Closed-loop control of anesthesia : survey on actual trends, challenges and perspectives

Automation empowers self-sustainable adaptive processes and personalized services in many industries. The implementation of the integrated healthcare paradigm built on Health 4.0 is expected to transform any area in medicine due to the lightning-speed advances in control, robotics, artificial intelligence, sensors etc. The two objectives of this article, as addressed to different entities, are: i) to raise awareness throughout the anesthesiologists about the usefulness of integrating automation and data exchange in their clinical practice for providing increased attention to alarming situations, ii) to provide the actualized insights of drug-delivery research in order to create an opening horizon towards precision medicine with significantly improved human outcomes. This article presents a concise overview on the recent evolution of closed-loop anesthesia delivery control systems by means of control strategies, depth of anesthesia monitors, patient modelling, safety systems, and validation in clinical trials. For decades, anesthesia control has been in the midst of transformative changes, going from simple controllers to integrative strategies of two or more components, but not achieving yet the breakthrough of an integrated system. However, the scientific advances that happen at high speed need a modern review to identify the current technological gaps, societal implications, and implementation barriers. This article provides a good basis for control research in clinical anesthesia to endorse new challenges for intelligent systems towards individualized patient care. At this connection point of clinical and engineering frameworks through (semi-) automation, the following can be granted: patient safety, economical efficiency, and clinicians' efficacy

Robust fractional order PI control for cardiac output stabilisation

Drug regulatory paradigms are dependent on the hemodynamic system as it serves to distribute and clear the drug in/from the body. While focusing on the objective of the drug paradigm at hand, it is important to maintain stable hemodynamic variables. In this work, a biomedical application requiring robust control properties has been used to illustrate the potential of an autotuning method, referred to as the fractional order robust autotuner. The method is an extension of a previously presented autotuning principle and produces controllers which are robust to system gain variations. The feature of automatic tuning of controller parameters can be of great use for data-driven adaptation during intra-patient variability conditions. Fractional order PI/PD controllers are generalizations of the well-known PI/PD controllers that exhibit an extra parameter usually used to enhance the robustness of the closed loop system. (C) 2019, IFAC (International Federation of Automatic Control) Hosting by Elsevier Ltd. All rights reserved

Opioid modulation of luteinizing hormone, progesterone, and cortisol secretion in the prepubertal zebu heifer

Reproductive efficiency in zebu cattle is very low. Besides genotype, poor nutrition is a major cause of this low efficiency. Poor nutrition delays puberty onset by causing a dysfunction of the hypothalamo-pituitary-gonadal axis, and may also activate the general stress syndrome to inhibit reproduction. Endogenous opioid peptides (EOP) have been implicated in the regulation of luteinizing hormone, and are also released during stress;Naloxone, a potent opioid receptor antagonist, infused to prepubertal zebu heifers maintained under sub-optimal feeding conditions, caused a significant transient, dose-dependent increase in plasma progesterone and cortisol concentrations. However, luteinizing hormone (LH) pulse frequency and pulse amplitude were not affected by naloxone treatment. Further, chronic naloxone treatment of zebu heifers did not induce puberty;In a follow-up study, the effects of dietary restriction and endogenous opioidergic tone on the regulation of progesterone, cortisol and LH were investigated. Feed restriction induced a marked decrease in all LH parameters, increased basal cortisol, and decreased progesterone concentrations. These effects were reversed by refeeding. Reducing the endogenous opioid tone in full-fed heifers tended to increase LH pulse frequency, but increased basal and LH pulse amplitude. However, nalaxone had no effect on LH parameters in the feed-restricted zebu heifer. Irrespective of the nutritional status, opioid antagonism increased progesterone secretion, but the effect on cortisol was divergent, increasing slightly in full-fed heifers, and inducing an insignificant decrease in acutely feed-restricted animals;These studies suggest that undernutrition induces a dysfunction of the reproductive endocrine axis in zebu heifers. There is little support that EOP may be involved in the nutrition-induced suppression of LH, however hypercortisolemia arising from nutritional stress may indirectly inhibit LH. Further, opioidergic restraint of progesterone secretion may prevent the normal prepubertal elevation, an important event for the establishment of high frequency LH secretion

A nonovershooting controller with integral action for multi-input multi-output drug dosing control

In this paper, a nonovershooting tracking controller is proposed for the continuous infusion of multiple drugs that have interactive effects. The proposed controller design method exploits the freedom of eigenstructure assignment pertinent to the design of feedback controllers for multi-input, multi-output (MIMO) systems. For drug dosing, a nonovershooting tracking controller restricts the undesirable side effects of drug overdosing. The proposed tracking controller is based on an estimate of the full state using a hybrid extended Kalman filter (EKF) that is used to reconstruct the system states from the measurable system outputs. An integral control action is included in the controller design to achieve robust tracking in the presence of patient parameter uncertainty. Simulation results and performance analysis of the proposed control strategy are also presented using 20 simulated patients. 2018Qatar National Research FundScopu

Long-Term Impacts of Acute Stressor Exposure on Locus Coeruleus Function and Anxiety-Like Behavior in Rats

Stress is a physiological state characterized by behavioral arousal that occurs during exposure to harmful or threatening stimuli, and usually facilitates an adaptive behavioral response. The persistence of stress sometimes causes it to become maladaptive, potentially contributing to disease development, including physiological complications with altered neuroendocrine signaling and impaired function of organ systems, and psychological conditions including depression and anxiety. Anxiety disorders in particular are associated with a history of stress and are the most common class of mental disorders, with a lifetime prevalence of 33.7% in the general population. The locus coeruleus (LC) is a major node in the stress response, which integrates input from multiple stress responsive neural circuits and releases norepinephrine throughout the central nervous system (CNS) to promote vigilance and anxiety. Stress-induced adaptations in LC may lead to impaired noradrenergic transmission throughout the CNS and is thought to contribute to mood disorder pathogenesis. Although immediate cellular actions of stress on LC have been extensively studied, the long-term changes in LC are poorly described. It is well-established that acute stress causes the release of corticotropin-releasing factor (CRF) in the CNS, including in LC, where it increases tonic firing to promote increased norepinephrine in target brain areas, thereby promoting anxiety-like behavior. However, LC morphology and stress responsiveness varies among males and females and changes throughout development. In addition, CRF activity on the LC is counteracted by endogenous opioid neurotransmission. The endogenous opioid peptides Leu- and Met-enkephalins act through d and m opioid receptors, which decrease cAMP and increase potassium conductance through a Gi-coupled mechanism, leading to cell hyperpolarization and decreased firing. Therefore, we hypothesized that acute stressor exposure would have variable impacts on LC physiology and anxiety-like behavior in rats of different ages in both sexes. We further postulated that dysregulation of LC following stress is associated with altered function of opioid receptors in LC. To test this, we used a combination of whole-cell patch clamp recordings of LC neurons, rodent assays of anxiety-like behavior, and analysis of gene and protein expression. Finally, by using a viral-genetic method, we assessed the impact of overexpression of δ-opioid receptors in LC on stress responsiveness. Here we report that acute intense stressor exposure results in opposing changes in anxiety-like behavior and LC physiological properties in adolescent male and female rats. No such changes were observed in adult animals. We also found that the same stressor during adolescence in males is associated with impaired δ opioid receptor expression and function, which may contribute to a reduced capacity to terminate the stress response. These results suggest that endogenous opioid signaling in LC, particularly in adolescent males, is a key target, and regulator of, the stress response, and may have critical implications for the development and treatment of various stress-associated pathological conditions

Arterial pressure control with isoflurane using fuzzy logic

Arterial pressure is still one of the most important measures in estimating the required dose of inhaled anaesthetics. It is measured easily and reacts rapidly which makes it suitable as a variable for feedback control of depth of anaesthesia. Fuzzy logic, a novel approach to feedback control, was used to control arterial pressure in 10 patients during intra-abdominal surgery by automatic adjustment of the concentration of isoflurane in fresh gas. During anaesthesia, fuzzy control periods of 45-min duration were alternated randomly with human control periods of equal duration. During the skin incision period (−3 to +12min) 48.2% of all fuzzy control pressure values were within ±10% of the desired mean arterial pressure compared with 40.4% of the human control values (P < 0.05). The corresponding values for the remainder of the operation were 78.3% and 83.2%, respectively. Thus fuzzy outperformed human control at skin incision, but was slightly inferior during the rest of the operation. We conclude that fuzzy logic is a promising new technique for control of isoflurane delivery during routine anaesthesi

The effects of beta-endorphin on glucose homeostasis and hormonal responses during exercise

Despite the fact that Beta-Endorphin (B-EP) has been shown to cause hyperglycemia at rest, it is not known if it influences glucose homeostasis and the glucoregulatory hormones during exercise. In an attempt to clarify the role of B-EP in glucose regulation and hormonal responses to prolonged dynamic exercise, 72 untrained, male Sprague-Dawley rats were assigned to one of three treatments: a) a control group infused with normal saline, b) a group infused with rat synthetic B-EP (0.05 mg*kg-l*h-l after a 0.05 mg/ kg bolus), and c) a group infused with naloxone (0.4 mg*kg-l *h-l after a 0.8 mg*kg-l bolus). All animals were familiarized with treadmill running for 4 days. On the fifth day they were catheterized in the jugular vein, and allowed 4 days recovery period. All recovered catheterized animals went through a second familiarization running period for 4 days. Finally, animals in each group were infused and killed either at 0 time or after 60, 90 and 120 minutes of running. Mixed venous samples were collected and subsequently analyzed for plasma glucose, lactate, insulin, C-peptide (C-P), glucagon, and B-EP

Parturition in the pig: relationships between pain, stress and maternal behaviour

The thesis examines the relationships between pain, stress and behaviour of the pig around parturition. This includes the effects of pregnancy and parturition on maternal nociception, and environmental restriction on stress physiology and behaviour. The main findings are:1. Late pregnancy and parturition in the pig is associated with an endogenous analgesic system which is, at least in part, mediated via endogenous opioids.2. Passivity and inactivity are major components of maternal behaviour in the pig and are suggested to be indicative of good maternal care in this species. The thesis provides evidence of an opioid mediation of maternal behaviour which could arise through several potential routes, namely: the action of the analgesic system, general sedation, the inhibition of oxytocin release.3. A rise in plasma Cortisol, ACTH and P-endorphin concentrations were found in pre-parturient gilts housed in both straw bedded pens and conventional farrowing crates. However crates caused further stimulation of the HPA axis reflecting thwarting of nestbuilding behaviour in this restrictive environment.4. The farrowing crate did not cause further HPA activity during the expulsive phase which may reflect the inactivity of the pig at this time. A rise in plasma Cortisol was found as the expulsive phase progressed irrespective of environment however the thesis found that the expulsion of a piglet does not appear to play a major role in this.Overall the thesis has realised a better understanding of parturition in the pig by relating the physiology and behaviour of the pig at this time. The possibility of maternal pain influencing the progress of parturition and maternal behaviour is discussed in relation to possible mechanisms by which this may occur. The thesis has also highlighted welfare implications regarding the use of farrowing crates, and provides information which may be used when considering changes to housing for parturient pigs