Nociception level during anaesthesia : analysis and control

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Nociception Level During

Anaesthesia

Analysis and Control

Ana Castro

Departamento de Engenharia Electrotécnica e de Computadores Faculdade de Engenharia da Universidade do Porto

A thesis submitted for the degree of Doctor in Biomedical Engineering

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Nociception Level During Anaesthesia

Analysis and Control

by Ana Castro

Advisor: Catarina S. Nunes (PhD)

(King's College London, United Kingdom)

Co-Advisor: Fernando Gomes de Almeida (PhD)

(Faculdade de Engenharia da Universidade do Porto, Portugal)

Clinical Advisor: Pedro Amorim (MD)

(Instituto de Ciências Biomédicas de Abel Salazar da Universidade do Porto, Portugal)

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Financial Support by the Fundação para a Ciência e a Tecnologia. Under the reference SFRH/BD/35879/2007.

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Reserve your right to think, for even to think wrongly is better than not to think at all. Hypatia of Alexandria

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Acknowledgements

The work developed during the course of this doctoral program, and here presented, was possible with the contribution of a wide group of people that somehow touched me during this period, and to only some of whom it is possible to give particular mention. Let me begin by thanking the support and scientic rigor forwarded by my advisor Prof. Catarina S. Nunes, as well as for the refreshing look and tireless meetings with my co-advisor Prof. Fernando Gomes de Almeida.

My special thanks to the person who introduced me into the hospital environment, and gave me a privileged knowledge on the medical specialty of Anesthesiology, Dr. Pedro Amorim, for his endless enthusiasm for discovery and readiness to face new chal-lenges and projects.

I would like to acknowledge the Investigação Clínica do Serviço de Anestesiologia, of Santo António Hospital, who welcomed me during this period, to the Director of the Serviço de Anestesiologia Dra. Isabel Aragão Fechs, the Director of the Serviço de Bloco Operatório Dr. Simão Barros Esteves, and to the Director of the Departamento de Anestesiologia Cuidados Intensivos e Emergência Dr. António Marques da Silva, for their support in the approved research studies.

I would like to thank the prompt and tireless collaboration of a large group of professionals, who always made available to support data collection performed at the Urology operating room: nurses, surgeons, auxiliaries, anesthesiologists, interns, there were many who contributed for a successful outcome, and to which I leave a warm thank you. I leave my special thanks to the anesthesiologists who accompanied me throughout these years Dra. Eduarda Amadeu, Dra. Fátima Martins and Dra. Paula Sá Couto, it was thanks to their support, patience, teaching, and personal involvement that this

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work has gained strength, it was with them that I have learned and gained inspiration for Medicine. A warm thank you to the intern Diana Afonso, to which was a pleasure to work and share experiences with.

I would like to thank all patients and volunteers who agreed to participate in the studies, from whom I always received the maximum collaboration. I also would like to acknowledge Neurinbloc, Helena and Filipe, for their expertise and collaboration.

I was fortunate to nd several funny and interesting friends during the course of this work, I would like to leave a particular warm mention to my lab mates, Susana Brás and Nadja Bressan, who attended over the years always with a friendly word and stories of happiness. To Sónia Gouveia for the wise counsels, and Ana Maria and Aura Maia for the interesting discussions, my warm thank you.

To my friends Fernanda and Tiago, for the friendship and good years in the uni-versity, and to my friend Célia Cruz, who has accompanied me since the rst steps in school, companion and witness of life, thank you for the certainty of mutual support that has always united us.

A special and caring thank you to Silvio for the love, and companionship that carried and kept me going in the nal moments.

Of course, I would not forget my doggy roommates, Óscar and Maggie, for the love, friendship, and no doubt endless joy with which they wake me up, and receive me at home, every single day.

I thank my family, in particular my parents in my heart for all the dedication and unconditional love. My eternal gratitude and love.

Last but not least, I would like to acknowledge the nancial support provided by the Fundação para a Ciência e a Tecnologia, Portugal (SFRH/BD/35879/2007), for the scholarship which allowed my dedication in full time to the development of this thesis. Porto, November 2011 Ana Castro

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Abstract

Nociception Level During Anaesthesia: Analysis and

Control

This thesis aims to study and develop objective measures of the nociception/anti-nociception balance during anaesthesia. In spite of the increasing interest in recent years on both pain regarding to surgery and objective assessment of the analgesia component adequacy, these are still open issues due mainly to the fact that general anaesthesia pre-supposes an unconscious subject, which implies lack of collaboration from the subject. Due to this fact, the term nociception is used instead of pain whenever regarding to unconscious subjects. However, diculties in assessing pain in the conscious sub-ject also apply to the nociception/anti-nociception assessment under anaesthesia, due to the particular characteristics of pain sensing, and the inter-patient variability re-garding baseline and amplitude responses to stimulus intensity and attenuation drugs, which makes the identication of the optimum state for the individual a dicult task. This thesis is focused on the problem of analysis and control of nociception, in subjects submitted to general anaesthesia.

Seeking to answer some of the questions on nociception/anti-nociception balance assessment in anaesthesia, this thesis comprises a survey applied to clinical anaesthesio-logists, a clinical study in surgical patients under general anaesthesia, a clinical study in volunteers, and a simulation study on closed-loop control of an anaesthetic drug. This thesis also provides a comprehensive review on the the topic of objective assessment of nociception and analgesia balance during general anaesthesia.

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The rst step to a objective nociception/anti-nociception balance assessment is to answer the question how intense is the noxious stimulus applied to the patient triggering the observed physiological responses?. To answer this question a survey was conducted in clinical anaesthesiologists to assess clinical perception of the intensity of noxious stimuli related to anaesthetic and surgical procedures. A total of 57 anaesthesiologists answered the survey, rating 35 stimuli in an ordinal scale from 0 to 10. Later, this information was used to construct a measure of noxious stimulus intensity, using Rasch analysis, which was presented in the form of scale. Regarding to a surgical procedures under general anaesthesia, this scale allows an estimative of the stimuli intensity during the procedures, and also allows to model the input drugs' doses and stimuli intensities impact on the physiological variables linked to noxious activation.

The rst clinical study was focused on the response to precise noxious stimuli, at dierent analgesic drug doses under a TIVA TCI general anaesthesia of propofol (hyp-notic) and remifentanil (analgesic). Collected physiological data were pre-processed, with emphasis on the collected waves in order to extract relevant information on no-xious activation. Such information includes heart rate, pulse plethysmography wave amplitude, systolic blood pressure, respiration rate and EEG derived indexes. Data were inspected in order to identify physiological variables responding adequately to the stimulus and to the analgesic dose attenuation. A total of 34 patients were enrolled in the study following informed consent and institutional approval, and randomly divided in three study groups according to the remifentanil dose (Ce=2.0, 3.0 or 4.0 ng/ml). Based on current state of the art, two dierent methodologies were used. The rst was an homeostasis index, combination of steady-state individual indexes of each va-riable shown to contain information on noxious activation, applying wavelet analysis adjusted to each physiological signal characteristics. The second was a physiological dynamic model incorporating the previously identied physiological signals linked to noxious activation, capable of estimating patients' perceived stimulus as a combination of the developed scale of noxious stimuli intensity and analgesic drug dose attenua-tion/depression. Both methodologies provided complementary information, and were shown to adequately respond to precise noxious stimulation and analgesic attenuation. The second clinical study was designed to investigate the applicability of somatosen-sory evoked responses to assess the nociception/anti-nociception balance, for dierent combinations of propofol and remifentanil. A total of 10 healthy volunteers were enrolled in this study, following informed consent and institutional approval. Evoked responses

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to painful electrical stimuli were measured on the somatosensorial brain area, and re-lated to the stimulation intensity and anaesthetic drugs' attenuation. This approach allowed the detection of individual sensing thresholds and expected response to pattern stimulation, which presented large interindividual variability. In this study cortical so-matosensory evoked potentials were found to be related to the stimulus intensity, to pain reported by the volunteer in a numerical rating scale (0 to 10), and to drug atte-nuation in a dose dependent manner, both with propofol and remifentanil. This may congure a direct and objective method to translate the nociception/anti-nociception balance in uncommunicative patients, allowing for the construction of normalized mea-sures, comparable between subjects.

Finally, a simulation study on the closed-loop control of a general anaesthetic drug was conducted. Control in anaesthesia has been extensively investigated in the last years, with proposed automatic administration systems for the muscle relaxant and hypnotic drug, which correspond to general anaesthesia components that already have validated monitors to translate the patient's state. A new approach to the control of anaesthetic drugs' administration is here presented for the hypnotic component, taking into account inter-patient variability described in the modelling process. The technique employed was a sliding-mode controller, that presented robust responses to patients diering from the nominal. The common features to the analgesia component, and the necessary studies to further evolve in the automatic administration of general anaesthe-sia were discussed.

Summarizing, two approaches to the nociception/anti-nociception balance assess-ment were proposed in this thesis, diering from the methods presented in the lite-rature, and shown to adequately respond to noxious stimulus and anaesthetic drugs. Future studies should be conducted to further develop and validate the proposed inde-xes. Following its validation, the indexes may be employed in the closed-loop control of the nociception/anti-nociception balance during anaesthesia, taking into account the observed inter-patient variability.

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Resumo

Análise e Controlo do Nível de Nocicepção Durante a

Anestesia

Esta tese tem como nalidade o estudo e desenvolvimento de medidas objetivas do balanço nocicepção/anti-nocicepção durante a anestesia. Apesar do crescente interesse, nos últimos anos, acerca da dor relativa à cirurgia e também de uma avaliação objectiva da adequação da componente analgesia, estas questões ainda permanecem em aberto devido, principalmente, ao facto da anestesia geral pressupor um indivíduo inconsciente, o que implica a impossibilidade de colaboração por parte do paciente. Devido a este facto, o termo nocicepção é usado no lugar de dor sempre no que se refere a indiví-duos inconscientes. No entanto, as diculdades em avaliar dor no indivíduo consciente também se aplicam à avaliação da nocicepção/anti-nocicepção sob anestesia, devido às características particulares da percepção de dor, e a variabilidade inter-individual observada nos valores basais e amplitude de respostas relativamente à intensidade do estímulo e drogas atenuantes, o que torna a identicação do estado óptimo para o indi-víduo, uma tarefa difícil. Esta tese foca o problema da análise e controlo da nocicepção em indivíduos submetidos a anestesia geral.

Procurando responder algumas das questões relacionadas com a avaliação do ba-lanço nocicepção/anti-nocicepção em anestesia, esta tese compreende um questionário aplicado a anestesiologistas clínicos, um estudo clínico em pacientes cirúrgicos sob anes-tesia geral, um estudo clínico em voluntários e um estudo em simulação do controlo em malha fechada de uma droga anestésica. Esta tese compreende ainda uma revisão

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abrangente sobre a avaliação objectiva da nocicepção e analgesia durante a anestesia geral.

O primeiro passo para uma avaliação objectiva do balanço nocicepção/anti-nocicepção é responder à questão quão intenso é o estímulo nóxico aplicado ao paciente que despo-leta as reacções siológicas observadas?. Para responder a esta questão um questionário foi conduzido e aplicado a anestesiologistas clínicos para avaliar a percepção da intensi-dade de estímulos nóxicos relativos aos procedimentos da anestesia e cirurgia. No total, 57 anestesiologistas responderam ao questionário, avaliando 35 estímulos, numa escala ordinal de 0 a 10. Posteriormente, esta informação foi utilizada na construção de uma medida de intensidade do estímulo nóxico, aplicando análise de Rasch, e apresentada sob a forma de uma escala. Relativamente a um procedimento cirúrgico sob anestesia geral, esta escala fornece uma estimativa da intensidade de estímulos nóxicos, e permite também a modelação do impacto das entradas intensidade de estímulo e doses de drogas atenuantes, nas variáveis siológicos relacionadas com activação nóxica.

O primeiro estudo clínico foi focado na avaliação das respostas a estímulos nóxicos precisos, para diferentes doses de anestésicos durante uma anestesia geral TIVA TCI de propofol (hipnótico) e remifentanil (analgésico). Os dados siológicos recolhidos foram pré-processados, com ênfase nas ondas recolhidas de modo a extrair informação rele-vante sobre activação nóxica. Tal informação inclui frequência cardíaca, amplitude da onda de pulso, pressão arterial sistólica, frequência respiratória e índices derivados do EEG. Os dados foram inspeccionados de modo a identicar as variáveis siológicas que respondem adequadamente ao estímulo e à atenuação pela droga analgésica. No total, 34 pacientes foram incluídos no estudo, após consentimento informado e aprovação ins-titucional, e divididos aleatoriamente em três grupos de estudo de acordo com a dose de remifentanil (Ce=2.0, 3.0 ou 4.0 ng/ml). Com base no estado da arte, duas metodologias diferentes foram aplicadas. A primeira, um índice de homeostasia, combinação de índi-ces individuais de estacionaridade para cada variável que se mostrou conter informação sobre activação nóxica, aplicando análise wavelet ajustada às características de cada sinal siológico. A segunda, um modelo siológico dinâmico incorporando as variáveis siológicas anteriormente identicadas como relacionadas com activação nóxica, capaz de estimar a percepção do estímulo por parte do paciente, como combinação da escala de intensidade de estímulos nóxicos e a atenuação/depressão fornecida pelo analgésico. As duas metodologias forneceram informação complementar, e demonstraram responder adequadamente a estímulo nóxicos precisos e à atenuação analgésica.

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O segundo estudo clínico foi desenhado para investigar a aplicabilidade das res-postas somatosensoriais evocadas na avaliação do balanço nocicepção/anti-nocicepção, para diferentes combinações de propofol e remifentanil. No total, 10 voluntários sau-dáveis foram incluídos no estudo, após consentimento informado e aprovação institu-cional. Respostas evocadas a estímulos eléctricos dolorosos foram medidas na área somatosensorial do córtex e relacionadas à intensidade de estimulação e atenuação por drogas anestésicas. Esta abordagem permitiu a detecção de limiares sensitivos e da resposta esperada a uma estimulação padronizada, apresentando elevada variabilidade inter-individual. Neste estudo, potenciais evocados somatosensitivos corticais foram re-lacionados com a intensidade do estímulo, com a dor reportada pelo voluntário numa escala numérica de dor (0 a 10), e com a atenuação fornecida pelas drogas propofol e remifentanil. Esta abordagem pode congurar um método directo e objectivo na tradução do balanço nocicepção/anti-nocicepção em pacientes incapazes de comunicar, permitindo a construção de medidas normalizadas, comparáveis entre indivíduos.

Finalmente, foi conduzido um estudo em simulação do controlo em malha fechada de uma droga anestésica geral. Controlo na anestesia tem sido consideravelmente inves-tigado no últimos anos, com sistemas propostos para o controlo automático das drogas relaxante muscular e hipnótico, que correspondem a componentes da anestesia geral que já dispõem de monitores validados para traduzir o estado do paciente. Uma nova abordagem ao controlo de drogas anestésicas é aqui apresentada para a componente da hipnose, levando em consideração a variabilidade inter-individual descrita no processo de modelação. A técnica utilizada foi slinding-mode control, que apresentou uma resposta robusta para pacientes diferentes do nominal. As características comuns à componente analgesia da anestesia geral, e os estudos necessários para o desenvolvimento de um sistema de controlo automático da anestesia geral foram discutidos.

Resumindo, duas abordagens para a avaliação do balanço nocicepção/anti-nocicepção durante a anestesia geral foram propostas nesta tese, diferindo dos métodos propostos na literatura, com resposta adequada à introdução de estímulos nóxicos e drogas anes-tésicas. Estudos futuros deverão ser conduzidos no sentido de desenvolver e validar os índices propostos. Após validação, os índices poderão ser aplicados no controlo em malha fechada do balanço nocicepção/anti-nocicepção durante anestesia, levando em consideração a variabilidade inter-individual observada.

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Résumé

Analyse et Contrôle de le Niveau de la Nociception dans

Anesthésie

Cette thèse adresse l'étude et le développement des mesures objectives de l'équilibre nociception/anti-nociception pendant l'anesthésie. En dépit de l'intérêt croissant sur l'étude des deux douleurs relatives à la chirurgie, et l'évaluation objective de la per-tinence de la composante analgésique, ces questions restent encore ouvertes en raison principalement du fait que l'anesthésie générale suppose un sujet inconscient, ce qui implique l'absence de collaboration du sujet. En conséquence, le terme nociception est utilisé au lieu de douleur à chaque fois qu'on vise des sujets inconscients. Toutefois, la diculté en ce qui concerne l'évaluation également de la douleur dans le sujet conscient s'appliquer à l'évaluation nociception/anti-nociception sous anesthésie, en raison des caractéristiques particulières de la détection de la douleur, et de la variabilité inter-patient concernant les réponses de base et l'amplitude de l'intensité du stimulus et de la drogue d'atténuation, ce qui rend une tâche dicile l'identication de l'état optimal pour l'individu. Cette thèse est axée sur le problème de l'analyse et du contrôle de la nociception, chez les sujets soumis à une anesthésie générale.

Cherchant des réponses à certaines questions sur l'équilibre nociception et anti-nociception en anesthésie, cette thèse comporte une étude appliquée des anesthésistes clinique, une étude clinique chez les patients chirurgicaux sous anesthésie générale, une étude clinique chez des volontaires, et une étude de simulation sur la fermeture d'une

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boucle de contrôle d'un drogue anesthésique. Cette thèse propose également un exa-men complet sur le sujet de l'évaluation de l'objectif de la nociception et l'équilibre analgésique pendant l'anesthésie générale.

La première étape d'une évaluation de l'équilibre nociception/anti-nociception est de répondre à la question suivante Quelle est l'intensité de la stimulation nociceptive appliquée au patient qui déclenche les réponses physiologiques observées ?. Pour ré-pondre à cette question, une questionnnaire a été menée dans les anesthésistes cliniques an d'évaluer la perception clinique de l'intensité des stimuli nocifs liés aux procédures d'anesthésie et de chirurgie. Un total de 57 anesthésistes ont répondu, classiant 35 stimuli dans une échelle ordinale allant de 0 à 10. Ultérieurement, cette information a été utilisée pour construire une mesure de l'intensité du stimulus nociceptif, en utilisant l'analyse de Rasch, qui a été présenté sous la forme d'échelle. En ce qui concerne une intervention chirurgicale sous anesthésie générale, cette échelle permet une estimative de l'intensité des stimuli au cours des procédures, et permet également de modéliser les doses des drogues d'entrée et les stimuli intensités impact sur les variables physiologiques liés à l'activation nocives.

La première étude clinique a portée sur la réponse à des stimuli nocifs, notamment à diérentes doses de drogues anesthésiques sous anesthésie générale TIVA TCI du propo-fol (hypnotique) et rémifentanil (analgésique). Les données physiologiques recueillies ont été prétraitées, en mettant l'accent sur les ondes recueillies visant l'extraction des infor-mations pertinentes sur l'activation nocives. Ces inforinfor-mations comprennent le rythme cardiaque, pouls pléthysmographie amplitude de l'onde, la pression artérielle systolique, taux de respiration et EEG dérivé indexes. Les données ont été inspectées an d'iden-tier les variables physiologiques qui permettent une réponse adéquate à la stimulation et à l'atténuation de la dose analgésique. Un total de 34 patients ont été inclus dans l'étude après consentement éclairé et à l'approbation institutionnelle, et répartis au ha-sard en trois groupes d'étude en fonction de la dose de rémifentanil (Ce=2,0, 3,0 ou 4,0 ng/ml). Basé sur l'état actuel de la technique, deux méthodologies diérentes ont été utilisées. Le premier était un indice homéostasie, la combinaison de l'état stable des indices individuels de chaque variable a montrée contenir des informations sur l'activa-tion nocive, en appliquant l'analyse en ondelettes ajustés à chaque caractéristique du signal physiologique. Le second était un modèle physiologique dynamique intégrant les signaux physiologiques liée à l'activation nocives précédemment identiées, capable de reproduire les relations entre l'estimation de relance perçu par le patient comme une

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combinaison de l'échelle développée de l'intensité des stimuli nocifs et dose de drogue analgésique d'atténuation/dépression . Les deux méthodologies ont fourni des informa-tions complémentaires, et ont montré être capables de répondre adéquatement à une stimulation nociceptive précis et d'atténuation analgésique.

La seconde étude clinique a été conçue pour étudier l'applicabilité des réponses so-mesthésiques évoquées pour évaluer l'équilibre nociception/anti-nociception, pour dif-férentes combinaisons de propofol et de rémifentanil. Un total de 10 volontaires sains ont été inclus dans cette étude, après consentement éclairé et à l'approbation institu-tionnelle. Des réponses évoquées à des stimuli électriques douloureuses ont été mesurées sur la zone du cortex somatosensoriel, et liées à l'intensité de la stimulation et l'at-ténuation des drogues anesthésiques. Cette approche a permis la détection de seuils individuels de sensibilité et réponse attendue à la stimulation standardisée, qui présen-tait une grande variabilité interindividuelle. Dans cette étude, a été trouvée une liaison entre les potentiels évoqués somesthésiques corticaux et l'intensité du stimulus de la douleur rapportée par le bénévole dans une échelle d'évaluation numérique (0 à 10), et à l'atténuation de drogue d'une manière dose dépendante, à la fois avec du propofol et de rémifentanil. Cela peut congurer une méthode directe et objective de traduire l'équi-libre nociception/anti-nociception chez les patients peu communicatifs, permettant la construction de mesures normalisées, comparables entre les sujets.

Finalement, il a aussi été menée une étude de simulation sur le contrôle en boucle fer-mée d'un drogue anesthésique général. Le contrôle de l'anesthésie a été largement étudié dans ces dernières années, en ce qui concerne les systèmes d'administration automatique pour le relaxant musculaire et hypnotique, qui correspondent aux composantes géné-rales de l'anesthésie qui ont été déjà validés moniteurs qui traduisent l'état du patient. Une nouvelle approche pour le contrôle de l'administration des drogues anesthésiques est ici présentée pour la composante hypnotique, en tenant compte de la variabilité inter-patient décrite dans le processus de modélisation. La technique employée est ba-sée sur un contrôleur en mode glissant, qui a présenté des réponses robustes dans le cas des patients qui dièrent de la valeur nominale. Les caractéristiques communes à la composante analgésique, et les études nécessaires pour continuer l'évolution dans l'administration automatique de l'anesthésie générale ont été discutés.

En résumé, deux approches pour la évaluation de l'équilibre nociception et anti-nociception ont été proposées dans cette thèse, qui dière de la méthode présentée dans la littérature. Ces approches ont montré une réponse adéquate aux stimuli nocifs et

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aux drogues anesthésiques. Études futures doivent être menées an de développer et de valider les indices proposés. Après sa validation, les indices pe uvent être utilisées dans le contrôle en boucle fermée de l'équilibre nociception/anti-nociception pendant l'anesthésie, en tenant compte de la variabilité inter-individuelle.

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List of Figures

1.1 First public demonstration of diethyl ether general anaesthesia at the Massachusetts General Hospital, on October 16, 1846. Recreation of the event by Robert Cutler Hinckley completed in Paris in 1892. . . 2

1.2 General anaesthesia components and corresponding informative physio-logical signals. . . 3

1.3 Guedel's stages and planes of ether anaesthesia. . . 5

1.4 Bispectral index monitor during data collection: manufacturer recom-mended target range for general anaesthesia of 40 to 60. . . 8

1.5 Schematic representation of the sensory process in the human body. . . . 9

1.6 Schematic representation of the dorsal horn of the spinal cord layers and terminations of the three types of primary aerent neurons pathways. . . 13

1.7 Brain areas involved in somatic sensation. . . 14

1.8 Schematic representation of pain assessment techniques. From top to bottom: visual analogue scale, numerical rating scale (0 meaning no pain and 10 worst possible pain), and a verbal scale. . . 19

1.9 McGill pain questionnaire: on left the original version in English, and on right the adapted version in Portuguese (Brazil). . . 20

1.10 Remifentanil 2D molecular schematic representation (methyl 1 (3 -methoxy - 3 - oxopropyl) - 4 - (N-phenylpropanamido) piperidine - 4 - carboxylate). . . 21

1.11 Propofol 2D molecular schematic representation (2,6 bis(propan 2 -yl)phenol). . . 23

1.12 Drugs' action path in the human body, from drug dose administration to observed clinical eect. . . 24

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LIST OF FIGURES

1.13 Three compartments pharmacokinetic (PK) model, followed by the phar-macodynamic (PD) model and Hill equation, translating the eect-site concentration into the output measurable eect. Where kij, represents

the drug transfer rate from compartment i to the compartment j (k10

is the elimination rate), and V1, V2 and V3 are the compartments'

volu-mes; in the Hill equation E0 is the eect baseline value, when there is no

drug in the system (Ce = 0), EC50 is the drug eect-site concentration

necessary to achieve half of the maximum measurable eect (E), and γ represents the steepness of the descent of the eect response to the drug. 26

1.14 Screenshot of the educational software specially developed for the simu-lation of target-controlled infusion anaesthesia using BIS or Entropy. It shows the surface relational model between propofol and remifentanil's synergistic eect on the hypnosis indexes. . . 28

1.15 Results obtained by Seitsonen and colleagues: Relative (to prestimulus interval) group average (± standard error of mean) responses to skin in-cision in movers (dashed line) and non-movers (solid line) of (A) EEG response entropy (n=10 and n=12 for movers and non-movers, respecti-vely), (B) RRI (n=12 and n=14), (C) PPG amplitude (n=12 and n=14), and (D) PPG notch amplitude (n=12 and n=14). Skin incision marked with t=0. . . 33

1.16 Bispectral Index (BIS) trend during general anaesthesia, with the in-duction, maintenance and recovery phases. The dashed lines represent the BIS manufacturer recommended target range for general anaesthesia (40-60). Data from one of the patients in this study. . . 36

1.17 Facial muscles involved in the innate response to noxious stimulation. . . 38

1.18 Control structure for a complete automatic administration of general anaesthesia, considering its three components: hypnosis, analgesia and muscle paralysis. . . 41

1.19 Nociception/anti-nociception balance index, translating the optimum state (around 0), the use of excessive analgesic leading to system depression (near -10), and the use of insucient analgesic for the noxious stimulation (near 10). . . 44

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LIST OF FIGURES 1.20 Representation of the relation between the stimulus and administered

drugs on a specic patient, producing an amplitude response (patient sensitivity) in the nociception/anti-nociception balance index. . . 45

2.1 Representation of the dened study groups, according to the eect-site concentration of the analgesic (remifentanil) using Minto model. . . 49

2.2 Flow diagram of the hospital's required procedures to obtain institutional approval for the realization of clinical studies. . . 55

2.3 Clinical setup used in data collection: A) BIS VISTAT M _{monitor; B)}

Orchestra R _{Base Primea syringe pumps in TCI mode (propofol and}

re-mifentainl); C) General Electric Aisys R _{monitor and ventilator; D)}

Com-puter used in data collection with Rugloop c _{Waves installed. . . .} ₅₆

2.4 Monitored patient during a standard data collection with a BIS bilateral sensor, on the left, and the BIS monitor with corresponding BIS and CVI trends for the left channel, on the right. . . 57

2.5 Software developed to analyze and navigate o-line through the collected data for each patient (pati, where i = 1, ..., 34). . . 61

2.6 Original ECG signal (black line), ltered ECG signal (QRS complex enhancing, gray line), and correspondent QRS complex detection (black dot). . . 65

2.7 Original RR time intervals (black line), and interpolated signal re-sampled at 1 Hz: using hermitian cubic spline interpolation (gray line), and cubic spline interpolation (dashed line). . . 65

2.8 Original RR sequence (black line) obtained after interpolation at 1 Hz, correspondent ltered signal after outlier removal (gray line), and RR sequence provided by the Aisys monitor through the heart rate sequence (dashed line). Data from one of the patients in the study. . . 66

2.9 Invasive blood pressure signal with overlapping systolic pressure peaks detected (black dot). Data from one of the patients in the study. . . 67

2.10 Photoplethysmography wave and correspondent wave amplitude deni-tion (PPGA): A is the local minimum at the beginning of the pulse, and B is the local maximum. PPGA is dened as the dierence between the two. . . 68

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LIST OF FIGURES

2.11 Photoplethysmography wave and detected points for amplitude assess-ment (A, white dot, dened as the local minimum and B, black dot, as the wave local maximum). Data from one of the patients in the study. . 69

2.12 CO2 wave and detected point of maximum CO2 for each respiration cycle,

corresponding to the end of an expiratory cycle. Data from one of the patients in the study. . . 69

3.1 Schematic representation of the patient's system and involved variables in the triggered noxious responses. The amplitude of response to noxious stimulation, in this simplied version, is dependent of the drugs' doses (known) and of the stimulus intensity (estimated). Other outer inter-ferences may modify the exhibited relations (signal contamination and changes in pharmacokinetics e.g.). . . 73

3.2 Representation of the hypnotic-analgesic drugs' interaction as an hierar-chical model. . . 78

3.3 Anaesthesiologists' division considering their opinion on which is the most painful stimulus, abdominal incision for apendicectomy (26%), or larin-goscopy/intubation (74%). . . 80

3.4 Total score for each stimulus within the three groups of stimuli studied: anaesthetic procedure stimuli (Ani, i=1,...,11), pre-incision and incision surgical stimuli (PreIncj, j=1,...,10), and post-incision surgical stimuli (PostInck, k=1,...,14). . . 80

3.5 Total scores for each respondent, considering the 35 evaluated stimuli. . 81

3.6 Anaesthesiologist's choice on the preferred range for a nociception/anti-nociception balance index. . . 81

3.7 Representation of the measurement continuum: stimulus location (δi,

i = 1, ..., 35, in the Rasch model), and correspondent expected score in the original rating scale. . . 84

3.8 Representation of the probability of response of each rating score (0 to 10), depending on the location in the pain intensity continuum (logit). . 85

3.9 Relation between score rates (0 to 10) and pain intensity measures (logit), with overlapping 0.5 points of expected score (squares). . . 86

3.10 Representation of raters' location (βn, n = 1, ..., 57, in the Rasch model)

distribution on the measurement continuum (logit). . . 86

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LIST OF FIGURES 3.11 Application of the developed stimulus intensity scale: schematic

repre-sentation of an urological procedure under general anaesthesia with iden-tied stimuli intensities of the anaesthetic and surgical actions. . . 87

3.12 Comparison between pre-intensities estimated in previous pharmacologi-cal studies, and the Rasch spharmacologi-cale obtained using anaesthesiologists noxious stimuli perception. . . 88

4.1 Schematic representation of proposed methods to assess amplitude res-ponses prior and post-stimulation: a) and b) average versus maximum response; c) and d) average values prior and post stimulation. . . 97

4.2 Schematic representation of the laringoscopy and intubation moments, registered in each data set, and the corresponding time lag - stimulus duration. . . 99

4.3 Steady-state detection in the input drugs' eect-site concentration using the arithmetic rule. . . 114

4.4 Diagram presenting the algorithm steps: the patient is the system, with propofol and remifentanil drugs' eect-site concentrations (Ce) as inputs, and output physiological variables entering the wavelet based algorithm to determine the combined steady-state index as summarized. Dashed line rectangle presents the initially used input detection rule, replaced by the wavelet based algorithm. . . 118

4.5 Detailed representation of steady-state detection of the systolic blood pressure trend, in one of the collected data sets. . . 121

4.6 Representation of the input and output steady-state indexes. The bottom trend may be interpreted as an homeostasis index of the subject conside-ring BIS, heart rate, systolic blood pressure, pulse wave amplitude and respiration rate. . . 122

4.7 Schematic representation of the signal processing steps to obtain the indi-vidual and combined steady-state indexes, from data collection, to signal pre-processing unit, and homeostasis index presentation (individual and combined), as implemented in the developed tool for on-line homeostasis assessment. . . 125

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LIST OF FIGURES

4.8 Designed software for on-line assessment of the developed steady-state in-dexes: individually for each input (propofol and remifentanil Ce), output (bispectral index, electromyography, heart rate, blood pressure, photo-plethysmography wave amplitude, respiration rate), and combinations of input and output signals (βInand βOut). Data presented in this example

is from one of the patients of the study, simulating an on-line assessment. 126

4.9 Combined periods of steady-state (SS) input/output in all data sets: relation between drugs' eect-site concentrations (Ce) and average heart rate (HR). The stimuli intensities are represented in dierent colors, with white representing periods without stimulation (0 in the Rasch scale), and increasing gray intensity with increasing stimulus intensity. . . 128

4.10 Representation of the attenuation and depression eects of the analge-sic drug on a stimulus of known intensity, with the introduction of an additional depression curve. . . 130

4.11 From top to bottom: stimulus intensity trend, using author's annotati-ons and intensities estimated by the Rasch analysis; preopioid intensity estimated based on the Rasch scale extrapolation; estimated remifenta-nil eect-site concentration (Ce in ng/ml); postopioidintensity estimates based on extrapolated preopioid intensity and remifentanil attenuation; total surgical stress. Data from one of the patients in the study. . . 134

4.12 Structure representing the impact of anaesthetic drugs and noxious sti-mulus on the physiological measurable eects. . . 135

4.13 Structure of the physiological model, taking into account physiological variables linked to noxious activation dynamical relations, hypnotic drug interference, and output estimation of the perceived stimulus. . . 135

4.14 Modelled perceived stimulus, based on the stimulus intensity and at-tenuation provided by the analgesic remifentanil (output), and bispec-tral index, frontal electromyography, heart rate, systolic blood pressure, pulse plethysmography wave amplitude, and propofol eect-site concen-tration as inputs. (a) Individually adjusted state-space model of or-der 1 to TSS. (b) Individually adjusted state-space model of oror-der 1 to postopioid intensity. . . 138

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LIST OF FIGURES 4.15 Modelled perceived stimulus, based on the stimulus intensity and

attenu-ation provided by the analgesic remifentanil, using total surgical stimulus (TSS) as output signal, and bispectral index, frontal electromyography, heart rate, systolic blood pressure, pulse plethysmography wave ampli-tude, and propofol eect-site concentration as inputs. (a) Individually adjusted state-space model of order 1, in the data set with higher cor-relation to the output signal TSS (corcor-relation of 0.97). (b) Individually adjusted state-space model of order 1, to the data set with lowest corre-lation (correcorre-lation of 0.51). . . 139

4.16 Modelled perceived stimulus, based on the stimulus intensity and attenu-ation provided by the analgesic remifentanil, using total surgical stimulus (TSS) as output signal, and bispectral index, frontal electromyography, heart rate, systolic blood pressure, pulse plethysmography wave ampli-tude, and propofol eect-site concentration as inputs. (a) Data set with higher correlation to the output signal TSS, considering the merged data model. (b) Data set with lowest correlation, considering the merged data model. . . 142

4.17 Designed software for on-line assessment of the developed steady-state indexes, individually or for combinations of input and output signals (βInand βOut), and the estimator of the perceived stimulus, based on the

physiological model for the population. Data presented in this example is from one of the patients of the study, for a simulation of an on-line assessment. . . 144

5.1 Schematic representation of the stimulation pathway from stimulus site to higher processing. . . 151

5.2 Somatosensory evoked potential representation with latency, amplitude and respective vertex potential marks (positive and negative): (a) cortical site; (b) cervical site. . . 153

5.3 Equipment to obtain somatosensory evoked potentials, and process data with time-locked stimulus. . . 154

5.4 Summary of a review of studies evaluating the impact of anesthetic drugs on evoked potentials. . . 158

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LIST OF FIGURES

5.5 Brain schematic representation with sensory, motor and auditory areas outlined. . . 161

5.6 International 10-20 system for electroencephalogram collection. The let-ters used stand for: F-frontal, T-temporal, C-central, P-parietal, O-occipital, and Z referring to the electrodes positioned in the midline. . . 166

5.7 Clinical setup used in the volunteer's study data collection: A) SEPs monitor and stimulation device EndeavorT M _{CR (Nicolet-Vyasis); B)}

Electrical stimulus electrodes placed on volunteer median nerve; C) Aisys monitor and ventilator; D) BIS sensor and SEPs needles montage. . . . 169

5.8 Collected cortical somatosensory evoked potential waves, with dened peaks by the neurophysiology technicians. . . 171

5.9 BIS trends for all volunteers during the experiment (a), and one case in detail (b), centered according to propofol start (time=0). The study was interrupted as soon as the volunteer lost response to verbal command, maintaining response to mechanical stimulation, or by clinical advice. . . 172

5.10 Sensitive (ST), motor (MT), painful (PT) and 1.3 painful (1.3×PT) th-reshold currents of stimulation for each volunteer. . . 173

5.11 Relation between the painful stimulus (a) and 1.3 painful stimulus (b) intensity and the SEPs' latency and amplitude responses prior drug ad-ministration. . . 174

5.12 Numerical rating scale pain evaluations (0-10) for each volunteer both for the painful threshold (PT) and 1.3×PT stimuli. . . 175

5.13 Numerical rating scale evaluations (NRS) versus original (a) and norma-lized (b) SEP amplitude. . . 178

5.14 Numerical rating scale evaluations (NRS) versus: (a) SEP amplitude/SEP latency; (b) normalized SEP amplitude/normalized SEP latency. . . 179

5.15 Anaesthetic drugs impact on somatosensory evoked potentials normalized ratio SEP Normalized Amplitude/SEP Normalized Latency versus: (a) Remifentanil only; (b) Propofol and remifentanil eect-site concentration of 1.0 ng/ml; (c) Remifentanil and propofol eect-site concentration of 1.2 µg/ml. . . 180

5.16 Original (a) and normalized (b) ratio between cervical SEP amplitude and latency, versus evaluations in the numerical rating scale. . . 181

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LIST OF FIGURES 5.17 Normalized cervical SEP ratio versus remifentanil eect-site

concentra-tions for each volunteer. . . 182

5.18 Boxplot of the normalized SEP amplitude/normalized SEP latency ra-tio (RN orm) for the maximum drug doses combination achieved in each

volunteer in each administration scheme: 1 - No drugs; 2 - Remifentanil only; 3 - Propofol increasing steps and constant remifentanil (1.0 ng/ml); 4 - Remifentanil increasing steps and constant propofol (1.2 µg/ml). . . . 182

5.19 Normalized SEP cortical ratio in the original linear scale (a) and loga-rithmic scale (b), versus evaluations in the numerical rating scale. . . 184

5.20 Collected data points from all volunteers considering propofol and re-mifentanil eect-site concentrations (Ce) as inputs, and the normalized SEPs ratio (RN orm) as output measurable eect. . . 185

5.21 Representation of a possible patch to place on the arm for example, to administer the somatosensory stimulus, with multiple sources of contact heat or lasers, that would be activated randomly, and irregularly in time. 189

6.1 Schematic representation of the analogy between the automatic pilot sys-tems in the airplane, and the anaesthesiologists' action during general anaesthesia: induction, maintenance, noxious stimulation regulation and recovery. . . 194

6.2 Schematic representation of the general anaesthesia triad, with corres-ponding anaesthetic drugs, and their direct or indirect interference on each other: line arrows represent the synergy relation between the hyp-notic and the analgesic drugs, dashed arrows represent the impact that the paralysis state of the patient has on the monitoring devices used to assess the hypnosis and analgesia components, and nally dash-dot arrow represents the impact that the hypnotic drug may have on the variables related to noxious activation used to monitor the analgesia component. . 199

6.3 Schematic representation of an automatic control system for the admi-nistration of general anaesthetics, using a input and multiple-output (MIMO) approach for the general anaesthesia triad. . . 201

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LIST OF FIGURES

6.5 Control activity for the nominal patient using the sign function: on top SE and SE reference, below the error sequence, and on bottom the infu-sion rate (ml/h). . . 211

6.6 Control activity for the nominal patient using the saturation function: on top SE and SE reference, below the error, and on the bottom the infusion rate (ml/h). . . 212

6.7 Control activity for the minimum patient using the saturation function: on top SE and SE reference, below the error, and on the bottom the infusion rate (ml/h). . . 212

6.8 Control activity for the maximum patient using the saturation function: on top SE and SE reference, below the error, and on the bottom the infusion rate (ml/h). . . 213

6.9 Representation of the patient modelled system, with possible error in-puts, controller, and state observer, for an on-line implementation of the automatic control of the hypnotic. . . 214

6.10 Schematic representation of the necessary steps to model the relation between the administered analgesic drug dose and the measurable eect, when a tool for this eect is fully validated in the translation of the nociception/anti-nociception balance. . . 215

E.1 Simulink block diagram for the three compartments pharmacokinetic and dynamic model. The kij constants are transfer rates between

compart-ments, massiis the drug mass in each compartment and ce the eect-site

concentration estimated (i, j = 1, ..., 3). . . 250

E.2 Step response simulations for the Schnider model, considering dierent combinations of age, weight, height and gender. . . 251

E.3 Step response simulations for the Minto model, considering dierent com-binations of age, weight, height and gender. . . 252

E.4 Block diagram implemented in Simulink Matlab R_{, with the system}

re-presentation and feedback for the sliding-mode controller, used in the simulations for the nominal, minimum and maximum patients. . . 253

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LIST OF FIGURES E.5 Representation of the diagram block for a possible on-line

implementa-tion, with the input incoming from the monitored values of State Entropy (SE) in the patient, and with the output infusion rate (ml/h) directed to the syringe pump actuator. . . 254

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LIST OF FIGURES

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List of Tables

1.1 The Modied Observer Assessment of Awareness and Sedation Score (OAAS/S). . . 6

1.2 Sensory modalities and corresponding receptors and sense organs. . . 11

1.3 Types of nerve bers that carry aerent impulses to the central nervous system. A and B bers are myelinated, C bers unmyelinated. . . 12

1.4 Stimulus' modalities for induction of experimental cutaneous pain in hu-mans. . . 17

1.5 Stimulus' modalities for induction of muscular pain in humans. . . 18

1.6 Stimulus' modalities for induction of visceral pain in humans. . . 18

1.7 Estimated relations for the parameters of the three compartments Minto pharmacokinetic and dynamic model, and corresponding percent coe-cient of variation (% CV). The parameters incorporate patient's age and lean body mass (LBM). . . 30

1.8 Estimated relations for the Schnider three compartments pharmacokine-tic model parameters. It incorporates patient's age, weight, height and lean body mass (LBM). . . 31

1.9 Average and standard-deviation of the estimated θi (1=1,...,11)

parame-ters in the Schnider pharmacokinetic and dynamic model. . . 31

2.1 Study interruption rules: for each case the anaesthesiologist should re-dene drugs' theoretical eect-site concentration targets, according to patient's needs. . . 51

2.2 Patients' demographics according to the division in the three study groups: no statistical dierence between groups, with P < 0.05 (data as mean±standard-deviation). . . 56

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LIST OF TABLES

2.3 Collected variables (47 in total) at a sampling rate of 1 Hz, exported to *.mat les for each data set. . . 58

2.4 Collected waves, number of channels, sampling rate, and data units. . . 59

2.5 List of noxious stimuli annotated by the author during the procedure, and corresponding code number attributed to the stimulus variable scale. 60

3.1 List of stimuli analyzed in the study, divided according to three groups: stimuli derived from the anaesthesia procedure; stimuli derived from the surgical procedure, pre-incision and incision; and stimuli derived from the surgical procedure post-incision. . . 75

3.2 Total and average scores obtained for each stimulus, divided according to the considered groups, stimuli measures (δi, i = 1, ..., 35, in the Rasch

model, with greater logit values indicating higher pain perception), stan-dard errors (S.E.), expected raw score, Rasch measure parameterized in a scale from 0 to 10, and stimulus identication, in descending order of stimulus intensity perception (reliability of 0.98). . . 83

3.3 Estimated pre-intensities in previous pharmacological studies, and Rasch measures obtained using anaesthesiologists noxious stimuli perception. . 88

4.1 Patients' demographic data (original and phase I nal sample): global and for each considered study group of remifentanil target eect-site con-centration (data as mean±standard-deviation). . . 100

4.2 Patients' distribution on the three possible incision sites, for each group of study, in the nal sample (no statistical dierence between groups). . 101

4.3 Median values for each cardiovascular variable analyzed in the study, for each stimulus (average pre and post stimulation), divided according to the drug dose group: remifentanil eect-site concentration (RemiCe) of 2.0, 3.0, or 4.0 ng/ml (* stands for signicant dierences with P < 0.05). 102

4.4 Median values of BIS related variables analyzed in the study, for each stimulus (average pre and post stimulation), divided according to the drug dose group: remifentanil eect-site concentration (RemiCe) of 2.0, 3.0, or 4.0 ng/ml (* stands for signicant dierences with P < 0.05). . . 103

4.5 Median amplitude response of cardiovascular variables for each stimulus and remifentanil eect-site concentration (RemiCe) target considered in the study. . . 105

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LIST OF TABLES 4.6 Median amplitude response of BIS related variables for each stimulus and

remifentanil eect-site concentration (RemiCe) target considered in the study. . . 106

4.7 Median normalized amplitude response of cardiovascular variables for each stimulus and remifentanil eect-site concentration (RemiCe) target considered in the study. . . 107

4.8 Median normalized amplitude response of BIS related variables for each stimulus and remifentanil eect-site concentration (RemiCe) target con-sidered in the study. . . 108

4.9 Median values of available CVI trends, for each stimulus (average pre and post stimulation), divided according to the drug dose group: remifentanil eect-site concentration (RemiCe) of 2.0, 3.0, or 4.0 ng/ml. . . 109

4.10 Finite impulse response of the lters H, G, K and L that correspond to the quadratic spline wavelet. . . 119

4.11 Normalization coecients λj for the quadratic spline wavelet. For j > 5,

λj = 1, 0. . . 119

4.12 Estimated thresholds based on historic data for each signal analyzed, in a training set of ve patients. . . 120

4.13 Percentage of total time (total of 31 patients), that each signal analyzed in this study phase was found to be in steady-state (SS) conditions (data as mean±standard-deviation). . . 121

4.14 Median values of the proposed homeostasis index (HI): average value in the periods baseline, prior and post-stimulation, for each remifentanil eect-site concentration (RemiCe) group. . . 123

4.15 Normalized amplitude responses of the proposed homeostasis index (HI) to the precise stimuli considered in study phase I, for each remifentanil eect-site concentration (RemiCe) group. . . 124

4.16 Variable scale identies each stimulus with a code number. Stimulus intensities estimated and translated in the Rasch scale, as well as ex-trapolated values for the pre-intensities, considering the linear relation shown in Figure 3.12. Table entries presented in bold correspond to the stimuli that have pre-intensities estimations; original values presented between parenthesis. . . 132

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LIST OF TABLES

4.17 Order 1 state-space models adjusted to the individual data, t statistics, and correlation between output and modelled output. Model 1 corres-ponds to the output TSS, and Model 2 to the output postopioidintensity. Three input sets were considered using bispectral index (BIS), fron-tal electromyography (EMG), heart rate (HR), systolic blood pressure (SBP), pulse photoplethysmography wave amplitude (PPGA), and pro-pofol eect-site concentration (PropCe). Data presented as mean±standard-deviation. . . 137

4.18 Order 1 state-space models adjusted to the merged data sets, t statis-tics, and correlation between output and modelled output, considering baseline removed data, and baseline normalized data. Three input sets were considered using bispectral index (BIS), frontal electromyography (EMG), heart rate (HR), systolic blood pressure (SBP), pulse photo-plethysmography wave amplitude (PPGA), and propofol eect-site con-centration (PropCe). Data presented as mean±standard-deviation. . . . 141

4.19 Average, minimum and maximum values of the merged model output per-ceived stimulus during the maintenance phase, considering all data sets and input set of BIS, EMG, HR, SBP, PPGA and PropCe: population trends. Data presented as mean±standard-deviation. . . 143

4.20 Parameters of the state-space models using the merged data, considering the three input sets. . . 143

5.1 Volunteers' demographic data (data as mean±standard-deviation). . . . 170

5.2 Propofol and remifentanil eect-site concentration targets and interrup-tion rules applied in the study: the study began with remifentanil admi-nistration only, in increasing steps as described in the text, until one of the interruption rules occurred; after interruption the drug doses were re-duced to the rst step considered in the next phase, and drug doses were increased again according to the scheme. The study had three sequent schemes, rst remifentanil only, followed by constant remifentanil and propofol increasing steps, and nally constant propofol and remifentanil increasing steps. . . 170

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LIST OF TABLES 5.3 Numerical rating scale (NRS) evaluations in each volunteer for the

base-line and maximum drug doses combination achieved in each administra-tion scheme (NE - no evaluaadministra-tion). . . 175

5.4 Spearman correlation coecient (rho) for each volunteer between the normalized cortical somatosensory evoked potentials ratio (RN orm),

nu-merical rating scale evaluations, and remifentanil eect-site concentration in the rst administration scheme, where remifentanil is administered in ascending steps, without propofol (N is the number of points used to de-termine the correlation coecient, and * stands for signicant correlation with P<0.05). . . 176

5.5 Spearman correlation coecient (ρ) for the population data between the cortical somatosensory evoked potentials normalized ratio (RN orm) and

the numerical rating scale evaluations, and drug's eect-site concentra-tion in each administraconcentra-tion scheme (where N is the number of points used to determine the correlation coecient). . . 177

6.1 Estimated parameters for the Hill equation using State Entropy monitoring.205

A.1 Recommended doses of remifentanil in co-administration with other ana-esthetic agents for adult patients. . . 230

A.2 Recommended infusion rates of remifentanil according to body weight. . 231

A.3 Infusion velocity of remifentanil and equivalent plasmatic concentrations by approximations of several stabilized manually perfusion of remifentanil when using target controlled infusion. . . 232

E.1 Considered variation intervals in the simulations, regarding the reported parameters and dispersion measures of the pharmacokinetic and dynamic model. . . 255

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LIST OF TABLES

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List of Abbreviations

AAI Auditory Evoked Potential Index

ACC Anterior Cingulated Cortex

AEP Auditory Evoked Potential

ANSSI Autonomic Nervous System State Index

ASA American Society of Anaesthesiologists Physical Status Index

BIS Bispectral Index

BP Blood Pressure

Ce Drug Eect-Site Concentration

CHEPS Contact Heat Evoked Potentials

CO2 Carbon Dioxide

Cp Drug Plasma Concentration

CSSA Clinical Signs-Stimulus-Antinociception

CVI Composite Variability Index

DLPFC Dorsolateral Prefrontal Cortex DNIC Diuse Noxious Inhibitory Control

ECG Electrocardiogram

ECoG Electrocorticogram

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List of Abbreviations

EKF Extended Kalman Filter

EMG Electromyography

fMRI Functional Magnetic Resonance Imaging

HBI Heart Beat Interval

HR Heart Rate

HRbaseline Baseline Heart Rate

HRV Heart Rate Variability

IBP Invasive Blood Pressure

IIR Innite Impulse Response Filter

LOC Loss of Consciousness

MAC Minimum Alveolar Concentration

MIMO Multiple-Input and Multiple-Output

MIR Minimum Infusion Rate

Noc/ANoc Nociception/Anti-Nociception

NRS Numerical Rating Scale

NSRI Noxious Stimulation Response Index

PET Positron Emission Tomography

PKPD Pharmacokinetic and Dynamic

PPC Posterior Parietal Cortex

PPG Pulse Plethysmography

PPGA Pulse Plethysmography Wave Amplitude

RE Response Entropy

RespR Respiration Rate

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RN Response Index of Nociception

ROC Recovery of Consciousness

RR Time interval between QRS complexes

SBP Systolic Blood Pressure

SBPbaseline Baseline Systolic Blood Pressure

SD Standard-Deviation

SE State Entropy

SEP Somatosensory Evoked Potential

SI Primary Somatosensory Cortex

SII Secondary Somatosensory Cortex

SISO Single-Input and Single-Output

SPI Surgical Pleth Index (former SSI)

SS Steady-State

SSI Surgical Stress Index (see SPI)

TCI Target Controlled Infusion

TSS Total Surgical Stress

TTPE Time to Peak Eect

VAS Visual Analogue Scale

VEP Visual Evoked Potential

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Chapter 1

Introduction

The term anaesthesia derives from the Greek word 'anaisthesia', meaning lack of sensation, or insensibility.

Anaesthesiology is a medical specialty that has greatly evolved in the last 50 to 60 years, from the simple idea of inducing pain relief and unconsciousness for a clinical procedure to occur, to a complex set of concepts and interactions, with action in a wide range of clinical procedures [1].

Nowadays, anaesthesia involves sophisticated technology, administration of multiple drugs, trained professionals and demanding regulations. From being a very unsafe and simple procedure, requiring almost no specialized skills, equipment or monitoring (just a few drops of ether poured over the face were enough to provide anaesthetic state), to a complex and high technology procedure. In fact, Anaesthesiology is now a leading specialty in the use of technology and patient safety.

The care and medical standards have taken anaesthesia to a level of demanding and accuracy that challenges the clinician to an active interaction between patient observa-tion, monitoring and drugs' administration. Technological advances and the develop-ment of new drugs have changed the way anaesthesiologists behave in the operating room, improving patient care quality.

From an historical perspective, before anaesthesia was developed and introduced in clinical practice, surgical procedures occurred while the patient remained conscious

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1. INTRODUCTION

and sensible to painful stimulation. Besides being a traumatic and terrifying experience, these interventions had a high risk of complications, during and following the procedure. Aware of these facts, the concept of producing insensibility was quite appealing for both patients and clinicians, improving patients' wellbeing, and also allowing surgical technical developments with superior quality and success.

Figure 1.1: First public demonstration of diethyl ether general anaesthesia at the Mas-sachusetts General Hospital, on October 16, 1846. Recreation of the event by Robert Cutler Hinckley completed in Paris in 1892 [2].

The rst surgical procedure to occur under anaesthesia administration (Oct. 16 1846) was wrapped in controversy, due to the use of a secret compound which was in fact pure unadulterated sulfuric ether. Although ether use was registered two years before, for short dentistry procedures, however only in the referred public demonstration, a longer surgical intervention took place at the Massachusetts General Hospital (see Figure

1.1) [2,3].

Later, in 1847, the use of chloroform was introduced and the concept of general anaesthesia began to gain form. Although this technique showed great advantages com-pared to previous approaches, there were (and still are) associated risks that soon proved to be the worst possible. In January 1848, soon after the introduction of chloroform for anaesthetic use, the rst of many fatalities occurred: a 15-year-old girl died while recei-ving a chloroform anaesthesia [4], showing that it required careful titration, beginning the long road of drug development, patient monitoring and eects' balance, which the anaesthesiologist still needs to go through.

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1.1 General Anaesthesia Triad

Every cause produces more than one eect. Herbert Spencer

Figure 1.2: General anaesthesia components and corresponding informative physiologi-cal signals.

In the specic literature general anaesthesia is commonly described as being composed by three main components: hypnosis, analgesia and paralysis (see Figure1.2). For each of these components, the anaesthesiologist administers specic drugs, aiming at an op-timum combined state, conditioned by patient's characteristics, clinical background and individual response to the treatment. A major challenge anaesthesiologists face in their clinical practice resides in drug combination, titration, and anticipation of unwanted events. To respond to this challenge, the clinician uses all information available (pa-tient data, clinical history, monitored physiological responses to treatment) to provide and maintain homeostasis in the patient, i.e. to provide and maintain a stable and comfortable condition regarding the patient as a whole [5].

To evaluate patients' state regarding each component of general anaesthesia, the clinician stays alert for any indication of inadequate anaesthesia in dierent biological signals and derived measures. For example, Electroencephalogram (EEG) based moni-tors give information on the patient's state regarding the hypnosis component. Usually

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1. INTRODUCTION

these monitors translate the information contained in the EEG patterns into simple and easy to use indexes, varying from 0 (isoelectric EEG) to 100 (fully awake patient) [6].

For the paralysis component, neuromuscular monitors allow to assess the state of the patient regarding muscle relaxation, through the evaluation of the response to dierent electrical stimulation patterns and currents, using movement sensors (accerelerometry) or Electromyography (EMG) analysis, to evaluate the amplitude response and conse-quently the paralysis degree of the patient.

Regarding the analgesia, there is not yet a widely accepted monitor capable of ob-jectively translating this component. Currently, anaesthesiologists rely on physiological signals related to the autonomous nervous system to indirectly assess adequacy of anal-gesia (see Figure 1.2). Analgesia and pain are dicult to assess due to its subjective nature. In conscious subjects numerical scales are used to assess pain, however in un-conscious subjects these scales become useless. These factors account for absence of a monitor widely accepted or used to objectively assess the analgesic component of ana-esthesia. In the last few years, several researchers have applied their eorts in the search for a tool able to translate the Nociception/Anti-Nociception (Noc/ANoc) balance in unresponsive or uncommunicative patients. Such a tool would be of great importance to control drug administration and assure homeostasis throughout surgical procedu-res, preventing adverse eects of overdosing/underdosing potent drugs, with its adverse physiological responses.

1.1.1 Measuring Nociception - A Parallel Problem to the Hypnosis Measurement

To assess the Noc/ANoc balance it is necessary to identify the steps to be taken before a fully accepted and eective monitor to measure the patient's state regarding this anaesthesia component becomes available. Because this road has already been walked for the monitors developed in the assessment of the other anaesthesia components, it is useful to analyze the steps taken to produce hypnosis indexes, as a parallel problem to the analgesia.

Most of the hypnosis indexes available in the market are calculated using the EEG in the translation of drugs' eect on the human brain (frontal cortex EEG), and con-sequently the hypnosis state of a patient. As aforementioned, EEG analysis has been explored for years in the detection of normal and abnormal patterns considering all consciousness states, both in animal and human subjects [6, 7]. Due to the chaotic

Nociception level during anaesthesia : analysis and control

Nociception Level During

Anaesthesia

Analysis and Control

Ana Castro

Nociception Level During Anaesthesia

Analysis and Control

by Ana Castro

Acknowledgements

Abstract

Nociception Level During Anaesthesia: Analysis and

Control

Resumo

Análise e Controlo do Nível de Nocicepção Durante a

Anestesia

Résumé

Analyse et Contrôle de le Niveau de la Nociception dans

Anesthésie

Contents

List of Figures

List of Tables

List of Abbreviations

Chapter 1

Introduction

1.1 General Anaesthesia Triad