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The dose regimen of a drug gives important information about the dose sizes, dose frequency and the duration of treatment. Optimisation of dose regimens is critical to ensure therapeutic success of the drug and to minimise its possible adverse effects. The central theme of this thesis is the Efficient Dosing (ED) algorithm - a computation algorithm developed by us for optimisation of dose regimens. In this thesis, we have attempted to develop a quantitative framework for measuring the efficiency of a dose regimen for specified criteria and computing the most efficient dose regimen using the ED algorithm. The criteria considered by us seek to prevent over- and under-exposure to the drug. For example, one of the criteria is to maintain the drug's concentration around a desired target level. Another criterion is to maintain the concentration within a therapeutic range or window. The ED algorithm and its various extensions are programmed in MATLAB R . Some distinguishing features of our methods are: mathematical explicitness in the optimisation process for a general objective function, creation of a theoretical base to draw comparisons among competing dose regimens, adaptability to any drug for which the PK model is known, and other computational features. We develop the algorithm further to compute the optimal ratio of two partner drugs in a fixed dose combination unit and the efficient dose regimens. In clinical trials, the parameters of the PK model followed by the drug are often unknown. We develop a methodology to apply our algorithm in an adaptive setting which enables estimation of the parameters while optimising the dose regimens for the typical subject in each cohort. A potential application of the ED algorithm for individualisation of dose regimens is discussed. We also discuss an application for computation of efficient dose regimens for obliteration of a pre-specified viral load.

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 This thesis argues that adherence to this outdated system is confusing, causes drug administration errors, and puts patients at risk.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.

Bakgrund: Sedering används ofta som komplement till regional och lokal anestesi. Sedering kan ges av anestesipersonal (ACS) eller genom patientkontrollerad sedering (PCS). Denna litteraturöversikt syftar till att jämföra dessa metoder. Syfte: Att jämföra patientkontrollerad sedering med sedering given av anestesipersonal avseende skillnad i maximalt sederingsdjup, total läkemedelsdos och tid till utskrivning. Metod: Systematisk litteraturöversikt med narrativ syntes. Litteratursökning i databaserna Pubmed, CINAHL, Scopus och Embase. Det primära utfallet var maximalt sederingsdjup. Sekundära utfall var total läkemedelsdos, samt tid till utskrivning från uppvakningsavdelning. Resultat: 10 studier inkluderades i resultatet (totalt 717 patienter). Studierna hanterar olika ingrepp såsom koloskopier, bronkoskopier och ledplastik. Majoriteten av studierna visade signifikanta skillnader till PCS-gruppernas fördel, med ett ytligare sederingsdjup, en lägre total läkemedelsdos och en kortare tid till utskrivning från uppvakningsavdelning. Stor spridning sågs inom alla grupper gällande total läkemedelsdos. Diskussion/ slutsatser: Resultatet stöds av liknande studier. Ett ytligare sederingsdjup leder till mindre risk för biverkningar för patienten. Eftersom PCS återger ett visst självbestämmande till patienten, ger denne möjlighet att själv välja sederingsdjup i stunden, samt att patienten ges beslutet att tacka ja eller nej till PCS gör att denna sederingsmetod blir ett sätt att arbeta personcentrerat. Vidare forskning krävs, exempelvis större RCT och studier angående patienters upplevelser av PCS. Nyckelord: Patientkontrollerad sedering, sederingsdjup, läkemedelsdos, utskrivningstid, personcentrerad vård / Background: Sedation is often used as a supplement to regional and local anesthesia. Sedation can be given as anesthesia personnel-controlled sedation (ACS) or as patient-controlled sedation (PCS). This systematic review aims to compare these methods. Aim: To compare patient-controlled sedation with anesthesia personnel-controlled sedation regarding maximum depth of sedation, total drug dose and time to discharge. Methods: Systematic review with narrative synthesis. The research material was collected from Pubmed, CINAHL, Scopus and Embase. Primary outcome was maximum depth of sedation. Secondary outcomes were total drug dose and time to discharge from PACU (post anesthesia care unit). Result: 10 trials were included in the result (a total of 717 patients). The trials handle various procedures such as colonoscopies, bronchoscopies and arthroplasty. The majority of the trials showed significant differences in favour of PCS, with a lighter depth of sedation, a lower total drug dose and a shorter time to discharge from PACU. Regarding total drug dose, a large fluctuation was seen in all groups. Discussion/ conclusion: The result is supported by similar trials. A lighter depth of sedation reduces the risk of side effects for the patient. PCS is a way to practice person-centered care, when power is given back to the patient to freely choose the depth of sedation. The patient is also given the decision to say yes or no to PCS. Further research is required, for example larger RCT:s and studies regarding patients experiences of PCS. Keywords: Patient-controlled sedation, depth of sedation, drug dose, time to discharge, person-centered care