Anaesthetic Preconditioning; The Role of ATP-Sensitive K+ Channels

Stroke in general but especially in the postoperative period is a serious clinical problem that warrants new therapeutic approaches. Here neuroprotective strategies and especially preconditioning have recently emerged as promising. Preconditioning was originally demonstrated in the heart but was subsequently also found in other organs. Classically it describes a phenomenon where short periods of ischaemia render tissues less vulnerable to major infarcts. In addition to ischaemia neuronal preconditioning can be achieved pharmacologically as well as through inhalational anaesthetics or drugs that open ATP-sensitive K+(KATP) channels. However, the mechanisms through which anaesthetics produce protection remain elusive and the use of K+ channel openers is hampered by their inability to cross the blood-brain-barrier. This study was conducted to investigate the effects of inhalational anaesthetics on KATP channels and to explore whether their neuronal preconditioning properties were dependent on KATP channel opening. First, in whole-cell and excised patchclamp experiments the effects of inhalational anaesthetics on recombinant wild type neuronal (Kir6.2/SUR1) KATP and related as well as modified channels were evaluated. Secondly, the KATP channel dependence of anaesthetic preconditioning was tested in neuronal-glial co-cultures. Recombinant KATP channels were activated by xenon, but inhibited by halogenated volatiles. Moreover, it was shown that xenon acted directly on the Kir6.2 pore-forming subunit, reduced the ability of ATP to inhibit the channel and had no effect on the ATP-regulated Kir1.1 channel. Functionally both sevoflurane and xenon preconditioned neurons at clinically used concentrations but only the effect of xenon was dependent on KATP channel activation. Thus this study established xenon as a novel KATP channel opener. It interacts with the pore-forming Kir6.2 rather than the regulatory sulphonylurea receptor subunit and disinhibits the channel from the blocking actions of ATP. As a consequence xenon but not sevoflurane is able to precondition neurons in a KATP channel-dependent manner

Chronic Pain and Chronic Opioid Use After Intensive Care Discharge – Is It Time to Change Practice?

Almost half of patients treated on intensive care unit (ICU) experience moderate to severe pain. Managing pain in the critically ill patient is challenging, as their pain is complex with multiple causes. Pharmacological treatment often focuses on opioids, and over a prolonged admission this can represent high cumulative doses which risk opioid dependence at discharge. Despite analgesia the incidence of chronic pain after treatment on ICU is high ranging from 33–73%. Measures need to be taken to prevent the transition from acute to chronic pain, whilst avoiding opioid overuse. This narrative review discusses preventive measures for the development of chronic pain in ICU patients. It considers a number of strategies that can be employed including non-opioid analgesics, regional analgesia, and non-pharmacological methods. We reason that individualized pain management plans should become the cornerstone for critically ill patients to facilitate physical and psychological well being after discharge from critical care and hospital

The Influence of Chronic Pain and Cognitive Function on Spatial-Numerical Processing

Chronic pain (CP) is linked to changes in cognitive function. However, little is known about its influence on number sense, despite the fact that intact numerical-spatial processing is a prerequisite for valid scale-based pain assessments. This study aimed to elucidate whether number sense is changed in CP, to determine if changes have an impact on pain assessments using pain rating scales and what patient factors might contribute. N = 42 CP patients and n = 42 matched controls were analyzed (age range: 33–68 years). Numerical-spatial abilities were investigated by using number line tasks, where participants either estimated the position of a given number (position marking) or the value of a predefined mark (number naming). Pain intensity was assessed using numerical rating (NRS), verbal rating (VRS), and visual analog (VAS) scales. Additional measures included attention and working memory, verbal intelligence, medication and depression. Results revealed that in number naming, patients deviated more from expected (correct) responses than controls, and that VAS scores were significantly higher than both NRS and VRS and correlated with deviations in position making. Changes in number naming were predicted by pain intensity, sex and IQ but not by attention, memory or opioid medication. This article presents new insight on which cognitive mechanisms are influenced by CP with the focus on numerical spatial abilities. It could therefore provide useful knowledge in developing new pain assessment tools specifically for patients suffering from CP

Anaesthetic preconditioning : the role of ATP-sensitive K+ channels

Stroke in general but especially in the postoperative period is a serious clinical problem that warrants new therapeutic approaches. Here neuroprotective strategies and especially preconditioning have recently emerged as promising. Preconditioning was originally demonstrated in the heart but was subsequently also found in other organs. Classically it describes a phenomenon where short periods of ischaemia render tissues less vulnerable to major infarcts. In addition to ischaemia neuronal preconditioning can be achieved pharmacologically as well as through inhalational anaesthetics or drugs that open ATP-sensitive K+(KATP)channels. However, the mechanisms through which anaesthetics produce protection remain elusive and the use of K+ channel openers is hampered by their inability to cross the blood-brain-barrier. This study was conducted to investigate the effects of inhalational anaesthetics on KATP channels and to explore whether their neuronal preconditioning properties were dependent on KATP channel opening. First, in whole-cell and excised patch clamp experiments the effects of inhalational anaesthetics on recombinant wild type neuronal (Kir6.2/SUR1) KATP and related as well as modified channels were evaluated. Secondly, the KATP channel dependence of anaesthetic preconditioning was tested in neuronal-glial co-cultures. Recombinant KATP channels were activated by xenon, but inhibited by halogenated volatiles. Moreover, it was shown that xenon acted directly on the Kir6.2 pore-forming subunit, reduced the ability of ATP to inhibit the channel and had no effect on the ATP-regulated Kir1.1 channel. Functionally both sevoflurane and xenon preconditioned neurons at clinically used concentrations but only the effect of xenon was dependent on KATP channel activation. Thus this study established xenon as a novel KATP channel opener. It interacts with the pore-forming Kir6.2 rather than the regulatory sulphonyl urea receptor subunit and disinhibits the channel from the blocking actions of ATP. As a consequence xenon but not sevoflurane is able to precondition neurons in a KATP channel-dependent manner.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Replicability, Repeatability, and Long-term Reproducibility of Cerebellar Morphometry.

To identify robust and reproducible methods of cerebellar morphometry that can be used in future large-scale structural MRI studies, we investigated the replicability, repeatability, and long-term reproducibility of three fully automated software tools: FreeSurfer, CEREbellum Segmentation (CERES), and automatic cerebellum anatomical parcellation using U-Net with locally constrained optimization (ACAPULCO). Replicability was defined as computational replicability, determined by comparing two analyses of the same high-resolution MRI data set performed with identical analysis software and computer hardware. Repeatability was determined by comparing the analyses of two MRI scans of the same participant taken during two independent MRI sessions on the same day for the Kirby-21 study. Long-term reproducibility was assessed by analyzing two MRI scans of the same participant in the longitudinal OASIS-2 study. We determined percent difference, the image intraclass correlation coefficient, the coefficient of variation, and the intraclass correlation coefficient between two analyses. Our results show that CERES and ACAPULCO use stochastic algorithms that result in surprisingly high differences between identical analyses for ACAPULCO and small differences for CERES. Changes between two consecutive scans from the Kirby-21 study were less than ± 5% in most cases for FreeSurfer and CERES (i.e., demonstrating high repeatability). As expected, long-term reproducibility was lower than repeatability for all software tools. In summary, CERES is an accurate, as demonstrated before, and reproducible tool for fully automated segmentation and parcellation of the cerebellum. We conclude with recommendations for the assessment of replicability, repeatability, and long-term reproducibility in future studies on cerebellar structure