Adaptive control and identification for on-line drug infusion in anaesthesia.

Anaesthesia is that part of the medical science profession which ensures that the patient’s body is insensitive to pain and possibly other stimuli during surgical operations. It includes muscle relaxation (paralysis) and unconsciousness, both conditions being crucial for the operating surgeon. Maintaining a steady level of muscle relaxation as well as an acceptable depth of anaesthesia (unconsciousness), while keeping the dosage of administered drugs which induce those effects at a minimum level, have successfully been achieved using automatic control. Fixed gain controllers such as P, PI, and PID strategies can perform well when used in clinical therapy and under certain conditions but on the other hand can lead to poor performances because of the large variability between subjects. This is the reason which led to the consideration of adaptive control techniques which seemed to overcome such problems. Two control strategies falling into the above scheme and including the two newly developed techniques, i.e Proportional-Integral-Plus (PIP) control algorithm, and Generalized Predictive Control algorithm (GPC), are considered under extensive simulation studies using the muscle relaxation process associated with two drugs known as Pancuronium-Bromide and Atracurium. Both models exhibit severe non-linearities as well as time-varying dynamics and delays. Only the strategy corresponding to the GPC algorithm is retained for implementation on a 380Z disk-based microcomputer system, while the muscle relaxation process corresponding to either drugs is simulated on a VIDAC 336 analogue computer. The sensitivity of the algorithm is investigated when patient-to-patient parameter variability is evoked. The study is seen to provide the necessary basis for future clinical implementation of the scheme. Following the satisfactory results obtained under such a real-time environment, the self-adaptive GPC algorithm has been successfully applied in theatre to control Atracurium infusion on humans during surgery. This success later motivated further research work in which simultaneous control of muscle relaxation and anaesthesia (unconsciousness) was achieved. A good multivariable model has been derived and controlled via the multivariable version of the SISO GPC algorithm. The results obtained are very encouraging

On Automation in Anesthesia

The thesis discusses closed-loop control of the hypnotic and the analgesic components of anesthesia. The objective of the work has been to develop a system which independently controls the intravenous infusion rates of the hypnotic drug propofol and analgesic drug remifentanil. The system is designed to track a reference hypnotic depth level, while maintaining adequate analgesia. This is complicated by inter-patient variability in drug sensitivity, disturbances caused foremost by surgical stimulation, and measurement noise. A commercially available monitor is used to measure the hypnotic depth of the patient, while a simple soft sensor estimates the analgesic depth. Both induction and maintenance of anesthesia are closed-loop controlled, using a PID controller for propofol and a P controller for remifentanil. In order to tune the controllers, patient models have been identified from clinical data, with body mass as only biometric parameter. Care has been taken to characterize identifiability and produce models which are safe for the intended application. A scheme for individualizing the controller tuning upon completion of the induction phase of anesthesia is proposed. Practical aspects such as integrator anti-windup and loss of the measurement signal are explicitly addressed. The validity of the performance measures, most commonly reported in closed-loop anesthesia studies, is debated and a new set of measures is proposed. It is shown, both in simulation and clinically, that PID control provides a viable approach. Both results from simulations and clinical trials are presented. These results suggest that closed-loop controlled anesthesia can be provided in a safe and efficient manner, relieving the regulatory and server controller role of the anesthesiologist. However, outlier patient dynamics, unmeasurable disturbances and scenarios which are not considered in the controller synthesis, urge the presence of an anesthesiologist. Closed-loop controlled anesthesia should therefore not be viewed as a replacement of human expertise, but rather as a tool, similar to the cruise controller of a car

Regulation of Competitive Interactions During Neuromuscular Synapse Elimination

The subsequent chapters of this thesis address a number of issues related to the phenomena that occur during neuromuscular synapse elimination and to the rules and mechanisms that govern them. The results they describe are therefore based on observations of developmental processes in both normal animals and in those whose normal developmental interactions have been perturbed by alteration of activity for some of the elements involved. Chapter 2 addresses the question of whether the rate of neuromuscular synapse elimination might normally depend on the level of postsynaptic activity. Previous studies had strongly implicated activity in regulation of synapse elimination rate; e.g., increased activity evoked by chronic stimulation increased the elimination rate; but these studies did not differentiate between pre- and postsynaptic activity. Duxson (1982) treated the rat soleus muscle with α-bungarotoxin (α-BGT), completely blocking postsynaptic activity during the normal period of synapse elimination and reported that the number of terminal profiles per endplate observed in electron micrographs did not decrease as it does normally. I did not consider this study to be conclusive because complete activity blockade might invoke influences that are not normally present in active muscles during synapse elimination, and because the assay was indirect - an increase in the number of terminal profiles per endplate might reflect an increase in terminal complexity rather than maintenance of more terminals. For the experiments described in Chapter 2, postsynaptic activity was partially blocked by α-BGT superfusion of the neonatal rabbit soleus muscle. The toxin treatment resulted in slower synapse elimination, as assessed both physiologically and anatomically, even for muscle fibers whose activity was not completely blocked. While the interpretation of this result is dependent on the possibility that α-BGT has influences other than decreased activity, it appears quite likely that a partial block of postsynaptic activity can slow the rate of neuromuscular synapse elimination. Chapter 3 describes a separate series of experiments in which motor unit twitch tensions were assayed for the soleus muscles of neonatal rabbits. Synapse loss could be assayed separately for fast and slow populations by separating the motor units, based on their twitch rise times. Estimates of the rate of synapse elimination for the two populations suggested that slow muscle fibers were initially more heavily polyinnervated than fast fibers and that they lost synapses at a faster rate, so that both populations of fibers became predominantly singly innervated at about the same time. The remainder of the issues in Chapter 3 are related to the question of whether there are particular attributes of motor neurons that might place the inputs from some neurons at a competitive advantage over others. The first such issue was whether motor neurons with relatively large axonal arbors are at an advantage or disadvantage in the competition for synaptic sites. If this were the case, it would be expected that the diversity in motor unit sizes would decrease during synapse elimination if a large arbor were a disadvantage, and thediversity would increase if it were an advantage. Contrary to both hypotheses, no significant change in the diversity of motor unit sizes was observed. The next issue was whether motor neurons from particular positions in the spinal cord were at an advantage or disadvantage compared to the others. To test this issue, mean sizes of motor units from both rostral and caudal extremes of the soleus motor pool were compared to the mean sizes for those from the middle of the pool. At the earliest age tested, when the soleus is still heavily polyinnervated, the motor units from the extremes were no smaller than those from the middle. However, just four days later, the units from each extreme were significantly smaller than those from the middle; this difference persisted in older, singly innervated muscles. There was no significant difference between the rostral and caudal motor units at any age tested. It is concluded that motor neurons from rostral and caudal extremes are at a disadvantage when in competition with those from the middle of the motor pool during synapse elimination in the rabbit soleus. Finally, a small portion of the rabbit soleus motor neurons was inactivated by implantation of a tetrodotoxin-laden Silastic plug during synapse elimination. Since there was nearly complete overlap between the inactivated and active motor units at the time of the implant, this allowed a test of whether the level of activity of a motor neuron can influence the ability of its terminals to compete for sole occupancy of endplates. It was found that the inactive motor units ended up significantly larger than their active counterparts in normal and control implanted animals, and remained larger even after the endplates were virtually all singly innervated. It is concluded that inactivity can result in a significant competitive advantage during synapse elimination. The generality of these conclusions and their implications in terms of the ways in which neuromuscular synapse elimination might be regulated are discussed in detail.</p

Risk Management for the Future

A large part of academic literature, business literature as well as practices in real life are resting on the assumption that uncertainty and risk does not exist. We all know that this is not true, yet, a whole variety of methods, tools and practices are not attuned to the fact that the future is uncertain and that risks are all around us. However, despite risk management entering the agenda some decades ago, it has introduced risks on its own as illustrated by the financial crisis. Here is a book that goes beyond risk management as it is today and tries to discuss what needs to be improved further. The book also offers some cases

The Impact of a Changed Approach to Analgesia and Sedation Management in the Paediatric Intensive Care Unit

Background International best practice endorses the use of a standardised approach in the management of analgesic and sedative drugs in the Paediatric Intensive Care Unit (PICU). In adult intensive care settings incorporating analgesia and sedation guidelines has been associated with significant patient benefits including a reduction in the amounts of analgesia and sedative drugs used and a decrease in the duration of mechanical ventilation. In contrast, the evidence to support this change in practice in the paediatric setting is limited and inconsistent. Also the administration of analgesia and sedation has predominantly been based on personal preferences and ritualistic practice, without the support of an evidence base. The key role that PICU staff play in analgesia and sedation management, their perceptions around introducing changes in the management of analgesia and sedation has not been fully addressed. In an Irish context this study was seminal, as no previous studies had reported on current and alternate analgesia and sedation management practices within the PICU and the staff perception of a change of practice. Research Hypotheses Given the lack of evidence in this area for PICU practice, this study aimed to address the following primary and secondary hypotheses: Primary Hypothesis: “Standardised pain and sedation management did not cause a reduction in the dosage of morphine administered to patients in PICU” Secondary Hypothesis: “The implementation of standardised pain and sedation was not associated with a change in duration of mechanical ventilation and PICU stay.” Methods Ethical approval was obtained for the study. A quasi-experimental approach was used employing a before/after design. Kotter’s model of change was chosen to guide the change intervention, which comprised the introduction of multidisciplinary developed analgesia and sedation guidelines in the PICU and standardised pain and distress assessment using the validated COMFORT-B instrument. Patient census data were retrieved from the PICU census database for 12 month time period before and after the change in practice. P1-The before group; consisted of all patients admitted to the PICU between 1st March 2009 and 28th February 2010, treated according to standard analgesia and sedation management practices. P2-The after group comprised all patients admitted to the PICU between 1st August 2010 and 31st July 2011. This patient group were managed according to the changed approach to analgesia and sedation management. As census data are not conducive to deeper analysis, a subset of P1 and P2 was selected to facilitate more in-depth analysis. Strict inclusion and exclusion criteria were used to obtain 2 comparable groups. Using an instrument exclusively developed and validated for this purpose, the PASQ (Patient Analgesia and Sedation Questionnaire); data from these cardiac non-equivalent control (PASQ 1; n=61) and intervention (PASQ 2; n=64) patient groups were collected for the first 72h (3x 24 hour Epochs) post-operatively. In addition, staff surveys were conducted before and after guideline introduction using the SASQ (Staff Analgesia and Sedation Questionnaire) instrument. Chi-square analysis, t-tests and the Mann-Whitney-U test were used for group comparisons. Results The CIPP model of evaluation was employed to determine the impact of the change intervention, on both patients and staff. Before and after comparisons of study groups determined that: Patient Census Data: There was no statistically significant difference in the median duration of mechanical ventilation (3 days [2:7]) (p=0.44) or median length of PICU stay (4 days [2:8]) (p= p=0.47) between the before and after intervention groups P1 and P2. However, patients with Down Syndrome (Trisomy 21or T21) were noted to have a longer median duration of mechanical ventilation than non-T21 patients, which proved to be statistically significant (4 [2:9]) vs (3[2:7]), (p=0.017) and a significantly longer duration of PICU stay (6 [3:12]) vs 4 [2:8]), (p After the intervention, the duration of mechanical ventilation for patients with T21 was reduced by one day (P1 4[2:9] vs P2 3[2:6], p=0.04). No statistically significant reduction in length of PICU stay emerged for this group (P1 6 [3:12] vs P2 5 [3:9], p=0.09). After the intervention, the duration of mechanical ventilation between T21 and non-T21 patients was comparable 3[2:7] and 3[2:6] (p=0.36) respectively, as was the duration of PICU stay for both T21 and non-T21 patient groups (5[3:9] vs 4[2:8]) (p=0.28) respectively. PASQ Data: No statistically significant reduction in morphine administration by continuous intravenous infusion emerged after the intervention in either of the 3 Epochs (Epoch 1 PASQ 1 median 36mcg/kg/hr [27.7:43.9] vs PASQ 2 median 27.4mcg/kg/hr [29.0:37.1] (p=0.13)). However, after the change in practice a statistically significant reduction the mean rate of morphine infusion on return to PICU from the operating theatre was noted (PASQ 1 69.5mkg/kg/hr vs PASQ 2 55.38mkg/kg/hr (p= SASQ A statistically significant increase in PICU staff satisfaction with analgesia and sedation practice after the intervention emerged (p Conclusion This study reports how a change in analgesia and sedation management in line with best international practice has been successfully implemented. There are considerable potential patient benefits of basing analgesia and sedation management on robust assessment using validated tools. The resulting statistically significant reduction in duration of mechanical ventilation in the T21 population has the potential to reduce exposure to the complications of mechanical ventilation and hospital acquired infections, as well as decreasing interruptions to cognitive and social development and the parental bonding process. Reduced resource usage has significant cost implications and can facilitate increased patient turnover at a time when hospital resources are limited and inpatient waiting lists exist. An observed change in the pattern of analgesia and sedatives administered to patients in line with emerging evidence is welcome; acknowledging the risks associated with prolonged use of analgesia and sedation including withdrawal syndrome, and emerging evidence associating neuroapoptosis with use of certain sedatives. Using validated methods of assessing pain and distress leads to improved management which fulfils our humanitarian obligations and may increase job satisfaction. The neighbouring PICU has adopted the same approach to pain and sedation as it is seen best practice, moving towards standardisation at a National level. Valuable research collaborations have also evolved from the writers’ study and an important pharmacokinetic and pharmacodynamic study has been possible at the study site as a result of the implementation of validated pain assessment. High level dialogue about pain and sedation now occurs between clinicians and nurses, where previously uncertainty and a lack of direction prevented this from occurring

Investigations into the role of the metabotropic glutamate receptor, mGluR5, in incentive learning and some behavioural and neurobiological effects of cocaine

The metabotropic glutamate receptor, mGluR5, is densely expressed in brain regions involved in incentive learning processes. There is considerable evidence to suggest that following exposure to addictive drugs such as cocaine, adaptations in these brain areas may underlie the development and maintenance of behavioural responses related to addictive processes. The present thesis examines the role of mGluR5 in both incentive learning processes and some behavioural and neurobiological effects of cocaine. First, using a novel mutant mouse line in which mGluR5 is selectively knocked down in cells that express dopamine D1 receptors (D1R), I argue that this mGluR5 population is critically important for specific incentive learning processes. By blocking mGluR5 in wild-type mice with a selective antagonist, I then propose mGluR5 as necessary for the acquisition, but not the expression of an incentive association. Next, I present data showing that mGluR5 on dopaminoceptive neurons are not necessary for the „conditioned rewarding‟ properties of cocaine, measured in the conditioned place preference model, but do contribute to the psychomotor activating effects of cocaine. Finally, I present an immunohistochemistry study that examines cocaine-induced activation of the extracellular-signal related kinase (ERK) pathway. In the mGluR5 knock-down mice, activation of the ERK pathway in the striatum is disrupted following an acute injection of cocaine. Given the importance of the ERK pathway in establishing and maintaining long term memories, I propose that disruption of this pathway could contribute, in part, to some findings reported in the present thesis. Taken together, this thesis will argue that signalling through mGluR5 on D1R expressing neurons is important for the formation of incentive associations, and may contribute to neural adaptations necessary for the development and maintenance of behavioural responses related to addictive processes

Life Sciences Program Tasks and Bibliography

This document includes information on all peer reviewed projects funded by the Office of Life and Microgravity Sciences and Applications, Life Sciences Division during fiscal year 1995. Additionally, this inaugural edition of the Task Book includes information for FY 1994 programs. This document will be published annually and made available to scientists in the space life sciences field both as a hard copy and as an interactive Internet web pag