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In der Neonatologie ist die Verabreichung von Erythrozytenkonzentrat (EK) eine der häufigsten therapeutischen Maßnahmen. Ursachen dafür sind die Frühgeborenen-anämie und die iatrogen durch diagnostische Blutentnahmen hervorgerufene sekundäre Anämie. Obwohl ca. 80% der Frühgeborenen während des postnatalen stationären Aufenthaltes EK erhalten, gibt es noch immer keine einheitlichen Richtlinien zur Bluttransfusion bei Frühgeborenen. In der vorliegenden Studie sollte der Effekt einer EK-Gabe mit Hilfe der Messung der cerebralen und peripheren Gewebsoxygenierung (crSO2 und prSO2) erfasst werden. Und es wurde der Annahme nachgegangen, dass in der Neonatologie Subgruppen existieren, welche unterschiedlich von einer EK-Transfusion profitieren. Im Rahmen dieser Promotionsarbeit wurden Frühgeborene der neonatologischen Abteilung der Universitätsklinik und Poliklinik für Kinder- und Jugendmedizin Leipzig prospektiv analysiert. Es konnte gezeigt werden, dass bei allen untersuchten Patienten sowohl die cerebrale als auch die periphere Gewebsoxygenierung unter EK-Transfusion ansteigen und auch nach einem Intervall von 24 Stunden noch auf diesem gesteigerten Niveau konstant bleiben. Zudem konnte nachgewiesen werden, dass Kinder mit niedrigen crSO2-Ausgangswerten vor Transfusion mehr Sauerstoffsättigungsabfälle unter 80% (SaO2<80%) aufweisen. Nach Transfusion ist bei diesen Patienten zusätzlich ein stärkerer Rückgang der Anzahl der SaO2<80% zu beobachten. Somit ist die Gewebsoxygenierung möglicherweise ein sinnvoller Parameter für die Indikation zur EK-Transfusion, welcher bei der Erarbeitung neuer Transfusionsricht-linien in der Neonatologie mit einbezogen werden sollte.

When O2 uptake at the lung is used to characterise the oxidative metabolic response to increased contractile activity ( O2 kinetics) in exercising muscle, the O2 profile reflects the combined influence of all involved muscle fibres. Consequently, during high-intensity exercise that mandates activation of fibres with considerable metabolic diversity (e.g., both principal fibre types), response characteristics specific to discrete segments of the recruited pool cannot be determined. The purpose of this thesis was to identify fibre-type-specific effects of conditions that might impact O2 delivery and/or motor unit recruitment patterns on O2 kinetics by using two models that increase fibre recruitment homogeneity during exercise transitions. In four experiments, subjects initiated high-intensity exercise from a moderate baseline (i.e., performed ‘work-to-work’ transitions; M→H) to target higher-order fibres, and in two experiments, subjects cycled at extremely slow and fast pedal rates to skew recruitment toward slow- and fast-twitch fibres, respectively. At mid-range contraction frequency, O2 kinetics (as indicated by the primary time constant, τp) was slower for M→H compared to unloaded-to-high-intensity transitions (U→H) (e.g., 42 v. 33 s; Ch 4) and this slowing was ~50% greater for M→H in a supine body position (decreased oxygenation; Ch 6). Slower kinetics was also present for U→H cycling at fast compared to slow pedal rates (τp, 48 v. 31 s; Ch 8). Conversely, M→H slowing relative to U→H was absent at extreme cadences (36 v. 31 s and 53 v. 48 s for slow and fast, respectively; Ch 7). After ‘priming’ (increased oxygenation), τp was reduced for U→H after fast-cadence priming only (Ch 8) and for M→H in the supine position (Ch 6), but unaffected for upright cycle and prone knee-extension M→H, for which priming reduced the O2 slow component and delayed-onset fibre activation (as indicated by iEMG; Chs 4 and 5). These results provide evidence in exercising humans that high-order fibres possess innately slow O2 kinetics and are acutely susceptible to interventions that might alter O2 delivery to muscle.

Noninvasive measurements of myocardial carboxymyoglobin levels (%MbCO) and oxygen tensions (PtO2) are difficult to obtain experimentally. We have developed a compartmental model which allows prediction of myocardial %MbCO levels and PtO2 for varied carbon monoxide (CO) exposures. The cardiac compartment in the model consists of vascular subcompartments which contain two tissue subcompartments varying in capillary density. Mass-balance equations for oxygen (O2) and CO are applied for all compartments. Myocardial oxygen consumption and blood flow are quantified from predictive formulas based on heart rate. Model predictions are validated with experimental data at normoxia, hypoxia, exercise and hyperoxia. CO exposures of varying concentration and time (short-high, long-low), CO rebreathing during 100% O2, and exposure during exercise is simulated. Results of the simulations demonstrate that during CO exposures and subsequent therapies, the temporal changes of %MbCO in the heart differ from those of carboxyhemoglobin levels (%HbCO). Analysis of correlation between %HbCO, %MbCO and PtO2 was done to understand myocardial injury due to CO hypoxia. This thesis demonstrates that the model is able to anticipate the uptake and distribution of CO in the human myocardium and thus can be used to estimate the extravascular burden (MbCO, PtO2 ) of CO on the human heart.

In resting muscle, blood flow is regulated to meet the demand for O2 by the tissue. A modified ischemia (I)/reperfusion(R) investigation was systematically run and PISFO2, PaO2, Q and VO2 were observed. Twenty-nine spinotrapezius muscles from male Sprague-Dawley rats (284±20 grams) were surgically exteriorized for intravital microscopy to test a model relating blood flow, O2 supply and O2 demand. The model can aid in the understanding of the regulation of tissue PO2. The interstitial PO2 (PISFO2) and perivascular PO2 (PaO2) measurements were made using phosphorescence quenching microscopy (PQM). O2 consumption (VO2) values were obtained with a quasi-continuous, flash-synchronized, pressurized airbag to initiate ischemia and sample the rate of O¬2 change (dPO2/dt). Centerline red blood cell velocity was measured with an Optical Doppler Velocimeter and converted to flow using vessel diameter. 5-, 15-, 30-, 60-, 300- and 600-second ischemic durations were used to observe changes in PISFO2, Q, and VO2. A critical point was observed following 30 seconds of (I) where dPISFO2/dt during recovery was the fastest (4.25±0.72 mmHg/s) and was 1.00±0.16 mmHg/s following 600 seconds. Flow recovery, dQ/dt, peaked to 3.88±0.64 (µl•min-1)/s after 60 seconds of (I) but significantly dropped to 2.83±0.55 (µl•min-1)/s following 300 seconds of (I) but increased to 2.92±0.45 (µl•min-1)/s following 600 seconds. This gives evidence to a no-reflow phenomenon occurring in the extended periods of ischemia. A peak in VO¬2 to 309.2±45.0 nl O2/cm3•s with a time course of 160 seconds occurred following 600 seconds of ischemia. As the ischemic duration decreased, the time course and peak VO2 also decreased. VO2 following 300 seconds of (I) was significantly higher than 5-60 seconds of (I) (p <0.05) but was not significantly different from 600 seconds of (I). The information collected during the Q and VO2 studies can be incorporated into a factor, M, that relates VO2, Q and ∆PO2. M calculated for the recovery of 5- through 60-second (I) groups reasonably relates the three variables due to consistency and little variability. However, recovery in 600- and especially 300-second (I) groups showed higher variability in M which requires more consideration.

Traumatic brain injury (TBI) is a major cause of death and disability. TBI is frequently followed by cerebral ischemia which is a great contributor to secondary brain damage. The main causes of cerebral ischemia are pathophysiological changes in cerebral blood flow and metabolism. Treatment of TBI patients is currently based on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) targeted treatment protocols. However, ICP and CPP alone do not provide information of the oxygen availability in the brain. Monitoring of brain tissue oxygenation (BtipO2) may give additional and valuable information about the risk for development of ischemia in TBI patients. The aims of this thesis were to study BtipO2 monitoring devices in-vitro regarding accuracy and stability, to detect threshold level of cerebral ischemia in-vivo and finally to examine the cerebral oxygen levels and cerebral metabolism in TBI patients. The BtipO2 probes performed with high accuracy and stability at different clinically relevant oxygen concentrations. A pig TBI model was developed by step-wise intracranial volume/pressure increase. Volume increase resulted in a gradual increased ICP, decreased CPP, intracranial compliance and BtipO2, respectively. Brain death (BD) was confirmed by negative CPP and negligible amount of previously injected microspheres in the brain tissue. The model simulated the clinical development of BD in humans with a classical pressure-volume response and systemic cardiovascular reactions. The model should be suitable for studies of brain injury mechanisms. From the same in-vivo model it was also possible to detect the threshold level of cerebral ischemia in the pig, where BtipO2 below 10 mmHg and CPP below 30 mmHg was associated with an impaired cerebral metabolism (microdialysis lactate to pyruvate ratio &gt;30). BtipO2 together with cerebral microdialysis were studied in 23 severe TBI patients. We observed different patterns of changes in BtipO2 and cerebral microdialysis biomarkers in focal and diffuse TBI.  Increased cerebral microdialysis levels of glutamate, glycerol or the lactate/pyruvate ratio were observed at BtipO2 &lt; 5 mmHg, indicating increased vulnerability of the brain at this critical level of tissue oxygenation in TBI patients.

The purpose of this study was to compare the exercise and recovery muscle oxygenation response of Women and Girls during two 30s Wingate anaerobic tests separated by two minutes of active cycling recovery (resistance ≈ 2.5% body weight, 60-80rpm). Oxygenated hemoglobin (HbO2), deoxygenated hemoglobin (HHb), total hemoglobin (tHb), and tissue saturation index (TSI) were monitored at the right vastus lateralis muscle using near infrared spectroscopy (NIRS) throughout exercise, recovery, and a post-exercise femoral artery occlusion to TSI plateau. Pressure was preset at 250mmHg for Women and 210mmHg for Girls, achieved by rapid inflation in 0.3 seconds, and maintained until a 2 minute TSI plateau occurred or 10 minutes had passed. Twenty Women (23.8[2.12] years) and 13 Girls (9[1] years, combined Tanner stage <4) completed all tasks excepting 1 girl who did not complete occlusion. Significant group, time, and group by time interaction effects were observed for peak and mean power (Watts.kgFFM-1). Women had significantly greater power output compared to Girls for both Wingates. While both groups had reduced power output in Wingate 2, the reduction was significantly greater in Women compared to Girls. No significant group differences were found for resting TSI, recovery TSI, minimum TSI during either Wingate test, or for minimum TSI during occlusion, however a time main effect for Women was observed with minimum TSI being significantly lower in Wingate 1 compared to Wingate 2. Girls had similar minimum TSI for both Wingate tests. Women also demonstrated a significantly greater difference between Wingate minimum TSI and occlusion minimum TSI in Wingate 2 compared to Wingate 1. During Wingate 1, HHb increase was greater in Girls compared to Women and remained elevated during recovery compared to women. Changes in HbO2, HHb, and tHb were reduced in Wingate 2 for both groups, more so in Women for tHb and in Girls for HHb. Recovery was not different between groups with the exception of a faster TSI time constant of recovery in Women (τ =20.25 [13.01]s) compared to Girls (τ =36.77 [13.38]s) which is attributed to a faster HHb time constant in Women (τ =13.6 [0.44]s) compared to Girls (τ =30.77[19.47]s). Both groups demonstrated similar power output results and TSI response across the two Wingate tests but Girls were better able to repeat the anaerobic performance with a consistent TSI minimum between the two tests despite a faster recovery of HHb and TSI in women. These findings, in the context of observed Hb variable differences between groups, provide evidence of greater oxidative metabolism in Girls during a high intensity exercise. / Graduate / December 18, 2016

In der Neonatologie ist die Verabreichung von Erythrozytenkonzentrat (EK) eine der häufigsten therapeutischen Maßnahmen. Ursachen dafür sind die Frühgeborenen-anämie und die iatrogen durch diagnostische Blutentnahmen hervorgerufene sekundäre Anämie. Obwohl ca. 80% der Frühgeborenen während des postnatalen stationären Aufenthaltes EK erhalten, gibt es noch immer keine einheitlichen Richtlinien zur Bluttransfusion bei Frühgeborenen. In der vorliegenden Studie sollte der Effekt einer EK-Gabe mit Hilfe der Messung der cerebralen und peripheren Gewebsoxygenierung (crSO2 und prSO2) erfasst werden. Und es wurde der Annahme nachgegangen, dass in der Neonatologie Subgruppen existieren, welche unterschiedlich von einer EK-Transfusion profitieren. Im Rahmen dieser Promotionsarbeit wurden Frühgeborene der neonatologischen Abteilung der Universitätsklinik und Poliklinik für Kinder- und Jugendmedizin Leipzig prospektiv analysiert. Es konnte gezeigt werden, dass bei allen untersuchten Patienten sowohl die cerebrale als auch die periphere Gewebsoxygenierung unter EK-Transfusion ansteigen und auch nach einem Intervall von 24 Stunden noch auf diesem gesteigerten Niveau konstant bleiben. Zudem konnte nachgewiesen werden, dass Kinder mit niedrigen crSO2-Ausgangswerten vor Transfusion mehr Sauerstoffsättigungsabfälle unter 80% (SaO2<80%) aufweisen. Nach Transfusion ist bei diesen Patienten zusätzlich ein stärkerer Rückgang der Anzahl der SaO2<80% zu beobachten. Somit ist die Gewebsoxygenierung möglicherweise ein sinnvoller Parameter für die Indikation zur EK-Transfusion, welcher bei der Erarbeitung neuer Transfusionsricht-linien in der Neonatologie mit einbezogen werden sollte.

The neurological wake-up test, NWT, is a clinical monitoring tool that can be used to evaluate the level of consciousness in patients with traumatic brain injury (TBI) and subarachnoid haemorrhage (SAH) during neurocritical care (NCC). Since patients with severe TBI or SAH are often treated with mechanical ventilation and sedation, the NWT requires that the continuous sedation is interrupted. However, interruption of continuous sedation may induce a stress response and the use of the NWT in NCC is controversial. The effects of the NWT on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) were evaluated in 21 patients with TBI or SAH. Compared to baseline when the patients were sedated with continuous propofol sedation, the NWT resulted in increased ICP and CPP (p&lt;0.05). Next, the effects of the NWT on the stress hormones adrenocorticotrophic hormone (ACTH), cortisol, epinephrine and norepinephrine were evaluated in 24 patients. Compared to baseline, the NWT caused a mild stress response resulting in increased levels of all evaluated stress hormones (p&lt;0.05). To compare the use of routine NCC monitoring tools, the choice of sedation and analgesia and the frequency of NWT in Scandinavian NCC units, a questionnaire was used. The results showed that all 16 Scandinavian NCC units routinely use ICP and CPP monitoring and propofol and midazolam were primary choices for patient sedation in an equal number of NCC units. In 2009, the NWT was not routinely used in eight NCC units whereas others used the test up to six times daily. Finally, intracerebral microdialysis (MD), brain tissue oxygenation (PbtiO2) and jugular bulb oxygenation (SjvO2) were used in 17 TBI patients to evaluate the effect of the NWT procedure on focal neurochemistry and cerebral oxygenation. The NWT did not negatively alter interstitial markers of energy metabolism or cerebral oxygenation. In conclusion, the NWT induced a mild stress response in patients with TBI or SAH that did not result in a detectable, significant secondary insult to the injured brain. These results suggest that the NWT may safely be used as a clinical monitoring tool in the NCC of severe TBI and SAH in a majority of patients.