doses of the anaesthetic drugs, since lighter doses are associated with fewer hemodynamic adverse effects, such as hypotension, and a more rapid recovery of consciousness once drug administration is stopped. Furthermore, some anaesthetists might opt for lighter anaesthesia because of recent evidence that the anaesthetic agents have neurotoxic effects (particularly in the brains of the very young and the elderly) and because of controversial evidence suggesting that deeper anaesthesia is associated with a worse 1 year mortality rate [1±3]. Light anaesthesia however is associated with a risk of inadvertent return of consciousness during supposed anaesthesia, which is a feared complication of anaesthesia [ 4 ]. To avoid this problem of `awareness' anaesthetists commonly administer deeper anaesthesia. Many anaesthetists consider that anaesthetic exposure has no long-term consequences for the brain, and indeed there is evidence that anaesthesia might be neuroprotective [ 3 ]. Systemic hypotension is common during (...truncated)


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Setayesh R. Tasbihgou, Mina Netkova, Alain F. Kalmar, Janine Doorduin, Michel M. R. F. Struys, Regien G. Schoemaker, Anthony R. Absalom. Brain changes due to hypoxia during light anaesthesia can be prevented by deepening anaesthesia; a study in rats, PLOS ONE, 2018, Volume 13, Issue 2, DOI: 10.1371/journal.pone.0193062