Monro-Kellie 2.0: The dynamic vascular and venous pathophysiological components of intracranial pressure

For 200 years, the ‘closed box’ analogy of intracranial pressure (ICP) has underpinned neurosurgery and neuro-critical care. Cushing conceptualised the Monro-Kellie doctrine stating that a change in blood, brain or CSF volume resulted in reciprocal changes in one or both of the other two. When not possible, attempts to increase a volume further increase ICP. On this doctrine’s “truth or relative untruth” depends many of the critical procedures in the surgery of the central nervous system. However, each volume component may not deserve the equal weighting this static concept implies. The slow production of CSF (0.35 ml/min) is dwarfed by the dynamic blood in and outflow (∼700 ml/min). Neuro-critical care practice focusing on arterial and ICP regulation has been questioned. Failure of venous efferent flow to precisely match arterial afferent flow will yield immediate and dramatic changes in intracranial blood volume and pressure. Interpreting ICP without interrogating its core drivers may be misleading. Multiple clinical conditions and the cerebral effects of altitude and microgravity relate to imbalances in this dynamic rather than ICP per se. This article reviews the Monro-Kellie doctrine, categorises venous outflow limitation conditions, relates physiological mechanisms to clinical conditions and suggests specific management options

Measurements of rates of cooling of a manikin insulated with different mountain rescue casualty bags

Background: Accidental hypothermia is common in those who sustain injuries in remote environments. This is unpleasant and associated with adverse effects on subsequent patient outcomes. To minimise further heat loss, a range of insulating systems are available to mountain rescue teams although the most effective and cost-efficient have yet to be determined. Methods: Under ambient, still, dry, air conditions, a thermal manikin was filled with water at a temperature of 42 °C and then placed into a given insulation system. Water temperature was then continuously observed via an in-dwelling temperature sensor linked to a PROPAQ 100 series monitor and recorded every 10 min for 130 min. This method was repeated for each insulating package. Results: The vacuum mattress/Pertex©/fibrepile blanket system, either on its own or coupled with the Wiggy bag, was the most efficient with water temperatures only decreasing by 3.2 °C over 130 min. This was followed by the heavy-weight casualty bags without the vacuum mattress/Pertex©/fibrepile blanket system, decreasing by 4.2–4.3 °C. With the Blizzard bag, a decline in water temperature of 5.4 °C was seen over the study duration while a decrease of 9.5 °C was noted when the plastic survival bag was employed. Conclusions: Under the still-air conditions of the study, the vacuum mattress/Pertex©/fibrepile blanket was seen to offer comparable insulation effectiveness compared to be both heavy-weight casualty bags. In turn, these three systems appeared more efficient at insulating the manikin than the Blizzard bag or plastic survival bag

Capturing the Real Impact of Clinical Academics in Practice

The Clinical Academic Careers Framework proposes an over-arching structure to develop the clinical academic workforce whose activities have patient benefit within a clear UK programme. Traditionally this has centred on professionals from medicine and dentistry, but in the last ten years has developed into a more inclusive career framework for non-medical health professions which includes Nurses, Midwives and Allied Health Professionals (NMAHPs) and Healthcare Scientists (HCSs) that provide NHS services. As such, it is reported that clinical academic NMAHPs and HCSs can contribute to the generation and translation of new knowledge to help improve outcomes and experiences for patients. In this article, we explore key issues relating to the impact of clinical academic NMAHPs and HCSs on clinical practice in a UK context, as well as some measurements of impact, including the value and limitations of currently used metrics (such as Key Performance Indicators, or KPIs). We report that measuring the learning in practice of this novel role will need to include smart metrics alongside a person-centred approach. We share four national case studies, all of which are drawn from clinical academic researchers from different UK settings to show the real variety and differences in roles. We argue that this is the key both to learning in practice about this role, and to witnessing the real differences clinical academics make

Hypoxia is not the primary mechanism contributing to exercise-induced proteinuria.

Introduction: Proteinuria increases at altitude and with exercise, potentially as a result of hypoxia. Using urinary alpha-1 acid glycoprotein (α1-AGP) levels as a sensitive marker of proteinuria, we examined the impact of relative hypoxia due to high altitude and blood pressure-lowering medication on post-exercise proteinuria. Methods: Twenty individuals were pair-matched for sex, age and ACE genotype. They completed maximal exercise tests once at sea level and twice at altitude (5035 m). Losartan (100 mg/day; angiotensin-receptor blocker) and placebo were randomly assigned within each pair 21 days before ascent. The first altitude exercise test was completed within 24-48 hours of arrival (each pair within ~1 hour). Acetazolamide (125 mg two times per day) was administrated immediately after this test for 48 hours until the second altitude exercise test. Results: With placebo, post-exercise α1-AGP levels were similar at sea level and altitude. Odds ratio (OR) for increased resting α1-AGP at altitude versus sea level was greater without losartan (2.16 times greater). At altitude, OR for reduced post-exercise α1-AGP (58% lower) was higher with losartan than placebo (2.25 times greater, p=0.059) despite similar pulse oximetry (SpO2) (p=0.95) between groups. Acetazolamide reduced post-exercise proteinuria by approximately threefold (9.3±9.7 vs 3.6±6.0 μg/min; p=0.025) although changes were not correlated (r=-0.10) with significant improvements in SpO2 (69.1%±4.5% vs 75.8%±3.8%; p=0.001). Discussion: Profound systemic hypoxia imposed by altitude does not result in greater post-exercise proteinuria than sea level. Losartan and acetazolamide may attenuate post-exercise proteinuria, however further research is warranted

Applications of Hybrid Diffuse Optics for Clinical Management of Adults After Brain injury

Information about cerebral blood flow (CBF) is valuable for clinical management of patients after severe brain injury. Unfortunately, current modalities for monitoring brain are often limited by hurdles that include high cost, low throughput, exposure to ionizing radiation, probe invasiveness, and increased risk to critically ill patients when transportation out of their room or unit is required. A further limitation of current technologies is an inability to provide continuous bedside measurements that are often desirable for unstable patients. Here we explore the clinical utility of diffuse correlation spectroscopy (DCS) as an alternative approach for bedside CBF monitoring. DCS uses the rapid intensity fluctuations of near-infrared light to derive a continuous measure of changes in blood flow without ionizing radiation or invasive probing. Concurrently, we employ another optical technique, called diffuse optical spectroscopy (DOS), to derive changes in cerebral oxyhemoglobin (HbO2) and deoxyhemoglobin (Hb) concentrations. Our clinical studies integrate DCS with DOS into a single hybrid instrument that simultaneously monitors CBF and HbO2/Hb in the injured adult brain. The first parts of this dissertation present the motivations for monitoring blood flow in injured brain, as well as the theory underlying diffuse optics technology. The next section elaborates on details of the hybrid instrumentation. The final chapters describe four human subject studies carried out with these methods. Each of these studies investigates an aspect of the potential of the hybrid monitor in clinical applications involving adult brain. The studies include: (1) validation of DCS-measured CBF against xenon-enhanced computed tomography in brain-injured adults; (2) a study of the effects of age and gender on posture-change-induced CBF variation in healthy subjects; (3) a study of the efficacy of DCS/DOS for monitoring neurocritical care patients during various medical interventions such as head-of-bed manipulation and induced hyperoxia; and (4) a first feasibility study for using DCS to study hemodynamics at high altitudes. The work presented in this dissertation thus further develops DCS/DOS technology and demonstrates its utility for monitoring the injured adult brain. It demonstrates the promise of this new clinical tool to help neurocritical care clinicians make more informed decisions and thereby improve patient outcome

The Brain at Altitude: The Cerebral Vasculature, Hypoxia and Headache

This thesis studies the effect of hypoxia (at rest and during exercise) on the arterial and venous cerebral circulation, investigating the venous system role in high altitude headache. Methods: 1) Hypobaric hypoxic studies investigated 198 trekkers and 24 Investigators to 5300m, 14 to 6400m and 8 to 8848m. 2) Normobaric hypoxic studies used Magnetic Resonance Imaging (MRI)) at sea-level. Four domains were addressed: i. Arterial: Hypobaric hypoxia: (n=24) Transcranial Doppler (TCD) measured middle cerebral artery diameter (MCAD) and blood velocity (MCAv). Sea-Level normobaric hypoxia: (n=7) A hypoxicator (FiO2 = 11%) for 3 hours with a 3Tesla MRI scan measured MCAD and MCAv. ii. Brain Oxygenation: Near Infrared Spectroscopy (NIRS) monitored Regional Brain Oxygenation (rSO2). iii. Venous: Retinal imaging at altitude and MRI at sea-level assessed the venous system. iv. Headache: A daily diary recorded headache burden. Results: Arterial: Hypobaric and normobaric hypoxia induced MCA dilatation. Mean (±(SEM)) MCAD increased in hypoxia (from 5.23(±0.23)mm (at 5300m) to 9.34(±0.88)mm (at 7950m)(p<0.001) (TCD). At sea-level, (after 3 hours FiO2 = 11%) MCAD increased from 3.04(±0.13)mm to 3.27(±0.13)mm (MRI). Brain Oxygenation: rSO2 decreased more than peripheral arterial saturation (SaO2), especially during exercise. The relative percentage reduction in resting SaO2 and rSO2 from 75m to 5300m was -22.23 ±0.56% and -30.61 ±1.28% (p<0.001) respectively. Venous: Hypoxia induced retinal and cerebral venous distension. Twenty-three of 24 subjects exhibited retinal venous distension (range 5 to 44%). Degree of distension correlated with headache (r = 0.553, p=0.005). Possession of a narrow transverse sinus strongly related to retinal and cerebral venous distension and headache. Headache: Headache Severity Index (HSI) (headache score x duration) correlated inversely to both lateral and third ventricular volumes summed (r = -0.5, p = 0.005) and pericerebellar CSF volume (r = -0.56, p = 0.03). Conclusions: Large cerebral arteries dilate and veins distend with hypoxia. This suggests an important influence of cerebral venous anatomy and physiology on headache, with implications for pathophysiological states and their management

Female endocrine adaptations to arduous military training

Women are able to train in arduous combat roles for the first time in the British military, yet data on sex differences in physiological responses to such physically demanding employment are lacking. Military women appear to experience high rates of fractures, menstrual disturbance and adverse psychological outcomes, conditions related to perturbations in metabolic and hormonal function. There is a paucity of studies investigating hypothalamic-pituitary-gonad (HPG) and hypothalamicpituitary-adrenal (HPA) axis function in military women. Low energy availability (EA) is an important cause of reproductive dysfunction and decreased bone mineral density (BMD) in athletes, while psychological stress and activation of the HPA axis are also associated with HPG axis suppression. Military training is physically demanding, psychologically stressful and frequently takes place in extreme climates. Therefore, the work in this thesis aimed to characterise female endocrine adaptations to arduous military in two settings: basic military training in the UK and highly arduous exercise in extreme cold. To address female responses to extreme heat, relative rates of heat illness (HI) among men and women were compared in a systematic review and meta-analysis. Female metabolic and endocrine adaptations to basic military training were explored in a cohort study of women undertaking the 11-month Commissioning Course at the Royal Military Academy, Sandhurst. Changes in body composition were measured by whole-body dual-energy-x-ray absorptiometry (DXA) at baseline and after 3, 7 and 11 months. Energy availability was assessed over 10-day periods using goldstandard techniques during months 3, 6 and 10 of training. Fasting blood sampling at baseline and after 7 and 11 months assessed leptin, insulin and glucose, as well as cortisol, cortisol binding globulin (CBG), oestradiol, anti-Müllerian hormone (AMH), inhibin B and bone turnover markers. Dynamic assessment of the HPG and HPA was undertaken using Combined Hypothalamic-pituitary-Ovarian and adrenal Cortex (CHOC) tests (LH/FSH and cortisol response to gonadotrophin releasing hormone (GnRH) and adrenocorticotrophic hormone, respectively, at five time points over 1 hour), at baseline and after 9 months. Psychological stress and mood were assessed regularly using questionnaires. Diurnal saliva cortisol was measured approximately every five weeks of training, and 1cm hair samples were assayed for cortisol to give an average monthly cortisol profile. A urinary progesterone: creatinine ratio cut-off was validated and used to determine if ovulation had taken place in women not using hormonal contraceptives, throughout the Commissioning Course. Changes in BMD were explored using DXA. Sixty one female Officer Cadets commenced the study (mean age 24.0 ±0.3 years) of whom 52 completed the study and the Course (8 withdrew due to musculoskeletal injuries; one changed career). Fat mass decreased 0.8kg from baseline to month 3 of training, increased 1.8kg to month 7 and reverted to baseline by month 11; fatfree mass did not change. Leptin and insulin resistance increased in association with fat mass. The assessment of EA was hampered by underreporting of energy intake by around 30%, however this measure of EA was weakly associated with physical performance, and paradoxically inversely associated with change in fat mass, suggesting compensatory over-eating after periods of arduous training and low energy intake. Questionnaires showed lower mood, increased stress and greater sleep deprivation during the course. Diurnal cortisol variability peaked in the first month of training, followed by habituation over the ensuing 10 months. Fasting plasma cortisol decreased, while CBG remained stable during the Course. Hair cortisol increased throughout, possibly reflecting physical exercise. Cortisol response to ACTH was modestly lower at 9 months than baseline. These data suggest a healthy overall response of the HPA axis to demonstrably arduous training. Of 22 participants (36%) not using hormonal contraceptives, 7 (32%) reported increased menstrual frequency and 7 (32%) reported amenorrhoea or oligomenorrhoea. Of cycles with corresponding urine concentrations, 80% were anovulatory. LH and FSH responses to GnRH were suppressed after 9 months and this effect was apparent in both users and non-users of hormonal contraceptives (regardless of type). Oestradiol, FSH and inhibin B increased during the course, but there was no change in AMH, suggesting hypothalamic suppression of the HPG axis and follicular dysgenesis. Bone turnover was modestly increased, reflected in higher markers of both bone formation and resorption after 8 and 11 months. Total BMD reduced slightly, with modest regional losses from arms, legs and ribs, while trunk, spine and pelvis BMD were preserved. The female response to arduous exercise in extreme cold was explored in six participants (median (range) 32.7 (28.6–36.1) years) undertaking the first unassisted all-female team crossing of Antarctica. The measures used above were adapted for use 1 month pre-expedition and 5 and 14 days post-expedition; no throughexpedition measurements were possible, and the CHOC test was performed after low-dose dexamethasone suppression. Mean (SD) weight loss was 10.1 (2.3) kg, constituting fat and not fat-free mass. Fasting oestradiol, cortisol and insulin resistance were unaffected, except leptin, which fell during the expedition and recovered partially after 14 days. Hair cortisol was elevated during the expedition. Cortisol, LH and FSH responsiveness were suppressed prior to the expedition, but were unchanged change immediately afterwards. LH responsiveness was higher than pre-expedition at expedition +14 days. Bone turnover was uncoupled immediately after the expedition, with higher resorption markers and lower formation markers, resolving after 14 days. Total BMD was unaffected. The systematic review and meta-analysis included data containing comparable male and female rates of HI. Incident rate ratios were calculated and adjusted, where possible, for severity, occupation and age. Contrary to expectations based on published laboratory studies of sex-related physiology, the systematic review of found consistently higher rates of HI reported among men than women. The metaanalysis found HI rates were over twice as high in men than women (mean (95% CI) incident risk ratio 2.28 (1.66-3.16)). This pattern was consistent across the age span and all severities of HI, and was greater in occupational HI than non-occupational HI (5.66 (2.53-13.64) vs 2.96 (2.14-4.10). In conclusion, this thesis demonstrated that women in basic military training do experience suppression of the HPG axis, despite long-term energy sufficiency with evidence of compensatory overeating and resilient HPA axis function. Resilient endocrine function in women who crossed Antarctica provides a proof of concept that with appropriate selection, nutrition and preparation, women can benefit from extremely arduous training. Women are also resilient to extreme heat, as evidenced by lower rates of HI than in men. The mechanism underlying reproductive dysfunction and associated pathology in women requires further elucidation but need not preclude women from entering such roles

Biophysical characterisation and profile of HLA-specific antibodies in transplantation

Abstract Following five decades of kidney transplantation, increasingly high risk immunological kidney transplantation (which previously was considered as sub-optimal) are carried out. The risk stratification with the current available assays have allowed safe transplantation in low risk non-sensitised patients and direct transplantation in high risk highly sensitised patients by removal of circulating donor specific antibodies (DSA) with reasonable outcomes. However, a large number of patients with chronic kidney disease and with low or intermediate antibody levels measured by current assay, the best way forward is uncertain resulting in denial of transplantation in some cases. Whilst in other cases, the solid phase Luminex assay may under or overestimate the risks of rejection and graft failure following direct kidney transplantation. Currently only IgG-class of DSA is considered immunologically important and routinely measured in clinical laboratories. Other bio-physiological characteristics such as class, sub-class and binding kinetics of DSA may be more specific for risk stratification of immunological risks. In this thesis, we studied effect of de novo IgM class of HLA-specific antibodies on outcome of kidney transplantation and characterised binding kinetics and strength of HLA-specific antibodies. De novo IgM or IgG HLA-specific responses alone were not associated with adverse outcomes following kidney transplantation. Presence of both IgM and IgG responses, however, was associated with poor graft function at 36 months. There was no temporal relationship of antibody response and episodes of rejections. De novo Donor specific responses were less frequent compared to non-specific responses. A shorter follow-up and use of modern triple immunosuppressant therapy (Tacrolimus, Mycophenolate and Steroid) may explain this. Binding kinetics measured by biosensor assay- surface plasmon resonance (SPR) on purified monoclonal HLA-specific antibodies showed binding kinetics and strength differed between HLA alleles despite same epitope and paratope interactions. There was a tendency towards higher affinity and faster association rate for HLA protein that was the initial immunizing antigen for the corresponding monoclonal HLA-specific antibodies. The dissociation constant (KD) of human monoclonal HLA-specific antibodies range between 10-8 to 10-10 M. Thermodynamic analysis showed higher Gibbs free energy released for interactions with higher binding strength. The binding strength of mixed monoclonal HLA-specific antibodies is generally average of the strength of individual monoclonal HLA-specific antibodies. Enriched polyclonal HLA-specific antibodies from clinical sample gave distinct binding response on bio-sensor based on SPR assay. Quantification of polyclonal HLA-specific antibodies using sandwich ELISA and SPR allowed quantitative measurement of binding kinetics and strengths. A range of binding strength was observed between patients and within same patient antibodies of different affinities was observed. Thus the antibodies could be grouped in four groups based on the strength of binding and this can serve as additional biomarker for risk stratifications