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Background Goal directed therapy, the utilisation of fluids and inotropes to optimise cardiovascular performance of tissue oxygen delivery during surgery, has been shown in small studies to reduce complications after major surgery. The OPTIMISE trial was conducted to see if this benefit of morbidity reduction seen with the use of goal directed therapy was replicated in a larger pragmatic trial. I hypothesised that there were potential barriers to the use of goal directed therapy under these conditions that may reduce the clinical effectiveness of this treatment approach. Methods This thesis is based on sub-studies of the OPTIMISE trial examining the difficulties in utilising goal directed therapy as a treatment that focused primarily on the administration of fluids via an algorithm and the effect of goal directed therapy on a specific complication. Acute kidney injury was chosen as an important postoperative complication that was directly affected by fluid administration. Results OPTIMISE did not demonstrate a statistically significant effect of a reduction in complications in a population of 732 high risk surgical patients receiving goal directed therapy. Compliance to the goal directed therapy algorithm was mostly good across seventeen hospital sites. The use of dynamic fluid markers was not shown to be beneficial as indicators of when to give fluid boluses in the perioperative period. Goal directed therapy did not protect against acute kidney injury in the high risk surgical population. There was no difference in the incidence of acute kidney injury in the goal directed therapy group and the usual care group as measured by standardised criteria and measured by a urinary biomarker. Conclusions Goal directed therapy did not result in a significant reduction in complications in a high risk surgical population. However, there are some barriers to the use of goal directed therapy particularly the evidence base for the effectiveness of goal directed therapy and understanding the mechanisms, if any, by which goal directed therapy improves outcomes. Further work should focus on establishing supporting the current evidence base for goal directed therapy and seeking the mechanism by which this may improve outcomes.

Major surgery triggers a physiological stress response that results in an increase in post-operative metabolic demand and oxygen consumption (V̇O2), which must be met by an increased oxygen delivery (DO2). Historical studies described the increase in V̇O2 in patients after major surgery and presented evidence that the inability to meet this increase oxygen demand and the temporal pattern of this oxygen deficit appears to differ according to whether patients survive, or develop complications or not. The survival and complication profile of patients in modern practice is different from that previously described, And the methods employed in these historical studies were invasive and inconsistent with contemporary practice. V̇O2 can be measured non-invasively with indirect calorimetery, and DO2 calculated from non-invasive cardiac output monitors, and haemoglobin and oxygen saturation measurement devices. This thesis describes two prospective observational studies which1) validate and 2) assess the feasibility of non-invasive measurements of V̇O2 and DO2 and explore their temporal patterns after contemporary abdominal surgery. These techniques demonstrate moderate to good trending ability when measuring changes in V̇O2 and DO2. The non-invasive measurement of V̇O2 and DO2 is feasible in patients after major abdominal surgery. There appear to be distinct patterns of V̇O2 and DO2 after contemporary abdominal surgery in those who develop complications or not. Contemporary patterns of net cumulative oxygen debt appear to differ from those previously described.

Abstract: The objective of this thesis is to describe two new methodologies for evaluating medical gas and nasal spray delivery, respectively, in vitro using nasal replicas. The first half of the body of thesis describes the development of a new in vitro benchtop method for evaluating the delivery of medical gases across different modalities (e.g. delivery of pulsed vs. continuous flows). The second half describes the design and validation of an idealized nasal replica which mimics the average in vitro and in vivo regional deposition of nasal sprays in adult subjects. Chapter 1 provides the background and justification for the use of nasal replicas in in vitro evaluations of the delivery of medical gas and nasal sprays. For medical gases, previous researchers have relied on highly simplified geometries, which cannot simulate physiologically accurate pressure changes in the airways during breathing, nor account for the effect of intersubject variability in patient airway geometries on gas delivery. For sprays and aerosols, an extensive history of in vitro studies evaluating regional intranasal deposition using realistic nasal replicas already exists. These studies tend to be performed with a single geometry, which is unlikely to be representative of the population at large, highlighting the potential utility of a standardized idealized geometry which would mimic average regional in vivo and in vitro deposition across an adult population. Chapter 2 introduces the problem of equivalency between continuous flow and pulse flow delivery of supplemental oxygen and describes the development of a predictive in vitro model for inhaled oxygen delivery using a set of realistic nasal airway replicas. Experiments are reported to compare pulse flow delivery from a commercial portable oxygen concentrator (POC) with continuous flow from a compressed oxygen cylinder. A volume-averaged fraction of inspired oxygen (FiO2) was calculated by numerically integrating inhaled oxygen flow rates sampled at the exit of each replica and used as a common basis for comparison between continuous and pulse flow. Pulse flow delivered consistently lower FiO2 than continuous flow rates equivalent to nominal pulse flow settings. To the extent that the POC triggered successfully at the start of inhalation, intersubject variability in airway geometries had a minimal effect on FiO2. Testing using airway replicas was also useful in identifying cases of impaired device function or failure. Chapter 3 investigates the relative performance of four POCs both against each other and against continuous flow oxygen using a single realistic nasal replica which had a reliably high triggering pressure and which delivered a medium FiO2 compared to the full replica set. Oxygen delivery to the deep lung was also analyzed in silico by combining in vitro oxygen concentration waveforms over time and a single-path mathematical model of the lungs. Significant differences in POC performance based on FiO2 were found between continuous and pulse flow, and between pulse modes in different POCs at the same nominal device setting. In silico simulations revealed that while pulse flow is a more efficient mode of delivery than continuous flow, continuous flow ultimately delivers a greater volume of oxygen per breath. Chapter 4 describes the manufacture and in vitro validation experiments needed for the development of an idealized nasal replica, based on a geometry previously developed using in silico simulations. This replica, manufactured in plastic, was validated by comparing with regional deposition in realistic, sectioned nasal replicas obtained from in vitro deposition experiments and in previously published in vivo data. A commercial nasal spray pump was actuated repeatably into each realistic or idealized nasal replica under a steady inspiratory flow at two different orientations. It was found that regional deposition in the idealized replica agreed well with average regional deposition in the realistic replicas and with previously published in vivo gamma scintigraphy data. In Chapter 5, an aluminum version of the idealized nasal replica from Chapter 4 was used in order to facilitate further in vitro experiments with a wider set of intranasal drug formulations (one aqueous solution, one aqueous suspension and one propellant-based formulation). Good agreement was seen between deposition measured using the idealized replica and in vivo deposition patterns for all three nasal drug formulations that were tested. Chapter 6 summarizes the main conclusions of the thesis and provides possible directions for future research.

The objective of this study was to evaluate the relationship between tissue oxygen saturation (StO2) and oxygen delivery index (DO2I). Oxygen delivery index is product of two factors arterial oxygen content (CaO2) and cardiac index (CI). In this study the relationship between DO2I and StO2 was evaluated by manipulating both of these factors independently. In phase one of the study, CaO2 was altered by manipulating the fractional inspired oxygen (FiO2) concentration. Anesthetized dogs were evaluated at both high (0.40 and 0.95) and low (0.15 and 0.10) FiO2 sequences. In phase two of the study, CI was altered by manipulating the volemic state. Anesthetized dogs were evaluated at hypovolemic, normovolemic and hypervolemic states. In each phase dogs were instrumented for thermodilution cardiac index (CI) and sartorius muscle StO2. Data collected included hemoglobin concentration, heart rate (HR), MAP, CI, StO2. Arterial oxygen content and DO2I were calculated at each time point. Data analysis included Pearson's correlation and mixed model ANOVA (p < 0.05). In both phases one (r = 0.97; p = 0.0013) and two (r = 0.97; p = 0.005) there was a strong correlation between StO2 and DO2I. Under the conditions of this study, there was a strong correlation between StO2 and DO2I, suggesting that StO2 may be used to estimate the adequacy of oxygen delivery in dogs.

Physiologists have traditionally studied elevated metabolic states in isolation (e.g., the physiological response to physical activity). However, under natural conditions animals may perform more than one elevated metabolic state simultaneously (e.g., predator avoidance while processing a recently ingested meal) and the integrated response to such a condition is not well understood. For my dissertation work, I used oviparous (Lamprophis fuliginosus) and viviparous (Thamnophis marcianus) snakes to test whether the oxygen delivery capacity of these species' cardiopulmonary systems would be sufficient to meet the oxygen demands from reproduction, physical activity, and digestion simultaneously (i.e., additivity). Flow-through respirometry was used to measure levels of gas exchange (i.e., oxygen consumption and carbon dioxide production) during standard conditions (i.e., standard metabolic rate, SMR), and then during reproduction, activity (while fasting), digestion of a large (i.e., 10 to 20% body mass) meal, and post-prandial activity. Results indicate that reproduction causes significant increments in oxygen consumption for females of both species. Levels ranged from 1.4 to 3.2 fold above SMR. During physical activity (while fasting), males and females of both species exhibited peak factorial increments in oxygen consumption that ranged from ~6 to 9.6 fold above SMR; digestion resulted in peak factorial increments of ~3 to 6 fold above SMR. Contrary to predictions, males and non-reproductive females of both species exhibited a prioritization pattern of oxygen delivery during post-prandial activity (i.e., factorial increments in oxygen consumption were similar to or lower than levels attained during activity while fasting). When reproduction and digestion were combined, female Lamprophis fuliginosus exhibited a prioritization pattern of oxygen delivery, while Thamnophis marcianus exhibited a more-than-additive pattern of oxygen delivery (i.e., there was a 30-50% increase in oxygen consumption above non-reproductive levels). Contrary to predictions, during the combination of reproduction and post-prandial activity females of both species exhibited a prioritization pattern of oxygen delivery. Overall, results from my dissertation work indicate that these species' cardiopulmonary systems' capacity for oxygen delivery is limited to increments of approximately 9 to 10 fold above SMR. In most cases, activity performance (i.e., time to exhaustion, TTE) was maintained, possibly at the expense of digestive and reproductive processes.

Hemoglobin (Hb) is a unique protein with both the ability to transport oxygen and to target monocytes and macrophages. Therefore, Hb could be used in the design of oxygen delivery systems and targeted drug delivery systems. This dissertation dedicates two chapters to each of the aforementioned areas. Chapters 2 and 3 discuss the ability of Hb to transport oxygen, in the form of polymerized Hb. In contrast, Chapters 4 and 5 describe the ability of Hb to deliver drugs towards monocytes and macrophages, in the form of Hb-drug conjugates and Hb surface conjugated liposomes.Although polymerized Hb solutions have long been studied as red blood cell substitutes, concerns about their side-effects have never been adequately addressed. Recent studies have demonstrated that these side-effects arise from the low molecular weight (MW) Hb components in solution. Therefore, to eliminate these side-effects, it is important to synthesize polymerized Hbs without these low MW fractions in solution. Chapter 2 shows that the novel cross-linking agent, 1,11-bis(maleimido)triethylene glycol, can be used to polymerize Hb without the presence of low MW fractions. Chapter 3 demonstrates the synthesis of high molecular weight glutaraldehyde polymerized Hb in a defined quaternary state, without low MW fractions. In contrast, the remaining chapters are devoted to the use of Hb as a targeted drug delivery ligand towards monocytes and macrophages.The Hb-haptoglobin complex is a natural ligand for the CD163 receptor on the surface of monocytes and macrophages. This unique characteristic makes Hb a natural ligand for developing a drug delivery system to target monocytes and macrophages. Chapter 4 shows that Hb can deliver drugs into monocytes and macrophages by chemically conjugating the surface of Hb with drug molecules. In a similar fashion, chapter 5 shows that liposomes surface modified with Hb can also target drug delivery into monocytes and macrophages.Taken together, the knowledge gained from this work should be helpful in the design of polymerized Hbs as RBC substitutes and in targeted drug delivery toward monocytes and macrophages.