The Role of Smoking Status in Making Risk-Informed Diagnostic Decisions in the Lung Cancer Pathway: A Qualitative Study of Health Care Professionals and Patients.

BACKGROUND: Lung cancer clinical guidelines and risk tools often rely on smoking history as a significant risk factor. However, never-smokers make up 14% of the lung cancer population, and this proportion is rising. Consequently, they are often perceived as low-risk and may experience diagnostic delays. This study aimed to explore how clinicians make risk-informed diagnostic decisions for never-smokers. METHODS: Qualitative interviews were conducted with 10 lung cancer diagnosticians, supported by data from interviews with 20 never-smoker lung cancer patients. The data were analyzed using a framework analysis based on the Model of Pathways to Treatment framework and data-driven interpretations. RESULTS: Participants described 3 main strategies for making risk-informed decisions incorporating smoking status: guidelines, heuristics, and potential harms. Clinicians supplemented guidelines with their own heuristics for never-smokers, such as using higher thresholds for chest X-ray. Decisions were easier for patients with high-risk symptoms such as hemoptysis. Clinicians worried about overinvestigating never-smoker patients, particularly in terms of physical and psychological harms from invasive procedures or radiation. To minimize unnecessary anxiety about lung cancer risk, clinicians made efforts to downplay this. Conversely, some patients found that this caused process harms such as delays and miscommunications. CONCLUSION: Improved guidance and methods of risk differentiation for never-smokers are needed to avoid diagnostic delays, overreassurance, and clinical pessimism. This requires an improved evidence base and initiatives to increase awareness among clinicians of the incidence of lung cancer in never-smokers. As the proportion of never-smoker patients increases, this issue will become more urgent. HIGHLIGHTS: Smoking status is the most common risk factor used by clinicians to guide decision making, and guidelines often focus on this factor.Some clinicians also use their own heuristics for never-smokers, and this becomes particularly relevant for patients with lower risk symptoms.Clinicians are also concerned about the potential harms and risks associated with deploying resources on diagnostics for never-smokers.Some patients find it difficult to decide whether or not to go ahead with certain procedures due to efforts made by clinicians to downplay the risk of lung cancer.Overall, the study highlights the complex interplay between smoking history, clinical decision making, and patient anxiety in the context of lung cancer diagnosis and treatment.

Leveraging Physiologically Based Modelling to Provide Insights on the Absorption of Paliperidone Extended-Release Formulation under Fed and Fasting Conditions.

Paliperidone was approved by the US FDA in 2006 as an extended-release (ER) tablet (Invega®) for the once-daily treatment of schizophrenia. This osmotic-controlled release oral delivery system (OROS) offers advantages, such as the prevention of plasma concentration fluctuation and reduced dosing frequency. The administration of the ER after a high-fat/high-calorie meal leads to increased maximum plasma concentration and area under the curve values by 60% and 54%, respectively. Food has various effects on gastrointestinal (GI) physiology, including changed transit times, changed volumes, altered pH in different GI compartments, secretion of bile salts, and increased hepatic blood flow. This may affect solubility, the dissolution rate, absorption, and the pharmacokinetics. The aim of this study was to apply physiologically based absorption modeling (PBAM) to provide insights on paliperidone ER absorption under fed and fasting conditions. The PBAM adequately predicted absorption from the OROS formulation under both conditions. Absorption primarily occurs in the ascending colon and caecum. After a high-fat/high-calorie meal, absorption is increased through the jejunum, ileum, and colon due to either increased solubilization or the better efficiency of the OROS technology. PBAM-guided approaches can improve the understanding of branded drugs and thereby aid in guiding the development of generic formulations or formulation alternatives.

What are the similarities and differences in lung cancer symptom appraisal and help-seeking according to smoking status? A qualitative study with lung cancer patients.

OBJECTIVE: Lung cancer in never-smokers represents a growing proportion of patients. The relationship between smoking status, symptom appraisal and help-seeking behaviour is complex. Little is known about cancer symptom-related health behaviours according to smoking status. The aim of the study was to explore lung cancer patients' experiences of a lung cancer diagnosis, identifying differences by smoking history. METHOD: This was a qualitative study involving telephone interviews with 40 lung cancer patients (20 never smokers, 11 former smokers and 9 current smokers). We used framework analysis to analyse the data using the Common Sense Model of Illness Self-Regulation as a theoretical framework, developed after initial analysis. RESULTS: All patients were likely to delay seeking help for symptoms in primary care regardless of smoking history, but for different reasons. Smoking history was instrumental to how individuals perceived and responded to early symptoms of lung cancer. Differences in interpretation and coping responses to new symptoms seemed to be caused by the higher presence of comorbidities due to smoking, and perceptions of the current state of health. Individuals with a smoking history reported acting with urgency in seeking help and follow up, whereas patients who experienced low levels of concern were more easily reassured by clinicians, resulting in delays. CONCLUSIONS: Never and former smokers perceive, interpret, and respond to symptoms of lung cancer differently to smokers. However, few people attribute their lung symptoms to cancer initially, even with a smoking history. Interventions that drive increased urgency and vigilance in never smokers may be effective.

How does safety netting for lung cancer symptoms help patients to reconsult appropriately? A qualitative study.

BACKGROUND: Safety netting in primary care is considered an important intervention for managing diagnostic uncertainty. This is the first study to examine how patients understand and interpret safety netting advice around low-risk potential lung cancer symptoms, and how this affects reconsultation behaviours. METHODS: Qualitative interview study in UK primary care. Pre-covid-19, five patients were interviewed in person within 2-3 weeks of a primary care consultation for potential lung cancer symptom(s), and again 2-5 months later. The general practitioner (GP) they last saw was interviewed face-to-face once. During the covid-19 pandemic, an additional 15 patients were interviewed only once via telephone, and their GPs were not interviewed or contacted in any way. Audio-recorded interviews were transcribed verbatim and analysed using inductive thematic analysis. RESULTS: The findings from our thematic analysis suggest that patients prefer active safety netting, as part of thorough and logical diagnostic uncertainty management. Passive or ambiguous safety netting may be perceived as dismissive and cause delayed reconsultation. GP safety netting strategies are not always understood, potentially causing patient worry and dissatisfaction. Telephone consultations and the diagnostic overshadowing of COVID-19 on respiratory symptoms impacted GPs' safety netting strategies and patients' appetite for active follow up measures. CONCLUSIONS: Safety netting guidelines do not yet offer solutions that have been proven to promote symptom vigilance and timely reconsultation for low-risk lung cancer symptoms. This may have been affected by primary care practices during the COVID-19 pandemic. Patients prefer active or pre-planned safety netting coupled with thorough consultation techniques and a comprehensible diagnostic strategy, and may respond adversely to passive safety netting advice.

Application of physiologically based absorption and pharmacokinetic modeling in the development process of oral modified release generic products.

Physiologically based pharmacokinetic (PBPK) modeling for biopharmaceutics applications holds great promise as modelling and simulation tool in the field of modern oral modified release (MR) products. Understanding of gastro-intestinal absorption related processes is crucial to ensure the successful development of complex oral drug generic products. In the recent years, PBPK approach has been gradually influencing decision making ability of pharmaceutical industry as well as regulatory agencies. However, there is a gap in understanding its contribution in the field of oral modified release products. In this review, we have collected different recent research articles illustrating the significant contribution of PBPK to the research and development process of oral MR products, with special emphasis on generic drug products. Concretely, literature examples on the utility of PBPK formulation development, for in vitro- in vivo correlations (IVIVC) and prediction of oral bioavailability, and for in-silico food effect predictions were included in the review.

Acceptability of a standalone written leaflet for the National Health Service for England Targeted Lung Health Check Programme: A concurrent, think-aloud study.

BACKGROUND: Many countries are introducing low-dose computed tomography screening programmes for people at high risk of lung cancer. Effective communication strategies that convey risks and benefits, including unfamiliar concepts and outcome probabilities based on population risk, are critical to achieving informed choice and mitigating inequalities in uptake. METHODS: This study investigated the acceptability of an aspect of NHS England's communication strategy in the form of a leaflet that was used to invite and inform eligible adults about the Targeted Lung Health Check (TLHC) programme. Acceptability was assessed in terms of how individuals engaged with, comprehended and responded to the leaflet. Semi-structured, 'think aloud' interviews were conducted remotely with 40 UK screening-naïve current and former smokers (aged 55-73). The verbatim transcripts were analysed thematically using a coding framework based on the Dual Process Theory of cognition. RESULTS: The leaflet helped participants understand the principles and procedures of screening and fostered cautiously favourable intentions. Three themes captured the main results of the data analysis: (1) Response-participants experienced anxiety about screening results and further investigations, but the involvement of specialist healthcare professionals was reassuring; (2) Engagement-participants were rapidly drawn to information about lung cancer prevalence, and benefits of screening, but deliberated slowly about early diagnosis, risks of screening and less familiar symptoms of lung cancer; (3) Comprehension-participants understood the main principles of the TLHC programme, but some were confused by its rationale and eligibility criteria. Radiation risks, abnormal screening results and numerical probabilities of screening outcomes were hard to understand. CONCLUSION: The TLHC information leaflet appeared to be acceptable to the target population. There is scope to improve aspects of comprehension and engagement in ways that would support informed choice as a distributed process in lung cancer screening. PATIENT OR PUBLIC CONTRIBUTION: The insight and perspectives of patient representatives directly informed and improved the design and conduct of this study.

Lung cancer symptom appraisal, help-seeking and diagnosis - rapid systematic review of differences between patients with and without a smoking history.

BACKGROUND: Lung cancer is the leading cause of cancer death in the world. A significant minority of lung cancer patients have never smoked (14% in the UK, and ranging from 10% to 25% worldwide). Current evidence suggests that never-smokers encounter delays during the diagnostic pathway, yet it is unclear how their experiences and reasons for delayed diagnoses differ from those of current and former smokers. This rapid review assessed literature about patient experiences in relation to symptom awareness and appraisal, help-seeking, and the lung cancer diagnostic pathway, comparing patients with and without a smoking history. METHODS: MEDLINE, PsychINFO and Google Scholar were searched for studies (2010-2020) that investigated experiences of the pathway to diagnosis for patients with and without a smoking history. Findings are presented using a narrative synthesis. RESULTS: Analysis of seven quantitative and three qualitative studies revealed that some delays during symptom appraisal and diagnosis are unique to never-smokers. Due to the strong link between smoking and lung cancer, and low awareness of non-smoking related lung cancer risk factors and symptoms, never-smokers do not perceive themselves to be at risk. Never-smokers are also likely to evaluate their experiences in comparison with other non-smoking related cancers, where prognosis is likely better, potentially leading to lower satisfaction with healthcare. CONCLUSION: Never-smokers appear to have different experiences in relation to symptom appraisal and diagnosis. However, evidence in relation to help-seeking, and what is driving diagnostic delays for never-smoker patients specifically is lacking.

Decision Support Tools for Low-Dose CT Lung Cancer Screening: A Scoping Review of Information Content, Format, and Presentation Methods.

Several countries mandate informed or shared decision-making for low-dose CT (LDCT) lung cancer screening, but knowledge is limited about the type of information and presentation techniques used to support decision-making in practice. This review aimed to characterize the content, format, mode, and presentation methods of decision support tools (DSTs) for LDCT lung cancer screening. DSTs reported within peer-reviewed articles (January 2000-April 2021) were identified systematically from PubMed, PsycInfo, EMBASE, and CINAHL Plus. Inclusion criteria revolved around the development or evaluation of a resource or tool intended to support individual or shared decision-making for LDCT lung cancer screening. The data-charting and extraction framework was based on the International Patient Decision Aids Standards instrument and Template for Intervention Description and Reporting. Extracted data were organized within two categories: (1) study characteristics and context, format, and mode of DST use and (2) DST content and presentation methods. This review identified 22 DSTs in paper, video, or electronic formats across 26 articles. Most DSTs (n = 13) focused on knowledge exchange, whereas seven used interactive techniques to support values clarification (eg, Likert scales) and nine DSTs guided deliberation (eg, suggested discussion topics). The DSTs addressed similar topics, but the detail, quantification of probability, and presentation methods varied considerably. None described all the potential screening harms and results. The heterogeneity in DST design may affect the quality of decision-making, particularly for participants with lower literacy and numeracy. Evidence-based consensus guidelines for DST content and presentation methods should be developed collaboratively with screening-eligible adults.

Ethnographic research as an evolving method for supporting healthcare improvement skills: a scoping review.

BACKGROUND: The relationship between ethnography and healthcare improvement has been the subject of methodological concern. We conducted a scoping review of ethnographic literature on healthcare improvement topics, with two aims: (1) to describe current ethnographic methods and practices in healthcare improvement research and (2) to consider how these may affect habit and skill formation in the service of healthcare improvement. METHODS: We used a scoping review methodology drawing on Arksey and O'Malley's methods and more recent guidance. We systematically searched electronic databases including Medline, PsychINFO, EMBASE and CINAHL for papers published between April 2013 - April 2018, with an update in September 2019. Information about study aims, methodology and recommendations for improvement were extracted. We used a theoretical framework outlining the habits and skills required for healthcare improvement to consider how ethnographic research may foster improvement skills. RESULTS: We included 283 studies covering a wide range of healthcare topics and methods. Ethnography was commonly used for healthcare improvement research about vulnerable populations, e.g. elderly, psychiatry. Focussed ethnography was a prominent method, using a rapid feedback loop into improvement through focus and insider status. Ethnographic approaches such as the use of theory and focus on every day practices can foster improvement skills and habits such as creativity, learning and systems thinking. CONCLUSIONS: We have identified that a variety of ethnographic approaches can be relevant to improvement. The skills and habits we identified may help ethnographers reflect on their approaches in planning healthcare improvement studies and guide peer-review in this field. An important area of future research will be to understand how ethnographic findings are received by decision-makers.

Adherence to Prophylaxis in Adolescents and Young Adults with Severe Haemophilia: A Quantitative Study with Patients.

INTRODUCTION: haemophilia is an inherited bleeding disorder caused by a deficiency in one of the blood coagulation factors. For people affected by severe haemophilia, the deficiency can cause spontaneous internal bleeding. Most young people with severe haemophilia in the UK follow a preventative treatment regimen (prophylaxis) consisting of several intravenous injections of factor concentrate each week. There is good evidence that prophylaxis reduces bleeds whilst also improving quality of life. However, levels of adherence among young people with haemophilia reported in the existing literature vary widely and are predominately based on estimations made by healthcare professionals and parents. Additionally, drivers of (non)adherence among young people specifically have not been evidenced. AIM: to assess self-reported adherence among young people with haemophilia, provide evidence of psychosocial predictors of adherence, and to establish the associations between non-adherence and number of bleeds and hospital visits. METHODS: 91 participants were recruited during outpatient appointments in 13 haemophilia centres across England and Wales, and invited to complete a questionnaire assessing self-reported adherence (VERITAS-Pro), Haemophilia-related pain and impact of pain, Illness Perceptions, Beliefs about Medications, Self-efficacy, Outcome expectations, Positive and Negative Affect, and Social support. Number of hospital visits and bleeds during the previous six months were collected from medical files. RESULTS: Of 78 participants with complete data, just 18% had scores indicating non-adherence. Psychosocial predictors differed between intentional (skipping) and un-intentional (forgetting) non-adherence. Overall, however, better adherence was reported where participants perceived the need for prophylaxis was greater than their concern over taking it as well as having a positive expectancy of its effectiveness, good social support and a stronger emotional reaction to having haemophilia. CONCLUSION: The findings indicate that adherence is generally good, and that assessing illness and treatment beliefs, social support and outcome expectations may play a valuable role in identifying which individuals are at risk of non-adherence. Interventions aimed at improving adherence should particularly consider improving social support, reducing patients' concerns about prophylaxis, increasing their belief in the necessity of prophylaxis, and increasing positive outcome expectations.

A phase I dose-escalation and bioequivalence study of a trastuzumab biosimilar in healthy male volunteers.

BACKGROUND: Trastuzumab (Herceptin(®)) is a humanized monoclonal antibody targeting the human epidermal growth factor receptor 2 (HER2) and is used in the treatment of HER2-overexpressing breast and gastric cancer. FTMB is being developed as a biosimilar of trastuzumab. OBJECTIVE: In this combined dose-escalation and bioequivalence study of parallel design, the pharmacokinetic profile of FTMB was compared with Herceptin(®). METHODS: Healthy male volunteers received single doses of 0.5, 1.5, 3.0 or 6.0 mg/kg FTMB, or placebo, in consecutive dose-escalation cohorts to assess the safety profile. Thereafter, the 6 mg/kg cohort was expanded to establish bioequivalence between FTMB (Test) and Herceptin(®) (Reference) based on an acceptance interval of 80.0-125.0 %. In total, 118 subjects were enrolled in the study. RESULT: The mean area under the concentration-time curve from time zero to infinity (AUC∞) was 1,609 µg·day/mL (Test) and 1,330 µg·day/mL (Reference). The log-transformed geometric mean Test/Reference (T/R) ratio for AUC∞ was 89.6 % (90 % confidence interval [CI] 85.1-94.4), demonstrating bioequivalence. For the secondary endpoint, the maximum concentration observed (Cmax), the geometric mean T/R ratio was 89.4 % (90 % CI 83.4-95.9). Non-linear, target-mediated pharmacokinetics were also observed. Adverse events other than the documented side effects of Herceptin(®) (fever, influenza-like illness, and fatigue) did not occur. No signs of cardiotoxicity were observed. CONCLUSIONS: This bioequivalence study with a trastuzumab biosimilar in healthy male volunteers demonstrated bioequivalence of FTMB with Herceptin(®). FTMB was well tolerated in doses up to 6 mg/kg. Non-linear target elimination was also observed in the pharmacokinetic profile of trastuzumab.

Dopamine D2R Agonist-Induced Cardiovascular Effects in Healthy Male Subjects: Potential Implications in Clinical Settings.

Dopamine D2 receptor agonists represent a first line treatment option in young patients with signs and symptoms of idiopathic Parkinson's disease. An association between the use of D2 receptor agonists in Parkinson's disease patients and heart failure has been reported. The identification of the underlying mechanism is needed to minimize the resultant cardiovascular morbidity. In a phase I clinical trial, a D2 receptor agonist (pramipexole) was administered to 52 healthy male subjects following a dose escalation scheme. Serial measurements of resting blood pressure, heart rate, and derived parameters including pulse pressure, pulsatile stress, and rate pressure product were analysed. Statistically significant and clinically relevant increases in most of the assessed parameters were found. Ten subjects were removed prematurely from the trial because of clinically significant increases in blood pressure and/or heart rate requiring immediate intervention with IV rescue medications including a selective ß -1 blocker. The observed drug-related changes in vital signs were of clinical relevance and might explain some of the cardiovascular morbidity reported in patients receiving D2 receptor agonist in clinical settings. We suggest that the additional use of a ß -1 blocking agent might mitigate the risk of cardiovascular morbidity among patients receiving long-term D2 receptor agonists.

Negative and positive illness representations of rheumatoid arthritis: a latent profile analysis.

This study extends previous work to consider whether individuals with rheumatoid arthritis (RA) can be categorised into groups with similar illness representations. Data from 227 RA patients attending outpatient clinics were collected prospectively at two time points, 6 months apart. The optimal number of illness representation groups at the baseline assessment was identified using latent profile analysis. Two groups of individuals sharing similar illness perception profiles were identified. The smaller group (43%), characterised by a negative representation of their illness, attributed more symptoms to their condition and reported stronger perceptions of the consequences, chronicity and cyclicality of their condition, and lower control compared to the positive representation group (57%). Cross-sectionally, membership of the negative representation group was associated with higher levels of pain and functional disability and, longitudinally, with increases in levels of pain, functional disability and distress. These data highlight the central role of illness perceptions in RA and suggest that individuals with RA can be categorised into groups with similar illness representations.

Can simvastatin improve erectile function and health-related quality of life in men aged ≥40 years with erectile dysfunction? Results of the Erectile Dysfunction and Statins Trial [ISRCTN66772971].

OBJECTIVE: To evaluate the effectiveness and cost-effectiveness of simvastatin on erectile function and health-related quality of life in men aged ≥40 years with erectile dysfunction (ED). PATIENTS AND METHODS: ED is common in men aged ≥40 years and impacts upon their overall health-related quality of life and that of their partners. Men aged ≥40 years who were not receiving lipid lowering or anti-hypertensive medication and not at high cardiovascular risk were recruited from 10 general practices in the East of England. In total, 173 eligible men with untreated ED were randomized to double-blind treatment with 40 mg of simvastatin or placebo once daily for 6 months. Data were collected at three points over 30 weeks. The main outcome was erectile function (International Index of Erectile Function-5 score). Secondary outcomes included male ED-specific quality of life (MED-QoL), quality-adjusted life years (QALYs) using the generic Euroqol measure (EQ-5D), endothelial function, cardiovascular risk, cholesterol and health service costs. RESULTS: There was no significant difference in erectile function between the simvastatin and placebo groups (mean change, 1.28 vs 0.07, z = 1.1, p = 0.27), although a significant improvement in MED-QoL was observed (5% vs 2%, z = 2.09, p = 0.04). Both 10-year cardiovascular risk and low-density lipoprotein were reduced (cardiovascular risk, z = -3.67, p < 0.001; low-density lipoprotein, z = -5.46, p < 0.001), with no consistent change in endothelial function. The frequency of sexual encounters is correlated with improved erectile function. The joint distribution of costs and QALY benefits indicates that the probability of simvastatin being cost-effective for willingness-to-pay thresholds of £20,000 and £30,000 is 86% and 83%, respectively. CONCLUSIONS: Identifying men with ED provides an opportunity to modify future cardiovascular risk and to improve MED-QoL by treating them with 40 mg of simvastatin. The joint analysis of costs and QALY benefits suggests that there is high probability that simvastatin is a cost-effective strategy in men with ED. The findings could influence urological and primary care practice by including questions on ED during routine consultations and relevant clinical protocols. This provides an opportunity to impart lifestyle advice.

Illness perceptions account for variation in positive outlook as well as psychological distress in rheumatoid arthritis.

Psychological distress in rheumatoid arthritis (RA) is associated with adverse clinical outcomes, and appears highly related to patients' illness perceptions. This study aimed to investigate the association between illness perceptions, psychological distress, positive outlook and physical outcomes in RA. Two hundred and thirty patients aged >18 years and prescribed at least one disease-modifying anti-rheumatic drug (DMARD) were recruited from outpatient clinics across Hertfordshire (England). Patients completed a questionnaire that assessed psychological distress and positive outlook (depression, anxiety and positive outlook scale), illness perceptions (IPQ-R) and functional disability (health assessment questionnaire). Information regarding prescribed medication and disease activity [disease activity score (DAS28)] was collected from medical notes. Psychological distress, but not positive outlook, was associated with functional disability and DAS28. After controlling for sex, age and DAS28, perceptions of greater symptomatology (identity) and lesser understanding of RA (coherence) were significantly associated with increased psychological distress. Perceptions of greater treatment control were associated with greater positive outlook, but only for those with low DAS28. Coherence was also associated with positive outlook. These findings indicate that illness perceptions may influence psychological distress and positive outlook in RA patients, and may therefore be a useful basis for future psychological interventions.

Cortical excitatory amino acid release and cell function during hypotension in near-term born lambs.

BACKGROUND: Energy failure due to insufficient cerebral O2-supply leads to excess accumulation of calcium ions in presynaptic neurons, followed by excess release of excitatory amino acids, which are potent neurotoxins, into the synaptic cleft. AIM: To investigate whether electrocortical brain activity (ECBA) can provide an adequate measure for excitatory amino acid release due to hemorrhagic hypotension. METHODS: Ten near-term lambs were delivered at 127 days of gestation (term: 147 days). After a stabilization period, hypotension was induced by stepwise withdrawal of blood. Cerebral microdialysis was used to measure the concentrations of glutamate and aspartate. RESULTS: During hypotension, mean arterial blood pressure, cerebral O2-supply and ECBA decreased and the extracellular concentration of glutamate increased significantly. ECBA was significantly related to glutamate (R2: 0.67, p < 0.001) and aspartate (R2: 0.57, p < 0.001) concentrations. CONCLUSION: The extracellular release of glutamate and aspartate in the cerebral cortex increases after hemorrhagic hypotension in near-term born lambs. The extracellular overflow of glutamate and aspartate were significantly inversely related to ECBA.

Excitatory amino acid release and electrocortical brain activity after hypoxemia in near-term lambs.

BACKGROUND: Energy failure due to insufficient cerebral O(2)-supply leads to excess accumulation of calcium ions in presynaptic neurons, followed by excess release of excitatory amino acids (EAAs), which are potent neurotoxins, into the synaptic cleft. AIM: The aim of the present study was to determine whether extracellular EAAs release after prolonged hypoxemia affects electrocortical brain activity (ECBA), as a measure of brain cell function, in near-term born lambs. METHODS: Ten near-term lambs (term: 147 days) were delivered at 131 days of gestation. After a stabilization period, prolonged hypoxemia (FiO(2): 0.10; duration 2.5h) was induced. Mean values of physiologic variables, including ECBA, were calculated over the last 3 min of normoxemia as well as of hypoxemia. Cerebral arterial and venous blood gases were determined at the end of the normoxemic and hypoxemic periods. Cerebrospinal fluid (CSF) was obtained at the end of the hypoxemic period. CSF from six normoxemic sibs was used for comparison. HPLC was used to measure EAAs in the CSF. RESULTS: During hypoxemia, aspartate and glutamate concentration increased significantly (4.8 and 6.0 times, respectively), while asparagine and glutamine did not. ECBA decreased to 30% of the normoxemic value. Glutamate was significantly higher in lambs with a flat cerebral function monitor (CFM) tracing than in lambs with a burst-suppression pattern. CONCLUSIONS: After prolonged hypoxemia aspartate and glutamate accumulated excessively in the CSF of near-term born lambs. Especially glutamate concentrations in CSF were related to the decline in brain cell function.

Cerebral cortical tissue damage after hemorrhagic hypotension in near-term born lambs.

Hypotension reduces cerebral O(2) supply, which may result in brain cell damage and loss of brain cell function in the near-term neonate. The aim is to elucidate 1) to what extent the functional disturbance of the cerebral cortex, as measured with electrocortical brain activity (ECBA), is related to cerebral cortical tissue damage, as estimated by MAP2; and 2) whether there is a relationship between the glutamate, nitric oxide (NO), cGMP pathway and the development of cerebral cortical tissue damage after hemorrhagic hypotension. Seven lambs were delivered at 131 d of gestation. Hypotension was induced by withdrawal of blood until mean arterial blood pressure was reduced to 30% of normotension. Cerebral O(2) supply, consumption, and ECBA were calculated in normotensive conditions and after 2.5 h of hypotension. Concentrations of glutamate and aspartate in cerebrospinal fluid (CSF), NO(2) and NO(3) (NOx) in plasma, and cGMP in cortical brain tissue were determined in both conditions. CSF and brain tissue from siblings were used to determine normotensive values. Cortical neuronal damage was detected after 2.5 h of hypotension. ECBA was negatively related to the severity of the cortical damage. ECBA was related to respectively glutamate, NOx, and cGMP concentrations. In conclusion, cortical neuronal damage is detected after 2.5 h of hemorrhagic hypotension in the near-term born lamb. The damage is reflected by a reduction of ECBA. The glutamate, NOx, cGMP pathway is likely to be involved in the pathogenesis of cerebral cortical damage.