The concentrations of some drug solutions are often expressed as ratios or percentages. This system simplified prescription and dispensing when Imperial measures such as grains and minims were used. Ampoules of powerful vasoactive drugs such as catecholamines and potentially toxic local anaesthetics are still labelled as ratios and percentages, seemingly through habit or tradition than for any useful clinical reason. This thesis argues that adherence to this outdated system is confusing, causes drug administration errors, and puts patients at risk. Internet-based questionnaires were used to quantify medical students’ and doctors’ understanding of ratios and percentages. A substantial minority of almost 3000 doctors could not convert between ratios, percentages and mass concentration correctly, made dosing errors of up to three orders of magnitude in written clinical scenarios, and struggled with conversions between metric units. These findings are strong arguments for expressing drug concentrations as mass concentration and providing better drug administration teaching. High fidelity patient simulation was used to examine the influence of clearer ampoule labelling and intensive drug administration teaching. This allowed critical incidents to be reproduced realistically, clinical performances to be assessed, and outcome measures to be accurately recorded. Randomised controlled trials were conducted that demonstrated positive influences of both interventions for doctors and students. The difficulties that nurses encounter when preparing infusions of these drugs on critical care units were also studied and are reported. The findings presented should be sufficient to persuade regulatory authorities to remove ratios and percentages from ampoule labels – a straightforward, cheap, commonsense intervention. The lack of effective clinical error reporting systems and the extreme practical difficulties of conducting clinical trials in this field mean that a firm link between this intervention and patient outcome is unlikely ever to be made, but this should not be an excuse for maintaining the status quo.

Hospitalization, surgery and anaesthesia are for some children associated with anxiety and could be a frightful experience which may result in later problematic behaviour. Pain is associated with the fears of hospitalization. The first aim was to investigate how pain in children is treated in Swedish hospitals as well as to assess the results of this treatment. Behaviour after hospitalization has been measured by the Post Hospital Behaviour Questionnaire (PHBQ). A second aim was to translate this instrument into Swedish and to validate it. The third aim was to analyze which factors (sociodemographic back¬ground; earlier experience; events at the hospital) that might be associated with changes in behaviour. Methods: A questionnaire regarding acute pain, its treatment methods and results of treatments as well as contributing factors to inadequate results, was sent to all departments in hospitals that might treat children. One form was answered by phy¬sicians and another form by nurses. In the second part of the study, a cohort of 340 children ages 2-13 were followed from two weeks before hospitalization until two weeks after. Data regarding socio¬demography and earlier health care experience were collected. The Child Behav¬iour Checklist was issued before and after hospitalization, the PHBQ was issued after. During hospitalization staff and parents assessed anxiety, pain and nausea mainly by VAS and Likert scales, (parents assessed own and child emotions). Children, older than 4-5 years of age, assessed their own pain using a faces scale. Results: Despite treatment, moderate to severe pain occurred postoperatively in 23% of patients and in 31% of patients with pain of other origin. Postoperative pain seemed to be a greater problem in units where children were treated together with adults and in departments where fewer children were treated. Pain could often or always be treated more efficiently according to 45% of physi¬cians and nurses. Of all departments, pain assessments were performed regularly in 43%, but pain measurement was less frequent. Opioids were never or infrequently used by 15 %. A five factor model fitted data better than the original 6 factor model when confir¬mative factor analyse was performed. Cronbach’s alpha was adequate for factors and excellent for the total score (0.92). Risk factors for increased problematic be¬haviour included the following: age less than 5 years of age, living in a one adult family, anxiety at anaesthesia induction, nausea at hospital and pain at home. Liv¬ing in a rural area and midazolam in premedication seem to be protective. Conclusions: Acute pain in children is still a problem. Inadequate pain treatment is mainly associated with organisational factors (missing prescriptions; a low rate of pain assessments). The PHBQ in Swedish translation is a reliable instrument and its relation to CBCL warrants its further use in research and quality control espe¬cially in younger children. Hospital-induced stress in older children needs further investigation. One third of the children who have been hospitalized and exposed to anaesthesia will have in¬creased problematic behaviour when returning home. Pro¬active interventions are suggested to prevent this by improving pain treatment at home.

A substantial number of patients undergoing cardiac surgery are on dual anti-platelet treatment with clopidogrel and aspirin. A disadvantage with this treatment is increased risk of bleeding. Bleeding is a complication of major concern associated with adverse outcome for the patient and increased hospital resource utilization. Great variability in individual response to clopidogrel has been reported. If in vitro measurements of platelet reactivity would correlate with clinical bleeding parameters, potential bleeders could be identified preoperatively. The aims of this thesis were: (1) to describe the degree of pre-operative platelet inhibition in patients scheduled for primary isolated coronary artery bypass graft surgery; (2) to prospectively investigate whether the pre-operative platelet inhibition correlated with intra- and postoperative bleeding and transfusion requirements; and (3) to test the ability of clinically relevant risk factors to predict re-exploration for bleeding. (4) In addition, a cost analysis was performed on patients re-explored for bleeding, to analyse the magnitude of added resource utilization and costs. Based on this, a cost model of prophylactic treatment with haemostatic drugs was calculated. Platelet function tests investigated were: (1) flow cytometry, (2) VASP, (3) VerifyNowSystem, (4) PlateletMapping (a modified TEG), and (5) PFA-100. Clinical risk factors for re-exploration and the influence of antiplatelet and antifibrinolytic therapy were evaluated in a retrospective analysis. Cost analysis at three cardiothoracic centres was performed in a case-control study. In conclusion, there was no clinically useful correlation between preoperative assessment of platelet inhibition and blood loss or transfusion requirements during coronary artery bypass surgery. Furthermore, there was only modest agreement between the methods evaluating ADP-receptor blockade. Pre-operative treatment with the P2Y12-receptor inhibitor clopidogrel was an essential risk factor for re-exploration due to bleeding. Except for clopidogrel, no strong clinical factor to predict the risk of re-exploration was identified. The resource utilisation costs were 47% higher in patients requiring re-exploration due to bleeding than in those not requiring re-exploration. Prolonged stay in the ICU and recovery ward accounted for half of the added cost, a third was due to the costs of surgery, one fifth due to increased cost of transfusions, and <2% was due to haemostatic drug treatment.

This thesis describes the host-guest chemistry between cucurbit[7]uril (CB[7]) and various series of guests, including neutral polar organic solvents, bis(pyridinium)alkane dications, local anaesthetics, acetylcholine analogues, as well as succinylcholine and decamethonium analogues, in aqueous solution. A focus of this thesis is the effects of varying the chemical structures within different series of guests upon the nature of the host-guest chemistry, such as the relative position and orientation of the guest relative to the CB[7] cavity, and the strengths of the binding affinities. The binding affinities of polar organic solvents with CB[7] depend upon the hydrophobic effect and dipole-quadrupole interactions. The polar guests align themselves so that their dipole moment is perpendicular to the quadrupole moment of CB[7]. The binding strengths of acetone and acetophenone to CB[7] decrease in the presence of alkali metals. Discrete 1:1 and 2:1 host-guest complexes are formed between CB[7] and a series of bis(pyridinium)alkane guests. In most cases the CB[7] initially occupies the aliphatic linker when the 1:1 complex is formed and migrates to the terminal regions as the second CB[7] is added. When bulky, hydrophobic tert-butyl substituents are present, however, the CB[7] occupies the terminal pyridinium region and not the central linker. Supramolecular complexes between CB[7] and a series of local anaesthetics have binding affinities 2-3 orders of magnitude greater than reported values with beta-cyclodextrin. The first pKa values of the guests increase by 0.5-1.9 units upon complexation. The binding positions of the guests within CB[7] differ in neutral and acidic media, with the systems thus behaving as pH-activated switches. With supramolecular complexes between CB[7] and various cationic cholines and their phosphonium analogues, the CB[7] cavity is occupied by the charge-diffuse cationic region. The binding affinities and positions vary depending on the nature of the onium group as well as the substituents within the guest molecule. Host-guest complexes between CB[7] and dicationic acetylcholinesterase inhibitors have very strong 1:1 binding affinities, with 2:1 binding being significantly weaker. These binding affinities are related to the nature of the cationic onium groups, and the length and hydrophobicity of the connecting linkers. / Thesis (Ph.D, Chemistry) -- Queen's University, 2010-01-28 12:27:37.833

Background: Loading conditions are recognized to influence ventricular function according to the Starling relationship for length/stretch and force.  Many modern echocardiographic parameters which have been announced as describing ventricular function and contractile status, may be confounded by uncontrolled and unmeasured load.  These studies aimed to measure the relation between four differ­ent types of assessments of ventricular dysfunction and degrees of load.  Study examined the ‘myo­cardial performance index’ (MPI).  Study II examined long axis segmental mechanical dyssynchrony.  Study III examined tissue velocities, and Study IV examined ventricular twist.  All studies aimed to describe the relation of these parameters both to load and to inotropic changes. Methods:  In anesthetized juvenile pigs, left ventricular (LV) pressure and volume were measured continuously and their relationship (LVPVR) was analysed.  Preload alterations were brought about by inflation of a balloon tipped catheter in the inferior vena cava (IVCBO).  Inotropic interventions were brought about by either an overdose of anesthetic (combine intravenous pentobarbital and inhaled isoflurane, Study I), or beta blocker and calcium channel blocker given in combination (Stud­ies III and IV).  In one study (II), global myocardial injury and dysfunction was induced by endotoxin infusion.  MPI measurements were derived from LVPVR heart cycle intervals for isovolumic contrac­tion and relaxation as well as ejection time.  Long axis segmental dyssynchrony was derived by ana­lyzing for internal flow and time with segmental dyssynchronous segment volume change during systole, hourly before and during 3 hours of endotoxin infusion.  Myocardial tissue velocities were measured during IVCBO at control, during positive and then later negative inotropic interventions.  The same for apical and base circumferential rotational velocities by speckle tracking.  Load markers (including end-diastolic volume) were identified for each beat, and the test parameters were analysed together with load for a relation.  The test parameters were also tested during single apneic beats for a relation to inotropic interventions. Results: MPI demonstrated a strong and linear relationship to both preload and after-load, and this was due to changes in ejection time, and not the isovolumic intervals.  Long axis segmental dyssyn­chrony increased during each hour of endotoxin infusion and global myocardial injury.  This dysyn­chrony parameter was independent of load when tested by IVCBO. Peak systolic velocities were strongly load-independent, though not in all the inotropic situations and by all measurement axes.  Peak systolic strain was load-dependent, and not strongly related to inotropic conditions.  Peak sys­tolic LV twist and untwist were strongly load-dependent. Conclusions: MPI is strongly load-dependent, and can vary widely in value for the same contractile status if the load is varied.  Mechanical dyssynchrony measures are load-independen in health and also in early global endotoxin myocardial injury and dysfunction.  Peak sytole velocities are a clinically robust parameter of LV regional and global performance under changing load, though peak systolic strain seems to be load-dependent.  Left ventricular twist and untwist are load-dependent in this pig model.

The aim of this study was to assess the effects of the four most used anaesthetics in European aquaculture MS 222, clove oil, 2-phenoxyethanol and Propiscin on barbel (Barbus barbus). The effects of anaesthetics were assessed based on haematological profile, biomarker of oxidative stress and antioxidant enzymes. This study contributed to the expansion of knowledge on the safety of tested anaesthetics and selected safe anaesthetics for barbel. Barbels were exposed to a 10-minute anaesthesia with MS 222 (in recommended concentration 100 mg×l-1), clove oil (in recommended concentration 33 mg×l-1), 2-phenoxyethanol (in recommended concentration 0.4 ml×l-1) and Propiscin (in recommended concentration 1 ml×l-1). The effects of anaesthetics were evaluated immediately after 10 min. anaesthesia and 24 hours after anaesthesia. Anaesthesia with MS 222, clove oil, 2-phenoxyethanol and Propiscin had no significant effect on haematological indices, level of oxidative stress (TBARS) and activity of glutathione reductase in barbel tissues. The activity of catalase was significantly increased in the muscle 24 h after anaesthesia of all anaesthetics compared to the control. Superoxide dismutase activity was changes in all experimental groups (immediately after 10 min. anaesthesia and 24 hours after anaesthesia). The tested anaesthetics not altered hematopoietic tissue and had not effect on the level of lipid peroxidation in barbel´s tissues. The results of this study suggest that the antioxidant systems of barbel are altered by Propiscin anaesthesia, but they are slightly affected by MS 222, clove oil, and 2-phenoxyethanol anaesthesia. On the basis of the results of this thesis, for anaesthesia of barbel we can recommend clove oil and 2-phenoxyethanol as an alternative MS 222.

Orientador: Angélica de Fátima de Assunção Braga / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-24T07:44:34Z (GMT). No. of bitstreams: 1 Carvalho_VanessaHenriques_D.pdf: 2552683 bytes, checksum: d3aa5b35758ce570c520c2ba8cc486fc (MD5) Previous issue date: 2013 / Resumo: Os anestésicos locais (AL) podem interagir com os bloqueadores neuromusculares (BNM) e modificar as suas propriedades farmacocinéticas e farmacodinâmicas, no entanto o mecanismo dessa interação é controverso. Este estudo experimental, realizado em preparações nervo frênico - hemidiafragma de rato e músculo biventer cervicis de pintainho, teve por objetivo avaliar o efeito de diferentes AL na transmissão neuromuscular e sua influência no bloqueio produzido pelo pancurônio. Foram avaliados os seguintes parâmetros: efeito na transmissão neuromuscular dos AL (ropivacaína, levobupivacaína, mistura em excesso enantiomérico de bupivacaína) e do pancurônio empregados isoladamente; o bloqueio produzido pelo pancurônio em preparações previamente expostas aos AL; a eficácia da neostigmina e da 4-aminopiridina na reversão do bloqueio neuromuscular produzido pelo pancurônio isoladamente e em preparações previamente expostas aos AL; a ação dos AL na resposta contraturante à acetilcolina; seus efeitos nos potenciais de membrana e nos potenciais de placa terminal em miniatura. Os resultados foram expressos em médias e desvios padrão e analisados através dos testes t de Student, Wilcoxon, Anova, Kruskall-Wallis e Mann-Whitney. Adotou-se um nível de significância de 5% (p<0,05). Na preparação nervo frênico - hemidiafragma de rato, os AL nas concentrações empregadas, não alteraram a amplitude das respostas musculares mas, potencializaram o efeito do pancurônio. O bloqueio neuromuscular foi parcial e totalmente revertido com a neostigmina e com a 4-aminopiridina, respectivamente. Não causaram alteração significativa nos potenciais de membrana e produziram diminuição progressiva na amplitude e na frequência dos potenciais de placa terminal em miniatura. Na preparação biventer cervicis de pintainho os AL, com exceção da ropivacaína, promoveram diminuição na resposta contraturante da acetilcolina. Os resultados obtidos neste estudo demonstram um sinergismo entre os fármacos estudados, resultante das ações pré e pós-juncionais dos anestésicos locais / Abstract: Local anaesthetics (LA) may interact with neuromuscular blockers and modify their pharmacokinetic and pharmacodynamic properties. However, the mechanism of this interaction is controversial. This experimental study, conducted in rat phrenic nerve diaphragm preparations and chick biventer cervicis, aimed to evaluate the effect of different LA in neuromuscular transmission and its influence on pancuronium induced blockade. The following parameters were evaluated: the effect on neuromuscular transmission of LA (ropivacaine , levobupivacaine mixture enantiomeric excess bupivacaine) and pancuronium used in isolation; the blockade produced by pancuronium in preparations previously exposed to LA; the effectiveness of neostigmine and 4 - aminopyridine in the reversal of neuromuscular blockade produced by pancuronium alone and in preparations previously exposed to AL; the action of LA in the contractile response to acetylcholine; its effects on membrane potentials and miniature endplate potentials. The results were expressed as means and standard deviations and analyzed using Student's t, Wilcoxon, ANOVA, Kruskal-Wallis and Mann-Whitney tests. A significance level of 5 % (p < 0,05) was adopted . In the rat phrenic nerve diaphragm preparation the LA, in the concentrations used, did not alter the amplitude of muscle response but potentiated the effect of pancuronium. Neuromuscular blockade was partially and fully reversed with neostigmine and 4- aminopyridine, respectively. There was no significant change in membrane potential and a progressive decrease in the amplitude and frequency of miniature endplate potentials was produced. In the chick biventer cervicis preparation the LA, with the exception of ropivacaine, led to a decrease in the contractile response to acetylcholine. The results of this study demonstrate a synergistic effect between the drugs studied, resulting from prejunctional and postjunctional actions of LAs / Doutorado / Farmacologia / Doutora em Farmacologia

Despite the consensus that glutamatergic and GABAergic imbalance is likely to be involved in anesthesia or coma, there is little known about molecular mechanisms of action of gaseous anesthetics. The target article by Smythies (1999) is engagingly analytical and insightful, proposing novel and testable hypotheses for the molecular mechanisms of action of anesthetics as well as for processes that may be involved in coma. The most creative and convincing of his hypotheses concerns the crucial role of iron in maintaining neural respiration and energy production as well as its involvement in synaptic plasticity. Smythies' paper is certain to stimulate new ideas and experiments on the molecular mechanisms of anesthesia and coma.

It is now widely accepted that the experience of pain is subject to cognitive influences that may determine the severity of subjectively perceived pain. Many of these top-down factors rely on memory-based processes, which in turn are related to prior experience, learned beliefs and behaviours about pain. As such, memory for pain heavily contributes to the physical pain experience. We posit that pain memory is bidirectional in that following each painful event a trace is stored and that these traces in turn may modify future pain perception prospectively. The following body of work explores aspects of what we have termed a memory template for pain. The results of these chapters taken together, examine these bidirectional aspects of short-term memory for pain employing a recall pain task. Specifically, we explore how, after an acute pain event, a short-term mental representation of the initial event persists. We show that during this time, sensory re-experiencing of the painful event is possible. Furthermore, we investigate aspects of recalled pain, namely intensity and vividness. Data suggests that the intensity and the vividness of this mental representation are determined by the intensity of the initial stimulus, as well as the time-to-test delay. We identify regions that characterise short-term memory for pain. Following on from studies in motor and visual imagery, we explore how pain imagery in the form of recall may affect subsequent pain perception. Our results demonstrate that the inclusion of pain-related imagery preceding physical pain events reduces affective qualities of pain. Testing healthy, naïve subjects, we replicate the effect observed in studies using attention management and imagery strategies, which normally require extensive training. Finally, in a cohort of neuropathic pain patients we show significant reductions in white matter connectivity between areas responsible for working and prospective memory. Collectively, these studies emphasise and elucidate the role of short-term memory of pain in physical pain perception. Acting both retrospectively and prospectively, cognitive reinforcement can increase or decrease the subjective feeling of pain, and therefore manipulating how pain is recalled may have therapeutic potential.

<p>Succinylcolin är ett icke-depolariserande muskelrelaxantia som används inom anestesisjukvård. En vanlig biverkning är postoperativ myalgi. Varför smärtan uppstår är inte helt klarlagd. Under många år har forskare runt om i världen försökt komma till rätta med problemet utan att helt lyckas.Olika läkemedel och strategier har prövats. En av de viktigaste uppgifter en sjuksköterska har är att förebygga och lindra lidande. Som anestesisjuksköterska finns det möjlighet att påverka den vård som ordineras. Syftet med studien var att undersöka vilka metoder som kan förebygga postoperativ myalgi orsakad av succinylcolin. En litteraturstudie baserad på tio vetenskapliga artiklar genomfördes. Resultatet visade att parecoxib preoperativt samt premedicinering med diklofenakplåster gav det bästa resultatet när det gäller reducerande av myalgi. Med hjälp av dessa så vanliga läkemedel kan onödigt lidande förebyggas och samhällsekonomiska resurser sparas.</p><p> </p>