British journal of anaesthesia
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The Minto remifentanil pharmacokinetic/pharmacodynamic (PK/PD) model is used in target-controlled infusion (TCI) devices. The endpoint used to calculate the PD parameters, including the ke0, was the electroencephalogram (EEG), which only changes at high remifentanil concentrations. As the ke0 should adequately predict the time course of drug effects at clinically relevant concentrations, we evaluated the temporal agreement between effect-site concentrations estimated with the Minto model and pressure pain thresholds during conscious sedation. ⋯ Our results demonstrate the limitation of the Minto PD model at low target remifentanil concentrations, with a discrepancy in the time course between EEG and pressure pain threshold changes. Clinicians should be aware that the time course of onset of analgesic effects is slower than the estimates of the Minto model. Investigators should consider using algometry data in future opioid PD modelling studies.
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A fundamental concept in pharmacology is that increasing dose increases drug effect. This is the basis of anaesthetic titration: the dose is increased when increased drug effect is desired and decreased when reduced drug effect is desired. In the setting of titration, the correlation of doses and observed drug effects can be negative, for example increasing dose reduces drug effect. We have termed this the drug titration paradox. We hypothesised that this could be explained, at least in part, by intrasubject variability. If the drug titration paradox is simply an artifact of pooling population data, then a mixed-effects analysis that accounts for interindividual variability in drug sensitivity should 'flip' the observed correlation, such that increasing dose increases drug effect. ⋯ The relationship between drug dose and drug effect must be determined under carefully controlled experimental conditions. In routine care, where the effect is profoundly influenced by varying clinical conditions and drugs are titrated to achieve the desired effect, it is nearly impossible to draw meaningful conclusions about the relationship between dose and effect.
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Observational Study
Change in healthcare utilisation after surgical treatment: observational study of routinely collected patient data from primary and secondary care.
Most patients fully recover after surgery. However, high-risk patients may experience an increased burden of medical disease. ⋯ High-risk patients who survive the immediate perioperative period experience large and persistent increases in healthcare utilisation in the years after surgery. The full implications of this require further study.
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Editorial Comment
Changes in healthcare utilisation after surgical treatment: mitigating risk through multidisciplinary and collaborative care.
A recent study by Fowler and colleagues identified increased utilisation of healthcare resources among patients, mostly from deprived social areas with chronic diseases, undergoing emergency and high-risk surgery. Reasons for these findings include the intrinsic risk of surgery, postoperative complications, and the need for chronically ill patients to have their usual treatment resumed after surgery. To improve the overall outcome of surgery in this category of patients, a number of elements in the process of care should be adjusted. This includes minimising the number of emergency procedures and enhancing collaboration between all healthcare professionals inside and outside hospitals.
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Interleukin-6 (IL-6), a pleiotropic cytokine with both degenerative and regenerative properties, is necessary and sufficient to provoke perioperative neurocognitive disorders after aseptic trauma in mice. IL-6 initiates its actions after binding to either membrane-bound IL-6 receptor α (mIL-6Rα) through classical signalling, or soluble IL-6 receptor (IL-6R) through trans-signalling; both signalling pathways require the transducer gp130. We investigated the site and type of IL-6 signalling that pertains in a tibial fracture aseptic trauma model of perioperative neurocognitive disorder. ⋯ After orthopaedic trauma, IL-6 produces perioperative neurocognitive disorders through IL-6 trans-signalling in mouse CA1 neurones. Druggable targets of the trans-signalling pathway should be sought to reduce perioperative neurocognitive disorders while allowing the healing properties of classical IL-6 signalling.