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This thesis investigated the possible use of transdermal iontophoresis in paediatric care, as an alternative strategy to the oral and intravenous routes. More specifically, the potential for non-invasive delivery of ranitidine, midazolam, and phenobarbital; and the clinical sampling of iohexol through the skin were examined. The feasibility for monitoring kidney function was assessed in vitro and in vivo using the glomerular filtration rate (GFR) marker, iohexol. Sampling of iohexol in vitro was sensitive to the changes in its subdermal concentration, and pharmacokinetic parameters estimated from skin sampling agreed well with reference subdermal values. Similar observations were confirmed in vivo in a pilot study performed in four children undergoing routine iohexol GFR test. Iontophoresis was well tolerated in all subjects and the marker was successfully extracted through the skin. In 3 of 4 subjects, the elimination rate constant estimated from skin sampling data agreed well with blood sampling results. This study demonstrated the potential of transdermal iontophoresis as a non-invasive sampling approach which could significantly improve the quality-of-life of children. Drug delivery by transdermal iontophoresis was examined in vitro for three commonly used paediatric medicaments: ranitidine, midazolam, and phenobarbital. Experiments used both intact and compromised pig skin to model the less resistant skin of premature babies. Iontophoretic delivery across intact skin was superior than passive delivery and optimised conditions were achieved by use of maximal molar fraction of the drug, higher current intensity, and appropriate vehicle pH. Pluronic® F-127 gels were suitable drug matrices for the iontophoretic delivery of ranitidine. Midazolam and phenobarbital transdermal delivery through partially compromised skin barriers was controlled by iontophoresis. Across highly compromised skin, however, passive diffusion increased drastically and iontophoretic control was lost. Overall, it was possible to deliver therapeutically meaningful fluxes of all three drugs with acceptable patch application area.

In this thesis, two potential applications of transdermal iontophoresis in the field of sports medicine were studied: (1) the local delivery of dexamethasone phosphate (Dex-Phos), a corticosteroid used to treat musculoskeletal inflammation, and (2) the extraction of systemic amino acids (AAs), potential biological markers of fatigue in athletes. The iontophoretic delivery of Dex-Phos was studied, in vitro, in order to evaluate the effects of competing ions and electroosmosis, and identify the optimal conditions for its delivery. The iontophoretic extraction of AAs from the skin was first studied in vitro, before evaluating the method in a group of human volunteers. Dex-Phos was best delivered by iontophoresis from the cathode in absence of background electrolyte in the drug solution. In this situation, the delivery of Dex-Phos is limited principally by the competition with counter-ions (mainly Na+) present subdermally and the small mobility of the drug inside the membrane. The accumulation of Cl-, released by the Ag/AgCl cathode in the drug solution during current passage, can also reduce Dex-Phos delivery. The extraction of zwitterionic AAs from the skin during iontophoresis was highly influenced by their presence in the outermost layer of the skin, the stratum corneum (SC). In the pig skin model, the amount of the AAs extracted during a short extraction period (1 hour) correlated with their abundance in the SC. Once this ‘reservoir’ was emptied (after ~3 hours of iontophoresis), the subdermal compartment could be sampled, suggesting that the method could be used to monitor systemic levels of AAs. The experiments in human volunteers revealed, however, that a 4-hour iontophoretic extraction period was insufficient to deplete the AAs SC ‘reservoir’. It follows that the method can be used to evaluate the abundance of AAs in the SC, but is unpractical for the clinical monitoring of their systemic levels.

Current monitoring tools in the intensive care units focus on displaying physiologically monitored parameters (e.g. vital signs such as heart rate, respiratory rate and blood pressure) at the present moment. Added clinical utility can be found by analyzing how the conditions of a patient evolve with time, and automatically relating that dynamics to population trends. Variability analysis consists of monitoring patterns of variation over intervals in time of physiological signals such as heart rate and respiratory rate. Given that illness has been associated in multiple studies with altered variability, most commonly lack of variation, variability monitoring represents a tool whose contribution at the bedside still needs to be explored. With the long term objective of improving care, this thesis promotes the use of variability analysis through three distinct types of analysis: facing the technical challenges involved with the dimensionality of variability analysis, enhancing the physiological understanding of variability, and showing its utility in real world clinical applications. In particular, the contributions of this thesis include: the review and classification into domains of a large array of measures of variability; the design of system and methods to integrate multiple measures of variability into a unique score, called composite measure, bringing relevant information to specific clinical problems; the comparison of patterns of heart rate variability during exercise and sepsis development, showing the inability of single measures of variability to discriminate between the two kinds of stressors; the analysis of variability produced from a physiologically-based model of the cardiovascular system, showing that each single measure of variability is an unspecific sensor of the body, thereby promoting multivariate analysis to the only means of understanding the physiology underlying variability; the study of heart rate variability in a population at high risk of sepsis development, showing the ability of variability to predict the occurrence of sepsis more than 48 hours in advance respect to the time of diagnosis of the clinical team; the study of heart and respiratory rate variability in intubated intensive care unit patients, showing how variability can provide a better way of assessing extubation readiness respect to commonly used clinical parameters. Overall, it is hoped that these novel contributions will help promoting bedside applications of variability monitoring to improve patient care.

Current monitoring tools in the intensive care units focus on displaying physiologically monitored parameters (e.g. vital signs such as heart rate, respiratory rate and blood pressure) at the present moment. Added clinical utility can be found by analyzing how the conditions of a patient evolve with time, and automatically relating that dynamics to population trends. Variability analysis consists of monitoring patterns of variation over intervals in time of physiological signals such as heart rate and respiratory rate. Given that illness has been associated in multiple studies with altered variability, most commonly lack of variation, variability monitoring represents a tool whose contribution at the bedside still needs to be explored. With the long term objective of improving care, this thesis promotes the use of variability analysis through three distinct types of analysis: facing the technical challenges involved with the dimensionality of variability analysis, enhancing the physiological understanding of variability, and showing its utility in real world clinical applications. In particular, the contributions of this thesis include: the review and classification into domains of a large array of measures of variability; the design of system and methods to integrate multiple measures of variability into a unique score, called composite measure, bringing relevant information to specific clinical problems; the comparison of patterns of heart rate variability during exercise and sepsis development, showing the inability of single measures of variability to discriminate between the two kinds of stressors; the analysis of variability produced from a physiologically-based model of the cardiovascular system, showing that each single measure of variability is an unspecific sensor of the body, thereby promoting multivariate analysis to the only means of understanding the physiology underlying variability; the study of heart rate variability in a population at high risk of sepsis development, showing the ability of variability to predict the occurrence of sepsis more than 48 hours in advance respect to the time of diagnosis of the clinical team; the study of heart and respiratory rate variability in intubated intensive care unit patients, showing how variability can provide a better way of assessing extubation readiness respect to commonly used clinical parameters. Overall, it is hoped that these novel contributions will help promoting bedside applications of variability monitoring to improve patient care.